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Ghanshani R, Lee K, Crew AB, Shi VY, Hsiao JL. A Guide to the Management of Hidradenitis Suppurativa in Pregnancy and Lactation. Am J Clin Dermatol 2025; 26:345-360. [PMID: 40131719 PMCID: PMC12085321 DOI: 10.1007/s40257-025-00935-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 03/27/2025]
Abstract
Hidradenitis suppurativa is a chronic inflammatory condition characterized by recurrent abscesses, nodules, tunnels, and scarring. Fluctuations in disease activity are common during pregnancy, and more than half of women with hidradenitis suppurativa report experiencing post-partum flares. Both treatment efficacy and safety of the woman and fetus or infant must be considered when developing a treatment plan for pregnant and lactating women with hidradenitis suppurativa. Although certain commonly used hidradenitis suppurativa medications, such as tetracyclines and spironolactone, are contraindicated during pregnancy, there are still various medical therapies, including topicals, systemic antibiotics, metabolic modulators, and biologics, as well as procedural therapies that may be utilized during pregnancy. This paper aims to provide an updated evidence-based review of the management of hidradenitis suppurativa in pregnancy with an emphasis on safety data.
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Affiliation(s)
- Raveena Ghanshani
- Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA
| | - Katrina Lee
- Department of Dermatology, University of Southern California, 1441 Eastlake Ave, Ezralow Tower, Suite 5301, Los Angeles, CA, 90033-9174, USA
| | - Ashley B Crew
- Department of Dermatology, University of Southern California, 1441 Eastlake Ave, Ezralow Tower, Suite 5301, Los Angeles, CA, 90033-9174, USA
| | - Vivian Y Shi
- Department of Dermatology, University of Washington, Seattle, WA, USA
| | - Jennifer L Hsiao
- Department of Dermatology, University of Southern California, 1441 Eastlake Ave, Ezralow Tower, Suite 5301, Los Angeles, CA, 90033-9174, USA.
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Ernest-Suarez K, Murguía-Favela LE, Constantinescu C, Fitzpatrick T, Top KA, Hu J, Jadavji T, Leung Y, Chan M, Panaccione R, Seow CH. Live Rotavirus Vaccination Appears Low-risk in Infants Born to Mothers With Inflammatory Bowel Disease on Biologics. Clin Gastroenterol Hepatol 2025; 23:835-845. [PMID: 39089515 DOI: 10.1016/j.cgh.2024.07.007] [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: 04/18/2024] [Revised: 06/22/2024] [Accepted: 07/03/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND & AIMS Biologic therapies in the context of inflammatory bowel disease and pregnancy lead to improved maternal and fetal outcomes. Placental transfer results in detectable drug concentrations in infants. Rotavirus infection results in diarrheal related hospitalizations; however, the live oral vaccine is not currently recommended in biologic exposed infants. The aim of this study was to assess the effect of maternal biologic therapies on the infant immune system and safety of live rotavirus vaccination in biologic-exposed infants. METHODS Biologic-exposed infants underwent standardized clinical assessments, drug concentration, and immune function testing (complete blood count, differential, immunoglobulin levels, extended B-cell and T-cell subset enumeration, Recent Thymic Emigrants, regulatory T-cell numbers, mitogen stimulation assays, and review of T-cell Receptor Excision Circles in the newborn screen). Rotavirus vaccine-specific adverse effects following immunizations up to 42 days post the last dose of the vaccine series were recorded. RESULTS There were 57 infants born to 52 mothers with inflammatory bowel disease exposed to infliximab (n = 21), adalimumab (n = 19), vedolizumab (n = 10), and ustekinumab (n = 7) in the third trimester for a median of 39 weeks (interquartile range, 38-39 weeks) at delivery. Immunologic assessments validated for age were normal in all infants despite median infliximab concentrations of 6.1 ug/mL (range, 0.4-28.8 ug/mL), adalimumab concentrations of 1.7 ug/mL (range, 0.7-7.9 ug/mL), ustekinumab concentrations of 0.6 ug/mL (range, 0-1.1), and undetectable for vedolizumab at 10.7 weeks (interquartile range, 9.4-12.4) of age. The live oral rotavirus vaccine series was provided to 50 infants with the first dose given at a median of 13 weeks of age. No adverse effects following immunization were reported. CONCLUSION Immune function testing was normal, and administration of live rotavirus vaccination appeared low-risk in biologic-exposed infants irrespective of circulating drug levels.
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Affiliation(s)
- Kenneth Ernest-Suarez
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Luis E Murguía-Favela
- Section of Hematology/Immunology, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Cora Constantinescu
- Section of Infectious Diseases, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Tiffany Fitzpatrick
- Public Health, Ontario and Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Karina A Top
- Department of Pediatrics, Dalhousie University and Canadian Center for Vaccinology, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Jia Hu
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Taj Jadavji
- Department of Microbiology, Immunology, and Infectious Diseases, and Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Yvette Leung
- Department of Medicine, Division of Gastroenterology, Physician Lead IBD and Pregnancy Clinic, University of British Columbia, Vancouver, British Columbia, Canada
| | - Melissa Chan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Remo Panaccione
- Inflammatory Bowel Disease Unit, Gastrointestinal Research, University of Calgary, Calgary, Alberta, Canada
| | - Cynthia H Seow
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
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Prentice R, Flanagan E, Wright EK, Gibson PR, Rosella S, Rosella O, Begun J, An YK, Lawrance IC, Kamm MA, Sparrow M, Goldberg R, Prideaux L, Vogrin S, Kiburg KV, Ross AL, Burns M, Bell SJ. Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero. Clin Gastroenterol Hepatol 2025; 23:124-133.e7. [PMID: 38492905 DOI: 10.1016/j.cgh.2024.02.025] [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: 09/28/2023] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND & AIMS Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.
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Affiliation(s)
- Ralley Prentice
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia; Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia; Centre of Inflammatory Disease, Department of Medicine, Monash University, Clayton, Victoria, Australia.
| | - Emma Flanagan
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia; University of Melbourne, Parkville, Victoria, Australia
| | - Emily K Wright
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia; University of Melbourne, Parkville, Victoria, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Sam Rosella
- Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Ourania Rosella
- Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Jakob Begun
- Department of Gastroenterology, Mater Hospital, Brisbane, Queensland, Australia
| | - Yoon-Kyo An
- Department of Gastroenterology, Mater Hospital, Brisbane, Queensland, Australia
| | - Ian C Lawrance
- School of Medicine and Pharmacology, Faculty of Medicine and Dentistry at the University of Western Australia, Perth, Western Australia, Australia; St John of God Subiaco Hospital, Perth, Western Australia, Australia
| | - Michael A Kamm
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia; University of Melbourne, Parkville, Victoria, Australia
| | - Miles Sparrow
- Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Rimma Goldberg
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia; Centre of Inflammatory Disease, Department of Medicine, Monash University, Clayton, Victoria, Australia
| | - Lani Prideaux
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia
| | - Sara Vogrin
- University of Melbourne, Parkville, Victoria, Australia
| | | | - Alyson L Ross
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
| | - Megan Burns
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia
| | - Sally J Bell
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia; Centre of Inflammatory Disease, Department of Medicine, Monash University, Clayton, Victoria, Australia; University of Melbourne, Parkville, Victoria, Australia
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Sousa P, Gisbert JP, Julsgaard M, Selinger CP, Chaparro M. Navigating Reproductive Care in Patients With Inflammatory Bowel Disease: A Comprehensive Review. J Crohns Colitis 2024; 18:ii16-ii30. [PMID: 39475080 PMCID: PMC11523042 DOI: 10.1093/ecco-jcc/jjae048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/26/2024] [Accepted: 04/27/2024] [Indexed: 11/02/2024]
Abstract
Inflammatory bowel disease [IBD] is often diagnosed in patients during their reproductive years. It is crucial that both healthcare providers and patients are adequately informed to avoid misguided decisions regarding family planning. One of the most important aspects during conception and pregnancy is to maintain disease remission, as disease activity is associated with adverse pregnancy outcomes. Apart from methotrexate, most conventional drugs used in IBD are considered low risk during conception and pregnancy. For newer agents, evidence is still limited. If needed, surgery must not be postponed and should ideally be performed in specialized centres. In most patients, delivery should be vaginal except for patients with complex perianal disease, with an ileoanal pouch anastomosis, or if there is an obstetric contraindication. In children exposed to biological treatments during pregnancy, the risk of infections appears to be low, and psychomotor development is probably not affected. Regarding immunizations, the standard vaccination schedule for inactivated vaccines should be followed for children exposed to biologics in utero. In the case of live vaccines, such as rotavirus, decisions should be individualized and take into consideration the risk-benefit ratio, particularly in developing countries. In this review, we provide a comprehensive and updated overview of aspects related to fertility, pregnancy, breastfeeding, and the impact on the care of children born to mothers with IBD. Both the available evidence and areas of uncertainty are discussed, with the goal of assisting healthcare professionals caring for IBD patients during this important stage of their lives.
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Affiliation(s)
- Paula Sousa
- Department of Gastroenterology, Hospital São Teotónio – Unidade Local de Saúde Dão Lafões, Viseu, Portugal
| | - Javier P Gisbert
- Department of Gastroenterology, Inflammatory Bowel Disease Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - Mette Julsgaard
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Centre for Molecular Prediction of Inflammatory Bowel Disease [PREDICT], Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | | | - María Chaparro
- Department of Gastroenterology, Inflammatory Bowel Disease Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
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Santos Pérez E, Calvo Moya M. General review on pregnancy in inflammatory bowel disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:369-373. [PMID: 35240849 DOI: 10.17235/reed.2022.8672/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2024]
Abstract
Given the age of maximum incidence of inflammatory bowel disease, aspects such as fertility and pregnancy are especially relevant in the management of these patients. This review article aims to provide a summarized description of the basic concepts that the gastroenterologist should know when assessing an IBD patient with procreative desires and/or who is pregnant. The review has been carried out selecting the most recent and relevant articles on these topics in order to offer updated information on the latest treatments available.
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Affiliation(s)
- Elena Santos Pérez
- Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro Majadahonda, España
| | - Marta Calvo Moya
- Gastroenterología y Hepatología, Hospital universitario Puerta de Hierro Majadahonda, España
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van Gendt J, Emaus R, Visschedijk MC, Touw DJ, Bouwknegt DG, de Leeuw K, Prins JR, Malik P, Mian P. Pharmacokinetics of Monoclonal Antibodies Throughout Pregnancy: A Systematic Literature Review. Clin Pharmacokinet 2024; 63:589-622. [PMID: 38583128 PMCID: PMC11106164 DOI: 10.1007/s40262-024-01370-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND AND OBJECTIVE Although little information is available on the pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy, multiple mAbs are being used during pregnancy for various indications. The aim of this systematic literature review was to characterize the PK of mAbs throughout pregnancy. METHODS A systematic literature search was carried out in PubMed and Embase on 21 April 2023. Articles were included when information on PK or exposure parameters of mAbs in pregnant women was available. RESULTS A total of 42 relevant articles were included, of which eight discussed adalimumab, three certolizumab pegol, five eculizumab, one golimumab, 12 infliximab (IFX), two natalizumab, one canakinumab, one omalizumab, five tocilizumab, eight ustekinumab, and five vedolizumab. One of the 42 studies reported information on clearance (CL) and volume of distribution (VD) of IFX; all other studies only reported on serum concentrations in the pre-pregnancy state, different trimesters, and the postpartum period. For all of the assessed mAbs except IFX, serum concentrations were similar to concentrations in the pre-pregnancy state or modestly decreased. In contrast, IFX trough concentrations generally increased in the second and third trimesters in comparison to the non-pregnant state. CONCLUSION Available information suggests that the anatomical and physiological changes throughout pregnancy may have meaningful effects on the PK of mAbs. For most mAbs (not IFX), modestly higher dosing (per mg) maybe needed during pregnancy to sustain a similar serum exposure compared to pre-pregnancy.
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Affiliation(s)
- J van Gendt
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - R Emaus
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - M C Visschedijk
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - D J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
- Department of Pharmaceutical Analysis, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands
| | - D G Bouwknegt
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - K de Leeuw
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J R Prins
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - P Malik
- Calico Life Sciences, South San Francisco, USA
| | - Paola Mian
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
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Wieringa JW, Kruizinga MD, Driessen GJA, van der Woude CJ, Julsgaard M. Validation of the Pharmacokinetic Model for Anti-TNFα Clearance in Infants Exposed to Anti-TNFα During Pregnancy. J Crohns Colitis 2024; 18:506-515. [PMID: 37823516 DOI: 10.1093/ecco-jcc/jjad172] [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: 06/13/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND AND AIMS The ECCO guideline recommends postponing live attenuated vaccines in infants exposed to anti-tumour necrosis factor alpha [anti-TNFα] in utero until drug clearance. The aim was to validate the predictive performance of the anti-TNFα clearance model. METHODS Newborns and data for anti-TNFα concentrations from the prospective PETIT cohort were included. The anti-TNFα clearance model was used to predict all measured concentrations in the PETIT cohort, based on the measured cord blood concentration and the mean population clearance described in the model. Bayesian maximum a posteriori optimization was used to estimate the use of drug monitoring. Predictive capability and drug monitoring were assessed through mean absolute error [MAE], root mean squared prediction error, and limits of agreement according to Bland and Altman. RESULTS Observed drug concentrations after birth were within the 80% prediction interval in 94% of adalimumab samples and 93% of infliximab samples. The anti-TNFα clearance model accurately predicted the concentration at 6 months after birth with an MAE of 0.03 µg/mL [SD 0.03] for adalimumab and 0.11 µg/mL [SD 0.18] for infliximab based on cord blood concentrations. Addition of an additional sample between 1 and 4 months after birth improved the predictive accuracy for infliximab (MAE 0.05 [SD 0.09]) but not for adalimumab. Guidance for use in clinical practice was formulated. CONCLUSIONS The validity of the anti-TNFα clearance model is high, and hence can be used to guide clinicians regarding the timing of live vaccines in infants exposed to adalimumab or infliximab in utero.
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Affiliation(s)
- Jantien W Wieringa
- Department of Pediatrics, Haaglanden Medical Center, The Hague, The Netherlands
- Department of Pediatrics, Division of Paediatric Infectious Diseases and Immunology, Erasmus MC University Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Matthijs D Kruizinga
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
- Juliana Children's Hospital, Haga Teaching Hospital, the Hague, The Netherlands
| | - Gertjan J A Driessen
- Department of Pediatrics, Maastricht University Medical Center, MosaKids Children's Hospital, Maastricht, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Mette Julsgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Center for Molecular Prediction of Inflammatory Bowel Disease [PREDICT], Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
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Gong C, Bertagnolli LN, Boulton DW, Coppola P. A Literature Review of Changes in Phase II Drug-Metabolizing Enzyme and Drug Transporter Expression during Pregnancy. Pharmaceutics 2023; 15:2624. [PMID: 38004602 PMCID: PMC10674389 DOI: 10.3390/pharmaceutics15112624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/02/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed®, a systematic search was conducted to identify literature relevant to drug metabolism and transport in pregnancy. PubMed was searched with pre-specified terms during the period of 26 May 2023 to 10 July 2023. The final dataset of 142 manuscripts was evaluated for evidence regarding the effect of gestational age and hormonal regulation on the expression of phase II enzymes (n = 16) and drug transporters (n = 38) in the pregnant woman and in the placenta. This comprehensive review exposes gaps in current knowledge of phase II enzyme and drug transporter localization, expression, and regulation during pregnancy, which emphasizes the need for further research. Moreover, the information collected in this review regarding phase II drug-metabolizing enzyme and drug transporter changes will aid in optimizing pregnancy physiologically based pharmacokinetic (PBPK) models to inform dose selection in the pregnant population.
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Affiliation(s)
- Christine Gong
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Lynn N. Bertagnolli
- AstraZeneca LP, Biopharmaceuticals R&D, Clinical Pharmacology & Safety Sciences, Clinical Pharmacology & Quantitative Pharmacology, Gaithersburg, MD 20878, USA
| | - David W. Boulton
- AstraZeneca LP, Biopharmaceuticals R&D, Clinical Pharmacology & Safety Sciences, Clinical Pharmacology & Quantitative Pharmacology, Gaithersburg, MD 20878, USA
| | - Paola Coppola
- AstraZeneca LP, Biopharmaceuticals R&D, Clinical Pharmacology & Safety Sciences, Clinical Pharmacology & Quantitative Pharmacology, Cambridge CB2 0AA, UK
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Eke AC, Gebreyohannes RD, Fernandes MFS, Pillai VC. Physiologic Changes During Pregnancy and Impact on Small-Molecule Drugs, Biologic (Monoclonal Antibody) Disposition, and Response. J Clin Pharmacol 2023; 63 Suppl 1:S34-S50. [PMID: 37317492 PMCID: PMC10365893 DOI: 10.1002/jcph.2227] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/17/2023] [Indexed: 06/16/2023]
Abstract
Pregnancy is a unique physiological state that results in many changes in bodily function, including cellular, metabolic, and hormonal changes. These changes can have a significant impact on the way small-molecule drugs and monoclonal antibodies (biologics) function and are metabolized, including efficacy, safety, potency, and adverse effects. In this article, we review the various physiologic changes that occur during pregnancy and their effects on drug and biologic metabolism, including changes in the coagulation, gastrointestinal, renal, endocrine, hepatic, respiratory, and cardiovascular systems. Additionally, we discuss how these changes can affect the processes of drug and biologic absorption, distribution, metabolism, and elimination (pharmacokinetics), and how drugs and biologics interact with biological systems, including mechanisms of drug action and effect (pharmacodynamics) during pregnancy, as well as the potential for drug-induced toxicity and adverse effects in the mother and developing fetus. The article also examines the implications of these changes for the use of drugs and biologics during pregnancy, including consequences of suboptimal plasma drug concentrations, effect of pregnancy on the pharmacokinetics and pharmacodynamics of biologics, and the need for careful monitoring and individualized drug dosing. Overall, this article aims to provide a comprehensive understanding of the physiologic changes during pregnancy and their effects on drug and biologic metabolism to improve the safe and effective use of drugs.
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Affiliation(s)
- Ahizechukwu C Eke
- Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Rahel D Gebreyohannes
- Department of Obstetrics and Gynecology, Addis Ababa University College of Medicine, Addis Ababa, Ethiopia
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Moreira FDL, Benzi JRDL, Pinto L, Thomaz MDL, Duarte G, Lanchote VL. Optimizing Therapeutic Drug Monitoring in Pregnant Women: A Critical Literature Review. Ther Drug Monit 2023; 45:159-172. [PMID: 36127797 DOI: 10.1097/ftd.0000000000001039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/18/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND More than 90% of pregnant women take at least one drug during pregnancy. Drug dose adjustments during pregnancy are sometimes necessary due to various pregnancy-induced physiological alterations frequently associated with lower plasma concentrations. However, the clinical relevance or benefits of therapeutic drug monitoring (TDM) in pregnant women have not been specifically studied. Clinical pharmacokinetic studies in pregnant women are incredibly challenging for many reasons. Despite this, regulatory agencies have made efforts to encourage the inclusion of this population in clinical trials to achieve more information on the pharmacotherapy of pregnant women. This review aims to provide support for TDM recommendations and dose adjustments in pregnant women. METHODS The search was conducted after a predetermined strategy on PubMed and Scopus databases using the MeSH term "pregnancy" alongside other terms such as "Pregnancy and dose adjustment," "Pregnancy and therapeutic drug monitoring," "Pregnancy and PBPK," "Pregnancy and pharmacokinetics," and "Pregnancy and physiological changes." RESULTS The main information on TDM in pregnant women is available for antiepileptics, antipsychotics, antidepressants, antibiotics, antimalarials, and oncologic and immunosuppressive drugs. CONCLUSIONS More data are needed to support informed benefit-risk decision making for the administration of drugs to pregnant women. TDM and/or pharmacokinetic studies could ensure that pregnant women receive an adequate dosage of an active drug. Mechanistic modeling approaches potentially could increase our knowledge about the pharmacotherapy of this special population, and they could be used to better design dosage regimens.
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Affiliation(s)
- Fernanda de Lima Moreira
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo; and
| | - Jhohann Richard de Lima Benzi
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo; and
| | - Leonardo Pinto
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo; and
| | - Matheus de Lucca Thomaz
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo; and
| | - Geraldo Duarte
- Department of Obstetrics and Gynecology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Vera Lucia Lanchote
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo; and
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11
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Hof T, Thimme R, Hasselblatt P. [Diversity in gastroenterology - A focus on inflammatory bowel diseases]. Dtsch Med Wochenschr 2023; 148:519-527. [PMID: 37094587 DOI: 10.1055/a-1892-4878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
Factors related to patient diversity may play a major role in the pathogenesis and clinical manifestation of intestinal and liver diseases and should be considered during diagnostic workup and therapeutic decisions. Here we discuss how diversity factors such as gender, ethnicity, age and socioeconomic parameters may affect the manifestation and disease course of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis). Consideration of such factors may help to pave the path towards personalized medicine approaches in clinical practice.
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12
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Tegenge MA, Mahmood I, Struble EB, Sauna Z. Pharmacokinetics of antibodies during Pregnancy: Impact of pregnancy on the pharmacokinetics of antibodies (Part 2). Int Immunopharmacol 2023; 119:109915. [PMID: 36842918 DOI: 10.1016/j.intimp.2023.109915] [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: 12/01/2022] [Revised: 02/15/2023] [Accepted: 02/16/2023] [Indexed: 02/26/2023]
Abstract
In Part 1, we provided a general description of macromolecules, pharmacokinetics (PK) characteristics in non-pregnant subjects, and the physiological changes during pregnancy. Here we further elaborate on the impact of pregnancy on the PK of antibodies through illustrative case studies (immunoglobulins, infliximab, adalimumab and eculizumab). Using published data from nonclinical and clinical studies, we present measured or calculated PK parameters from pregnant subjects comparing with data from non-pregnant subjects, if available. Due to the paucity of PK data evaluating PK of antibodies during pregnancy, we also provide examples of PK studies for small molecules. Finally, we draw conclusions on the nature and direction of PK changes for both antibodies and small molecules as well as provide recommendations for areas that would benefit from further studies.
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Affiliation(s)
- Million A Tegenge
- Division of Clinical Evaluation and Pharmacology/Toxicology, Office of Tissue and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
| | - Iftekhar Mahmood
- Mahmood Clinical Pharmacology Consultancy LLC, Rockville, MD, USA
| | - Evi B Struble
- Division of Plasma Protein Therapeutics, Office of Tissue and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Zuben Sauna
- Division of Plasma Protein Therapeutics, Office of Tissue and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
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13
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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: 126] [Impact Index Per Article: 63.0] [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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14
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Liu Z, Julsgaard M, Zhu X, Martin J, Barclay ML, Cranswick N, Gibson PR, Gearry RB, van der Giessen J, Connor SJ, Rosella O, Grosen A, Toong C, Flanagan E, Wieringa JW, Janneke van der Woude C, Bell SJ. Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children. J Crohns Colitis 2022; 16:1835-1844. [PMID: 35779236 DOI: 10.1093/ecco-jcc/jjac093] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. METHODS We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. RESULTS Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. CONCLUSIONS Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.
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Affiliation(s)
- Zheng Liu
- Clinical Pharmacology, School of Medicine and Public Health, University of Newcastle, Hunter Medical Research Institute, Kookaburra Circuit, Australia.,Clinical Pharmacology, Department of Medicine, The Royal Children's Hospital Melbourne, Australia.,Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Mette Julsgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Gastroenterology, St Vincent's Hospital, and University of Melbourne, Melbourne, Australia
| | - Xiao Zhu
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, China.,School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Jennifer Martin
- Clinical Pharmacology, School of Medicine and Public Health, University of Newcastle, Hunter Medical Research Institute, Kookaburra Circuit, Australia
| | - Murray L Barclay
- Departments of Gastroenterology & Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
| | - Noel Cranswick
- Clinical Pharmacology, Department of Medicine, The Royal Children's Hospital Melbourne, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Hospital, and Monash University, Melbourne, VIC, Australia
| | - Richard B Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Janine van der Giessen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Susan J Connor
- Department of Gastroenterology, Liverpool Hospital, Sydney.,South Western Sydney Clinical, University of NSW Sydney.,Ingham Institute of Applied Medical Research, Sydney, Australia
| | - Ourania Rosella
- Department of Gastroenterology, Alfred Hospital, and Monash University, Melbourne, VIC, Australia
| | - Anne Grosen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Catherine Toong
- South Western Sydney Clinical, University of NSW Sydney.,Sydney South West Pathology Service, Liverpool Hospital, University of NSW, Sydney, Australia
| | - Emma Flanagan
- Department of Gastroenterology, St Vincent's Hospital, and University of Melbourne, Melbourne, Australia
| | - Jantien W Wieringa
- Department of Pediatrics, Haaglanden Medical Center, the Hague, The Netherlands.,Department of Pediatrics, Division of Paediatric Infectious Diseases and Immunology, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Sally J Bell
- Department of Gastroenterology, St Vincent's Hospital, and University of Melbourne, Melbourne, Australia.,Department of Gastroenterology, Monash Health, and School of Clinical Sciences Monash University, Melbourne, VIC, Australia
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15
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Megna BW, Vaughn BP. Therapeutic Drug Monitoring in Practice for Inflammatory Bowel Disease. Curr Gastroenterol Rep 2022; 24:191-200. [PMID: 36459387 DOI: 10.1007/s11894-022-00854-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2022] [Indexed: 06/17/2023]
Abstract
PURPOSE OF REVIEW To outline the development, rationale, and practical use of therapeutic drug monitoring in patients with inflammatory bowel disease. RECENT FINDINGS Therapeutic drug monitoring is traditionally discussed in terms of a proactive or reactive approach. However, these terms are not always consistently defined and can be confusing when translating research to clinical practice. Personalized approaches incorporating clinical context and precision medicine are emerging. Personalized therapeutic drug monitoring combines a structured and proactive strategy for monitoring biologic concentrations as well as identification of antidrug antibody development or subtherapeutic dosing in the setting of loss of response. Optimizing biologic therapy can improve outcomes and avoid loss of response. Why, when, and how we measure drug troughs and anti-drug antibodies is a moving target, though what is known is that the appropriate and evidence-based use of this practice prevents adverse events and improves outcomes in patients with inflammatory bowel disease.
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Affiliation(s)
- Bryant W Megna
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA.
| | - Byron P Vaughn
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
- Inflammatory Bowel Disease Program, University of Minnesota, Minneapolis, MN, USA
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16
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A Practical Approach to IBD Care in the Pregnant Patient. Curr Gastroenterol Rep 2022; 24:201-209. [PMID: 36422770 DOI: 10.1007/s11894-022-00856-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW As the incidence of inflammatory bowel disease (IBD) rises, gastroenterologists are more commonly facing management of the disease in women of childbearing age. This coincides with the development of new IBD therapies whose use in pregnancy must be considered. RECENT FINDINGS This review provides updated recommendations for newer biologic agents and small molecules that have been approved for IBD treatment since the previous guidelines were published. In addition, recent research has found that prior IBD-related surgeries, not just ileal pouch-anal anastomosis, can impact pregnancy outcomes. Reassuringly, assisted reproductive technology for IBD patients has been found to have similar success rates to the non-IBD population. Ensuring disease remission prior to conception and throughout pregnancy is key for optimizing pregnancy and fetal outcomes. As gastroenterologists play an integral role in the management of IBD throughout the peripartum period, this review summarizes recent studies in combination with existing guidelines to address preconception counseling, medication safety, and management for quiescent and active disease throughout pregnancy.
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17
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Wang H, Hu Y, Chen F, Shen M. Comparative safety of infliximab and adalimumab on pregnancy outcomes of women with inflammatory bowel diseases: a systematic review & meta-analysis. BMC Pregnancy Childbirth 2022; 22:854. [DOI: 10.1186/s12884-022-05191-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/07/2022] [Indexed: 11/20/2022] Open
Abstract
Abstract
Background
Inflammatory bowel disease (IBD) is a condition that affects most of the digestive tract. There is no report of fertility reduction in medically managed IBD women compared with the general population. On the other hand, active IBD can lead to significantly decreased fertility. Over the previous 2 decades, anti-tumor necrosis factor (anti-TNF) has been an effective treatment for managing patients with IBD, increasing the use of infliximab and adalimumab in clinical practice. However, it is unclear which biologics are better for pregnant women with IBD.
Aim
We conducted a systematic review and meta-analysis for the risk of adverse pregnancy outcomes following treatment with infliximab and adalimumab in women with IBD.
Methods
Bibliographic databases were retrieved from their inception to July 2022. The results were adverse pregnancy outcomes, including congenital malformations and spontaneous abortion.
Results
A total of 8 studies included 527 pregnant women with IBD. Of these, 343 received infliximab, and 184 received adalimumab therapy. Compared to adalimumab, adverse pregnancy outcomes were not increased in infliximab therapy including congenital malformations and spontaneous abortion.
Conclusion
Infliximab and adalimumab therapy did not show the difference of risk in adverse pregnancy outcomes in women with IBD.
Systematic review registration
http://www.crd.york.ac.uk/PROSPERO, identifier: CRD 42,021,277,869.
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18
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Gottlieb ZS, Dolinger M, Kayal M, Rao BB, Bhattacharya A, Dubinsky MC, Ungaro RC. Clinical Challenge: Proactive Precise Management of Active Ulcerative Colitis During Pregnancy-Advantages of Point-of-Care Intestinal Ultrasound and Therapeutic Drug Monitoring. Dig Dis Sci 2022; 67:3557-3561. [PMID: 35579797 DOI: 10.1007/s10620-022-07532-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Zoë S Gottlieb
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
| | - Michael Dolinger
- Departments of Pediatrics and Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Maia Kayal
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Bhavana Bhagya Rao
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Abhik Bhattacharya
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marla C Dubinsky
- Departments of Pediatrics and Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Ryan C Ungaro
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
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19
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Zhong Z, Wang Y, Wang G, Zhou F. Case Report: TNF-Alpha Inhibitors to Rescue Pregnancy in Women With Potential Pregnancy Loss: A Report of Ten Cases. Front Immunol 2022; 13:900537. [PMID: 35693803 PMCID: PMC9174430 DOI: 10.3389/fimmu.2022.900537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Miscarriage poses a significant threat to pregnant women globally. Recurrent miscarriages or potential poor embryonic development indicated by early drops in serum human chorionic gonadotrophin (hCG) are even more catastrophic for pregnant women. However, these patients receive either individualized medical intervention supported by limited evidence or no treatment at all. In this study, we report ten patients who shared at least one episode of an early decline of hCG in the first trimester and were treated with compassionate use of tumor necrosis factor-alpha inhibitor (TNFi). They were then followed up regularly with caution. Their hCG trajectory all resumed a normal pattern within one week and the obstetric outcomes were promising. No adverse fetal, neonatal, or maternal health issues have been observed. This case series supports current safety evidence of TNFi and provides new insight into its use in pregnancy when the embryo is in danger. Further well-designed clinical trials should be carried out to consolidate the evidence.
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Affiliation(s)
- Zixing Zhong
- Center for Reproductive Medicine, Department of Obstetrics, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yuhan Wang
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Guiqin Wang
- Fertility Center of Melinda Women and Children's Hospital, Dalian, China
| | - Feifei Zhou
- Center for Reproductive Medicine, Department of Traditional Chinese Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.,Zhejiang Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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20
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The Effect of Pregnancy and Inflammatory Bowel Disease on the Pharmacokinetics of Drugs Related to Inflammatory Bowel Disease-A Systematic Literature Review. Pharmaceutics 2022; 14:pharmaceutics14061241. [PMID: 35745812 PMCID: PMC9227141 DOI: 10.3390/pharmaceutics14061241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/27/2022] [Accepted: 06/06/2022] [Indexed: 11/19/2022] Open
Abstract
Due to ethical and practical reasons, a knowledge gap exists on the pharmacokinetics (PK) of inflammatory bowel disease (IBD)-related drugs in pregnant women with IBD. Before evidence-based dosing can be proposed, insight into the PK has to be gained to optimize drug therapy for both mother and fetus. This systematic review aimed to describe the effect of pregnancy and IBD on the PK of drugs used for IBD. One aminosalicylate study, two thiopurine studies and twelve studies with biologicals were included. Most drugs within these groups presented data over multiple moments before, during and after pregnancy, except for mesalazine, ustekinumab and golimumab. The studies for mesalazine, ustekinumab and golimumab did not provide enough data to demonstrate an effect of pregnancy on concentration and PK parameters. Therefore, no evidence-based dosing advice was given. The 6-thioguanine nucleotide levels decreased during pregnancy to 61% compared to pre-pregnancy levels. The potentially toxic metabolite 6-methylmercaptopurine (6-MMP) increased to maximal 209% of the pre-pregnancy levels. Although the PK of the thiopurines changed throughout pregnancy, no evidence-based dosing advice was provided. One study suggested that caution should be exercised when the thiopurine dose is adjusted, due to shunting 6-MMP levels. For the biologicals, infliximab levels increased, adalimumab stayed relatively stable and vedolizumab levels tended to decrease during pregnancy. Although the PK of the biologicals changed throughout pregnancy, no evidence-based dosing advice for biologicals was provided. Other drugs retrieved from the literature search were mesalazine, ustekinumab and golimumab. We conclude that limited studies have been performed on PK parameters during pregnancy for drugs used in IBD. Therefore, more extensive research to determine the values of PK parameters is warranted. After gathering the PK data, evidence-based dosing regimens can be developed.
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21
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Gill KL, Jones HM. Opportunities and Challenges for PBPK Model of mAbs in Paediatrics and Pregnancy. AAPS J 2022; 24:72. [PMID: 35650328 DOI: 10.1208/s12248-022-00722-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/20/2022] [Indexed: 12/20/2022] Open
Abstract
New drugs may in some cases need to be tested in paediatric and pregnant patients. However, it is difficult to recruit such patients and there are many ethical issues around their inclusion in clinical trials. Modelling and simulation can help to plan well-designed clinical trials with a reduced number of participants and to bridge gaps where recruitment is difficult. Physiologically based pharmacokinetic (PBPK) models for small molecule drugs have been used to aid study design and dose adjustments in paediatrics and pregnancy, with several publications in the literature. However, published PBPK models for monoclonal antibodies (mAb) in these populations are scarce. Here, the current status of mAb PBPK models in paediatrics and pregnancy is discussed. Seven mAb PBPK models published for paediatrics were found, which report good prediction accuracy across a wide age range. No mAb PBPK models for pregnant women have been published to date. Current challenges to the development of such PBPK models are discussed, including gaps in our knowledge of relevant physiological processes and availability of clinical data to verify models. As the availability of such data increases, it will help to improve our confidence in the PBPK model predictive ability. Advantages for using PBPK models to predict mAb PK in paediatrics and pregnancy are discussed. For example, the ability to incorporate ontogeny and gestational changes in physiology, prediction of maternal, placental and foetal exposure and the ability to make predictions from in vitro and preclinical data prior to clinical data being available.
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Affiliation(s)
- Katherine L Gill
- Certara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK.
| | - Hannah M Jones
- Certara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK
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22
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Truta B, Canner JK, Fang SH, Efron JE, Safar B. Outcomes of Continuation vs Discontinuation of Adalimumab Therapy During Third Trimester of Pregnancy in Inflammatory Bowel Disease. GASTRO HEP ADVANCES 2022; 1:785-791. [PMID: 39131851 PMCID: PMC11307739 DOI: 10.1016/j.gastha.2022.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 04/12/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Adalimumab (ADA) transport across the placenta increases with gestational age advances. We evaluated child-mother health outcomes related to the timing of the last ADA dose before delivery. Methods Using IBM MarketScan data, we collected records for all children exposed to ADA during intrauterine life. We compared milestone achievements, congenital malformations, and respiratory infections rates in children from mothers of 2 groups: (1) a late ADA group, which continued therapy until 90 days or fewer before delivery; and (2) an early ADA group, which discontinued therapy more than 90 days before delivery. We also assessed the risk of flaring for mothers in the early group. Results There were no significant differences in growth (P = .48), developmental delays (P = .25), or congenital malformations (P = .61) in the 427 children of the late group vs 70 children of early ADA group. Continuing ADA late in pregnancy did not increase the respiratory infection rate (P = .38). No differences occurred between groups in cesarean and premature delivery, intrauterine growth retardation, and stillbirths. ADA discontinuation was the only predictor of flaring in the third trimester of pregnancy (odds ratio = 6.04, 95% confidence interval 2.66-13.7). In the late group, mothers' risk of flaring decreased (16/447 vs 13/73, P < .001). Mothers with active disease were more likely to deliver prematurely vs mothers with quiet disease (6/29 vs 31/491, P = .003). Conclusion Continuation of ADA in pregnancy close to delivery is of low risk for children. Early discontinuation, however, increases the risk of flaring in mothers and the likelihood of premature deliveries.
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Affiliation(s)
- Brindusa Truta
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph K. Canner
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sandy H. Fang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jonathan E. Efron
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bashar Safar
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Truta B. Therapeutic drug monitoring in inflammatory bowel disease: At the right time in the right place. World J Gastroenterol 2022; 28:1380-1383. [PMID: 35645545 PMCID: PMC9099186 DOI: 10.3748/wjg.v28.i13.1380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 01/17/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Therapeutic drug monitoring (TDM) was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease (IBD) was regarded with great anticipation. But implementation of the TDM in clinical practice was challenged by several factors including uncertainty of the optimal cut-off values, assay variable sensitivity in detecting drug levels and antibodies and, most importantly, individual pharmacokinetics. While reactive TDM was embraced in clinical practice as a useful tool in assessing lack of response to therapy, the utility of proactive TDM in managing IBD therapy is still challenged by the lack of consistency between evidence. Described here, there are four groups of IBD patients for whom proactive TDM has the potential to greatly impact their therapeutic outcomes: Patients with perianal Crohn's disease, patients with severe ulcerative colitis, pregnant women with IBD and children. As the future of IBD management moves towards personalizing treatment, TDM will be an important decision node in a machine learning based algorithm predicting the best strategy to maximize treatment results while minimizing the loss of response to therapy.
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Affiliation(s)
- Brindusa Truta
- Internal Medicine, Johns Hopkins University, Baltimore, MD 21210, United States
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Skejø C, Vestergaard T, Julsgaard M. Editorial: safety of ustekinumab in pregnancy-are we there yet? Aliment Pharmacol Ther 2022; 55:495-496. [PMID: 35092058 DOI: 10.1111/apt.16767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 12/29/2021] [Indexed: 12/09/2022]
Affiliation(s)
- Caecilie Skejø
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Thea Vestergaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Mette Julsgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Nielsen OH, Gubatan JM, Juhl CB, Streett SE, Maxwell C. Biologics for Inflammatory Bowel Disease and Their Safety in Pregnancy: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2022; 20:74-87.e3. [PMID: 32931960 DOI: 10.1016/j.cgh.2020.09.021] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/01/2020] [Accepted: 09/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Biologics are used routinely in pregnant women with inflammatory bowel disease (IBD), but large-scale data reporting adverse pregnancy outcomes among biologic users are lacking. We sought to estimate the prevalence of adverse pregnancy outcomes in women with IBD on biologic therapies. METHODS We searched major databases from inception to June 2020 for studies estimating the prevalence of adverse pregnancy outcomes in IBD when using biologics (anti-tumor necrosis factor [TNF], anti-integrins, and anticytokines). Prevalence and relative risk (RR) were pooled using a random-effects model. RESULTS Forty-eight studies were included in the meta-analysis comprising 6963 patients. Biologic therapy in IBD pregnancies was associated with a pooled prevalence of 8% (95% CI, 6%-10%; I2 = 87.4%) for early pregnancy loss, 9% (95% CI, 7%-11%; I2 = 89.9%) for preterm birth, 0% (95% CI, 0%-0%; I2 = 0%) for stillbirth, 8% (95% CI, 5%-10%; I2 = 87.0%) for low birth weight, and 1% (95% CI, 1%-2%; I2 = 78.3%) for congenital malformations. These rates are comparable with those published in the general population. In subgroup analyses of a small number of studies, the prevalence of early pregnancy loss and preterm birth were higher in vedolizumab vs anti-TNF users. Meta-regression did not show an association of disease activity or concomitant thiopurine on adverse outcomes. Continued TNF inhibitor use during the third trimester was not associated with risk of preterm birth (RR, 1.41; 95% CI, 0.77-2.60; I2 = 0%), low birth weight (RR, 1.32; 95% CI, 0.80-2.18; I2 = 0%), or congenital malformations (RR, 1.28; 95% CI, 0.47-3.49; I2 = 0%). CONCLUSIONS Adverse pregnancy outcomes among pregnant IBD women using biologics are comparable with that of the general population. PROSPERO protocol #CRD42019135721.
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Affiliation(s)
- Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
| | - John Mark Gubatan
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Carsten Bogh Juhl
- Research Unit for Musculoskeletal Function and Physiotherapy, University of Southern Denmark, Odense, Denmark; Department of Physiotherapy and Occupational Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Sarah Elizabeth Streett
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Cynthia Maxwell
- Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Ontario, Canada
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26
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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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27
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de Aragão MC, Beraldo RF, Marcondes MB, de Barros JR, Herrerias GSP, Saad-Hossne R, Baima JP, Sassaki LY. Management of inflammatory bowel disease and serum level of infliximab in newborn exposed to anti-TNF therapy during pregnancy: Case report and literature review. Medicine (Baltimore) 2021; 100:e28274. [PMID: 34941109 PMCID: PMC8702279 DOI: 10.1097/md.0000000000028274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 11/25/2021] [Indexed: 12/05/2022] Open
Abstract
RATIONALE Heightened inflammatory bowel disease (IBD) activity during pregnancy is associated with higher rates of preterm birth, miscarriage, and low birth weight. Therefore, its adequate treatment is essential, considering the risk-benefit of medication use. Although previous literature has described the management of IBD during pregnancy, few studies have assessed the pharmacokinetics of IBD drugs in the newborn. In this case report, we describe the management of ulcerative colitis during pregnancy and discuss the benefits of checking serum levels of infliximab in newborns exposed to the medication during pregnancy. PATIENT CONCERN A 37-year-old patient with ulcerative colitis in clinical and endoscopic remission had been undergoing treated with infliximab since 2008. The patient became pregnant in 2018. DIAGNOSIS AND INTERVENTION Infliximab medication was discontinued at the 29th week of pregnancy. OUTCOMES The pregnancy was uneventful, and the levels of infliximab in the umbilical cord were >20 μg/dL. Live vaccinations were postponed until the baby was 6 months old, when a new serum drug level proved to be undetectable. LESSONS Our case suggests that the use of infliximab is safe in pregnancy, and drug discontinuation could be considered from the 24th week of pregnancy onward to reduce placental transfer to the newborn in patients at low risk of relapse. Vaccines with live attenuated organisms should be delayed for at least 6 months or until the serum level of the medication is undetectable.
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Affiliation(s)
- Maria Cecília de Aragão
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Rodrigo Fedatto Beraldo
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Mariana Barros Marcondes
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Jaqueline Ribeiro de Barros
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | | | - Rogerio Saad-Hossne
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Júlio Pinheiro Baima
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
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28
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Trotta MC, Alfano R, Cuomo G, Romano C, Gravina AG, Romano M, Galdiero M, Montemurro MV, Giordano A, D'Amico M. Comparison of Timing to Develop Anti-Drug Antibodies to Infliximab and Adalimumab Between Adult and Pediatric Age Groups, Males and Females. J Pediatr Pharmacol Ther 2021; 27:63-71. [PMID: 35002561 PMCID: PMC8717619 DOI: 10.5863/1551-6776-27.1.63] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/05/2021] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To compare the timing of serum anti-drug antibodies in adult and pediatric age groups, males and females, treated for inflammatory bowel disease or arthritis with adalimumab or infliximab by retrospectively combining data collected during a 2-year therapeutic drug monitoring period. METHODS Four hundred thirty sera were divided in groups collected at 0, 3, 6, 12, and 24 months (T0, T3, T6, T12, and T24) after initiation of therapy and assayed for drug and relative anti-drug antibodies levels. At each time point, the percentage of sera presenting anti-drug antibodies, as well as the drug concentrations, were calculated and correlated with patient age and sex. RESULTS Anti-drug antibodies were present in 31.5% of sera and were significantly higher in the pediatric age group than in the adult age group, through all time points. The percentages of sera showing anti-drug antibodies were significantly different as early as 3 months and were sera from pediatric female group. The percentages of sera showing anti-drug antibodies reached the highest value at 6 months in the pediatric age group and at 12 months in the adult age group. CONCLUSIONS Sera from pediatric had an earlier presence of anti-drug antibodies than adults. In particular, pediatric females sera showed the fastest anti-drug antibodies development.
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Affiliation(s)
- Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli” (MCT, MG) Naples, Italy
| | - Roberto Alfano
- Department of Advanced Medical and Surgical Sciences “DAMSS”, University of Campania “Luigi Vanvitelli” (RA, CR), Naples, Italy
| | - Giovanna Cuomo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli” (GC, MR, AGG), Naples, Italy
| | - Ciro Romano
- Department of Advanced Medical and Surgical Sciences “DAMSS”, University of Campania “Luigi Vanvitelli” (RA, CR), Naples, Italy
| | - Antonietta Gerarda Gravina
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli” (GC, MR, AGG), Naples, Italy
| | - Marco Romano
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli” (GC, MR, AGG), Naples, Italy
| | - Marilena Galdiero
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli” (MCT, MG) Naples, Italy
| | | | - Antonio Giordano
- General Directorate, University Polyclinic “Luigi Vanvitelli” (AG), Naples, Italy
| | - Michele D'Amico
- Therapeutic Monitoring Unit for Biological Drugs, University “Luigi Vanvitelli” (MDA), Naples, Italy
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29
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Sako M, Yoshimura N, Sonoda A, Okano S, Ueda M, Tezuka M, Mine M, Yamanishi S, Hashimoto K, Kobayashi K, Takazoe M, Fukata M. Safety Prediction of Infants Born to Mothers with Crohn's Disease Treated with Biological Agents in the Late Gestation Period. JOURNAL OF THE ANUS RECTUM AND COLON 2021; 5:426-432. [PMID: 34746508 PMCID: PMC8553350 DOI: 10.23922/jarc.2021-021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/15/2021] [Indexed: 01/15/2023]
Abstract
Objectives: Knowledge gaps exist in the use of biologics for pregnant patients with Crohn's disease (CD), especially the usage of ustekinumab (UST) and infliximab (IFX) infusion during the late gestation period. In this case series, we investigated perinatal and neonatal outcomes and pharmacokinetics of these biologics in pregnant CD patients. Methods: Pregnant CD patients under treatment with IFX or UST during January 2017 to December 2019 were monitored. Growth and development of their babies were followed up to six months. Drug concentrations were measured in maternal peripheral and cord blood at delivery and infants' blood at six months of age. Results: Four cases were kept IFX treatment until late gestation (median last dose: 31.2 weeks). One case received UST until 23 weeks of gestation. All cases were in clinical remission but moderately undernourished. Babies were delivered by cesarean section at full term without any complications or congenital abnormalities. No growth or developmental defects and no susceptibility to infections were observed by six months. However, two babies whose mothers received IFX after 30 weeks of gestation were detected IFX in their blood at six months of age (0.94 and 0.24 pg/ml). Concentrations of UST in maternal and cord blood were 267.7 and 756.5 ng/ml, respectively. UST was not detected in the infant at six months of age. Conclusions: Administration of UST or IFX to pregnant patients with CD is safe, particularly IFX to be given in the late gestation period. Understanding of the pharmacokinetics of biologics in maternal-infant interactions may improve the management of pregnant CD patients.
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Affiliation(s)
- Minako Sako
- Center for Inflammatory Bowel Disease, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Naoki Yoshimura
- Center for Inflammatory Bowel Disease, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Akira Sonoda
- Center for Inflammatory Bowel Disease, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Soh Okano
- Center for Inflammatory Bowel Disease, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Miki Ueda
- Department of Pediatrics, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Maki Tezuka
- Department of Obstetrics and Gynecology, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Makiko Mine
- Department of Pediatrics, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Shingo Yamanishi
- Department of Pediatrics, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Koichi Hashimoto
- Department of Obstetrics and Gynecology, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Koichi Kobayashi
- Department of Obstetrics and Gynecology, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Masakazu Takazoe
- Center for Inflammatory Bowel Disease, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Masayuki Fukata
- Center for Inflammatory Bowel Disease, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
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30
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De Felice KM, Kane S. Safety of anti-TNF agents in pregnancy. J Allergy Clin Immunol 2021; 148:661-667. [PMID: 34489011 DOI: 10.1016/j.jaci.2021.07.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis are associated with adverse pregnancy outcomes. Active maternal disease during pregnancy is associated with additional negative outcomes. Anti-TNF agents are effective treatments for inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. These agents cross the placenta starting in the second trimester, with levels detected for several months after birth. This has led to safety concerns, with continued therapy during pregnancy for both the mother and the infant. This review covers retrospective and prospective data published from various cohorts of pregnant women exposed to anti-TNF agents during pregnancy. It highlights the safety of anti-TNF drugs in pregnancy, breast-feeding, and during the first year of life of the infant.
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Affiliation(s)
- Kara M De Felice
- Department of Gastroenterology, Louisiana State University, Department of Gastroenterology, New Orleans, La.
| | - Sunanda Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
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31
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Beghin D. [Placental transfer of monoclonal antibodies: The example of anti-TNF alpha drugs]. GYNECOLOGIE, OBSTETRIQUE, FERTILITE & SENOLOGIE 2021; 49:724-726. [PMID: 34214735 DOI: 10.1016/j.gofs.2021.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Indexed: 06/13/2023]
Abstract
Anti-TNF alpha monoclonal antibodies are used in the treatment of chronic inflammatory diseases, which commonly affect women of childbearing age. Due to their similar structure to native immunoglobulins, the evaluation of their placental transfer by a pharmacological approach of the mechanisms involved is an interesting source of information, useful to the risk-benefit assessment of drugs in pregnant women.
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Affiliation(s)
- D Beghin
- Centre de référence sur les agents tératogènes (CRAT), DMU Épidémiologie et biostatistique, Santé publique, Pharmacie, Pharmacologie, Recherche, Information médicale, Thérapeutique et médicaments (ESPRIT), GHU, AP-HP, Sorbonne université - site Trousseau, 26, avenue Dr-Netter, 75571 Paris cedex 12, France.
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Carnovale C, Parisi F, Battini V, Zavatta A, Cheli S, Cattaneo D, Gringeri M, Mosini G, Guarnieri G, Cammarata G, Cetin I. The use of biological agents in pregnant women affected by autoimmune disorders: Why we need more research of this neglected area. Pharmacol Res 2021; 171:105786. [PMID: 34314858 DOI: 10.1016/j.phrs.2021.105786] [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: 06/01/2021] [Revised: 07/12/2021] [Accepted: 07/22/2021] [Indexed: 11/20/2022]
Abstract
Women of childbearing age are largely affected by several autoimmune disorders (the estimates range between 1.5 and 10 per 10,000). The increasing number of effective biological agents has dramatically revolutionized the treatment of these clinical conditions, ameliorating the patient's quality of life. The use of these agents by women during pregnancy is growing to ensure the disease activity control and avoid adverse health outcomes. However, for many newer biological agents, the degree of information concerning their use in pregnancy is often incomplete to perform a conclusive risk assessment on fetal and maternal health given the exclusion of this specific population from pharmacological clinical trials. More recently, the COVID-19 pandemic has confirmed the unacceptable inequities of pharmacological research and medical treatment for pregnant and lactating women, exacerbating the need for filling the gaps of quantitative and qualitative pharmacology data in this sensitive population. ere we summarize (i) what is already known about safety and effectiveness of biological agents in this understudied population (with specific focus on pregnancy-related health outcomes), and what we are going to learn from the on-going studies among pregnant women treated with biological agents; (ii) the methodological and ethical considerations that characterize the pharmacological research in pregnancy, also discussing emerging evidence on the use of therapeutic drug monitoring (TDM) in this clinical setting.
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Affiliation(s)
- Carla Carnovale
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy.
| | - Francesca Parisi
- Department of Woman, Mother and Neonate, "V. Buzzi" Children Hospital, ASST Fatebenefratelli Sacco, 20141 Milan, Italy
| | - Vera Battini
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy
| | - Alice Zavatta
- Department of Woman, Mother and Neonate, "V. Buzzi" Children Hospital, ASST Fatebenefratelli Sacco, 20141 Milan, Italy
| | - Stefania Cheli
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Via GB Grassi 74, 20157 Milan, Italy
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Via GB Grassi 74, 20157 Milan, Italy
| | - Michele Gringeri
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy
| | - Giulia Mosini
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy
| | - Greta Guarnieri
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy
| | - Gianluca Cammarata
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy
| | - Irene Cetin
- Department of Woman, Mother and Neonate, "V. Buzzi" Children Hospital, ASST Fatebenefratelli Sacco, 20141 Milan, Italy; Department of Biomedical and Clinical Sciences, "Luigi Sacco", University of Milan, 20157 Milan, Italy
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33
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Guerrero Vinsard D, Kane SV. Biologics and pregnancy: a clinician's guide to the management of IBD in pregnant women. Expert Rev Gastroenterol Hepatol 2021; 15:633-641. [PMID: 33440996 DOI: 10.1080/17474124.2021.1876562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 01/12/2021] [Indexed: 10/22/2022]
Abstract
Introduction: Women with inflammatory bowel disease (IBD) endorse a tremendous amount of concern about medication exposure during pregnancy and their effects on the fetus. Medical providers caring for this patient population should be well informed and feel comfortable counseling their patients for the best pregnancy outcome possible.Areas covered: It is of particular importance to understand the implications of use of biologics in preconception, pregnancy, and postpartum timeframes. Herein, we aim to inform the clinician about the impact of uncontrolled inflammation during pregnancy, the mechanisms of biologic transport through the placenta, the effects of biologics in maternal and neonatal outcomes, and additional postpartum considerations such as breastfeeding and vaccination safety.Expert opinion: The groundwork already set by previous research in terms of safety of biologic therapy during pregnancy has been reassuring. With the advent of more mechanisms of action but similar protein structure, i.e. they are IgG1 antibodies; the authors anticipate the recommendation of continuation of therapy throughout pregnancy will be sustained.
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Affiliation(s)
| | - Sunanda V Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA
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34
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Nuñez F P, Quera R, Sepúlveda E, Simian D, Pizarro G, Lubascher J, Flores L, Ibañez P, Figueroa C, Kronberg U. Pregnancy in Inflammatory Bowel Disease: Experience of a Chilean cohort. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 44:277-285. [PMID: 33745519 DOI: 10.1016/j.gastrohep.2020.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/12/2020] [Accepted: 08/25/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND In inflammatory bowel disease (IBD) a high percentage of women are diagnosed during their reproductive age. IBD in remission is the ideal scenario when planning a pregnancy. AIMS To describe the clinical characteristics of pregnancy/newborn and assess disease activity at the time of conception and throughout the pregnancy in patients with IBD treated at a tertiary centre in Chile. METHODS We retrospectively reviewed women diagnosed with IBD who were pregnant or delivered between 2017 and 2020. Demographic, clinical, obstetric and delivery data were obtained from the IBD registry, approved by the local IRB. Descriptive statistics and association tests were performed (χ2, p ≤ 0.05). RESULTS Sixty women with IBD were included. At the beginning of pregnancy, 21 (35%) had active disease and 39 (65%) were in remission. Of those with active disease, 16 (66%) remained active and 6 had spontaneous abortions. In those who were in remission, 26 (69%) remained in this condition. Nine patients (15%) discontinued treatment, and 6 of these had inflammatory activity during pregnancy. Preconception counselling was performed in 23 of the 60 patients, being higher in the group that remained in remission during pregnancy (65% vs. 35%, p = 0.02). Patients who had a flare during pregnancy had more probability of preterm birth (<37 weeks) and newborn with lower weight compared with the group that always remained in remission (89% vs. 74%, p = 0.161) and (2.885 vs 3.370 g; p = 0.0014). CONCLUSION Remission presents better outcomes in pregnancy and preconception counselling would allow a better IBD control during pregnancy.
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Affiliation(s)
- Paulina Nuñez F
- Universidad de Chile, Facultad de Medicina Occidente, Hospital San Juan de Dios, Universidad de Chile, Santiago, Chile
| | - Rodrigo Quera
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Clínica Las Condes, Santiago, Chile.
| | - Eduardo Sepúlveda
- Departamento de Ginecología y Obstetricia Universidad de Chile, Santiago, Chile
| | - Daniela Simian
- Dirección Académica, Departamento Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Gonzalo Pizarro
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Jaime Lubascher
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Lilian Flores
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Patricio Ibañez
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Carolina Figueroa
- Unidad de Coloproctología, Departamento de Cirugía, Clínica Las Condes, Santiago, Chile
| | - Udo Kronberg
- Unidad de Coloproctología, Departamento de Cirugía, Clínica Las Condes, Santiago, Chile
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Montero-Vilchez T, Salvador-Rodriguez L, Rodriguez-Tejero A, Sanchez-Diaz M, Arias-Santiago S, Molina-Leyva A. Reproductive Potential and Outcomes in Patients with Hidradenitis Suppurativa: Clinical Profile and Therapeutic Implications. Life (Basel) 2021; 11:life11040277. [PMID: 33810294 PMCID: PMC8066603 DOI: 10.3390/life11040277] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/15/2022] Open
Abstract
There are scarce data available regarding the impact of hidradenitis suppurativa (HS) on fertility, course and outcome of pregnancy and risk associated with treatments. The aims of this study are (1) to describe the clinical profile of HS women of childbearing age with and without accomplished reproductive desires and (2) to describe the prescribed treatments based on the fulfillment of reproductive intentions. We conducted a prospective observational study that included 104 HS women of childbearing age, 50.96% (53/104) with unfulfilled reproductive desires. These women were younger (29.08 vs. 42.06 years, p < 0.001), less frequently married and higher educated than women with fulfilled reproductive desires. Their age of disease onset was lower, but disease duration was shorter, in concordance with a lower International Hidradenitis Suppurativa Severity Score System (IHS4) and lower number of draining tunnels. Combined oral contraceptives were more frequently prescribed in women with unfulfilled reproductive desires (30.19% vs. 9.80%, p = 0.013) while biologics were less used in this group (3.77% vs. 13.73%, p = 0.08). In conclusion, a higher educational level and an earlier disease onset, with potential implications in finding a partner, may make the fulfillment of reproductive desires difficult for patients with HS. This study could help clinicians to achieve a better understanding of the specific characteristics of HS during childbearing age and consider reproductive desires when making treatment decisions.
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Affiliation(s)
- Trinidad Montero-Vilchez
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18012 Granada, Spain; (T.M.-V.); (L.S.-R.); (A.R.-T.); (M.S.-D.); (A.M.-L.)
- Instituto de Investigación Biosanitaria GRANADA, 18012 Granada, Spain
| | - Luis Salvador-Rodriguez
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18012 Granada, Spain; (T.M.-V.); (L.S.-R.); (A.R.-T.); (M.S.-D.); (A.M.-L.)
- Instituto de Investigación Biosanitaria GRANADA, 18012 Granada, Spain
| | - Andrea Rodriguez-Tejero
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18012 Granada, Spain; (T.M.-V.); (L.S.-R.); (A.R.-T.); (M.S.-D.); (A.M.-L.)
- Instituto de Investigación Biosanitaria GRANADA, 18012 Granada, Spain
| | - Manuel Sanchez-Diaz
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18012 Granada, Spain; (T.M.-V.); (L.S.-R.); (A.R.-T.); (M.S.-D.); (A.M.-L.)
- Instituto de Investigación Biosanitaria GRANADA, 18012 Granada, Spain
| | - Salvador Arias-Santiago
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18012 Granada, Spain; (T.M.-V.); (L.S.-R.); (A.R.-T.); (M.S.-D.); (A.M.-L.)
- Instituto de Investigación Biosanitaria GRANADA, 18012 Granada, Spain
- Dermatology Department, Faculty of Medicine, University of Granada, 18001 Granada, Spain
- Correspondence: ; Tel.: +34-9580-23422
| | - Alejandro Molina-Leyva
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18012 Granada, Spain; (T.M.-V.); (L.S.-R.); (A.R.-T.); (M.S.-D.); (A.M.-L.)
- Instituto de Investigación Biosanitaria GRANADA, 18012 Granada, Spain
- Dermatology Department, Faculty of Medicine, University of Granada, 18001 Granada, Spain
- European Hidradenitis Suppurativa Foundation (EHSF), Dessau-Roßlau, Germany
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Romanowska-Próchnicka K, Felis-Giemza A, Olesińska M, Wojdasiewicz P, Paradowska-Gorycka A, Szukiewicz D. The Role of TNF-α and Anti-TNF-α Agents during Preconception, Pregnancy, and Breastfeeding. Int J Mol Sci 2021; 22:ijms22062922. [PMID: 33805757 PMCID: PMC7998738 DOI: 10.3390/ijms22062922] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 03/11/2021] [Indexed: 12/15/2022] Open
Abstract
Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.
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Affiliation(s)
- Katarzyna Romanowska-Próchnicka
- Department of Biophysics and Human Physiology, Faculty of Health Sciences, Warsaw Medical University, 02-091 Warsaw, Poland; (K.R.-P.); (P.W.); (D.S.)
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland;
| | - Anna Felis-Giemza
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland;
- Correspondence:
| | - Marzena Olesińska
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland;
| | - Piotr Wojdasiewicz
- Department of Biophysics and Human Physiology, Faculty of Health Sciences, Warsaw Medical University, 02-091 Warsaw, Poland; (K.R.-P.); (P.W.); (D.S.)
| | - Agnieszka Paradowska-Gorycka
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland;
| | - Dariusz Szukiewicz
- Department of Biophysics and Human Physiology, Faculty of Health Sciences, Warsaw Medical University, 02-091 Warsaw, Poland; (K.R.-P.); (P.W.); (D.S.)
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Beltagy A, Aghamajidi A, Trespidi L, Ossola W, Meroni PL. Biologics During Pregnancy and Breastfeeding Among Women With Rheumatic Diseases: Safety Clinical Evidence on the Road. Front Pharmacol 2021; 12:621247. [PMID: 34122062 PMCID: PMC8189556 DOI: 10.3389/fphar.2021.621247] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 01/04/2021] [Indexed: 12/31/2022] Open
Abstract
Females are generally more affected by autoimmune diseases, a fact that underlines the relationship with pregnancy and the safety of anti-rheumatic drugs in pregnancy and lactation. Biologic therapies are increasingly prescribed to treat and maintain remission in a significant number of systemic autoimmune rheumatic diseases. The experience with the use of biologics during gestation is extremely lacking because of the observational nature of the available studies and the difficulty in designing proper clinical trials in pregnancy. Among the studied biologics, more information was published on TNFα inhibitors and, in particular, on their potential passage through the placenta and impact on the fetus. Currently, a fragment of anti-TNFα monoclonal IgG, certolizumab pegol, is considered safe with almost no placental transfer. Subsequent observations are suggesting a comparable safety for the soluble TNFα receptor etanercept. Another biologic, eculizumab, the anti-C5a antibody used to treat complement-mediated microangiopathies, is also considered safe due to the unique engineered IgG2/4κ formulation that limits its passage through the placental barrier. Still, long-term data about children born to women treated with biologics in pregnancy are not attainable. Data on breastfeeding are currently available for several biologics. This article reviews the literature available about which drugs are considered safe during pregnancy and lactation, which are not, and on future prospects.
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Affiliation(s)
- Asmaa Beltagy
- Istituto Auxologico Italiano, IRCCS, Immunorheumatology Research Laboratory, Milan, Italy.,Rheumatology and Clinical Immunology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Azin Aghamajidi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Laura Trespidi
- Department of Obstetrics and Gynaecology, Fondazione Ca Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Wally Ossola
- Department of Obstetrics and Gynaecology, Fondazione Ca Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Pier Luigi Meroni
- Istituto Auxologico Italiano, IRCCS, Immunorheumatology Research Laboratory, Milan, Italy
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Grišić AM, Dorn-Rasmussen M, Ungar B, Brynskov J, Ilvemark JFKF, Bolstad N, Warren DJ, Ainsworth MA, Huisinga W, Ben-Horin S, Kloft C, Steenholdt C. Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease. United European Gastroenterol J 2021; 9:91-101. [PMID: 33079627 PMCID: PMC8259366 DOI: 10.1177/2050640620964619] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/16/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Infliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics. METHODS The study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed-effects population pharmacokinetic modeling. RESULTS Dose-normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10-21) compared to prepregnancy (7, 2-12; p = 0.003), the first trimester (9, 1-12; p = 0.04), or postpregnancy (6, interquartile range 3-11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7-36; p > 0.05). A one-compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti-infliximab antibodies, and not by pregnancy-imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre- and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester. CONCLUSION Infliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de-intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.
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Affiliation(s)
- Ana-Marija Grišić
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.,Graduate Research Training Program, PharMetrX, Berlin, Germany
| | - Maria Dorn-Rasmussen
- Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Bella Ungar
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel
| | - Jørn Brynskov
- Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Johan F K F Ilvemark
- Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - David J Warren
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Mark A Ainsworth
- Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | | | - Shomron Ben-Horin
- Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel
| | - Charlotte Kloft
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
| | - Casper Steenholdt
- Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev, Denmark
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Goodman WA, Erkkila IP, Pizarro TT. Sex matters: impact on pathogenesis, presentation and treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17:740-754. [PMID: 32901108 PMCID: PMC7750031 DOI: 10.1038/s41575-020-0354-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/27/2020] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD), as do most chronic inflammatory disorders, displays unique features and confers different risk factors in male and female patients. Importantly, sex-based differences in IBD exist for epidemiological incidence and prevalence among different age groups, with men and women developing distinct clinical symptoms and disparity in severity of disease. In addition, the presentation of comorbidities in IBD displays strong sex differences. Notably, particular issues exclusive to women's health, including pregnancy and childbirth, require specific considerations in female patients with IBD of childbearing age that can have a substantial influence on clinical outcomes. This Review summarizes the latest findings regarding sex-based differences in the epidemiology, clinical course, comorbidities and response to current therapies in patients with IBD. Importantly, the latest basic science discoveries in this area of investigation are evaluated to provide insight into potential mechanisms underlying the influence of sex on disease pathogenesis, as well as to design more personalized and efficacious care, in patients with IBD.
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Affiliation(s)
- Wendy A Goodman
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Ian P Erkkila
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Theresa T Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
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40
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Flanagan E, Gibson PR, Wright EK, Moore GT, Sparrow MP, Connell W, Kamm MA, Begun J, Christensen B, De Cruz P, Shelton E, Dowling D, Andrews JM, Brown SJ, Niewiadomski O, Ward MG, Rosella O, Rosella G, Kiburg KV, Ross AL, Bell SJ. Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure. Aliment Pharmacol Ther 2020; 52:1551-1562. [PMID: 32981127 DOI: 10.1111/apt.16102] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/21/2020] [Accepted: 09/10/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown. AIMS To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance METHODS: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable. RESULTS We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: -0.33 to -0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow-up testing. CONCLUSIONS During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Peter De Cruz
- Parkville, VIC, Australia.,Melbourne, VIC, Australia
| | | | | | | | | | | | | | | | | | | | | | - Sally J Bell
- Fitzroy, VIC, Australia.,Melbourne, VIC, Australia
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Ghalandari N, Dolhain RJEM, Hazes JMW, van Puijenbroek EP, Kapur M, Crijns HJMJ. Intrauterine Exposure to Biologics in Inflammatory Autoimmune Diseases: A Systematic Review. Drugs 2020; 80:1699-1722. [PMID: 32852745 PMCID: PMC7568712 DOI: 10.1007/s40265-020-01376-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Inflammatory autoimmune diseases are chronic diseases that often affect women of childbearing age. Therefore, detailed knowledge of the safety profile of medications used for management of inflammatory autoimmune diseases during pregnancy is important. However, in many cases the potential harmful effects of medications (especially biologics) during pregnancy (and lactation) on mother and child have not been fully identified. OBJECTIVE Our aim was to update the data on the occurrence of miscarriages and (major) congenital malformations when using biologics during pregnancy based on newly published articles. Additionally, we selected several different secondary outcomes that may be of interest for clinicians, especially information on adverse events in the use of a specific biologic during pregnancy. MATERIAL AND METHODS A search was conducted from 1 January 2015 until 4 July 2019 in Embase.com, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar with specific search terms for each database. Selection of publications was based on title/abstract and followed by full text (double blinded, two researchers). An overview was made based on outcomes of interest. References of the included publications were reviewed to include and minimize the missing publications. RESULTS A total of 143 publications were included. The total number of cases ranged from nine for canakinumab to 4276 for infliximab. The rates of miscarriages and major congenital malformations did not show relevant differences from those rates in the general population. CONCLUSION Despite limitations to our study, no major safety issues were reported and no trend could be identified in the reported malformations.
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Affiliation(s)
- N Ghalandari
- Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
- Medicines Evaluation Board (MEB), Graadt van Roggenweg 500, 3531 AH, Utrecht, The Netherlands.
- Academic Center of Inflammunity, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - R J E M Dolhain
- Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Academic Center of Inflammunity, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - J M W Hazes
- Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Medicines Evaluation Board (MEB), Graadt van Roggenweg 500, 3531 AH, Utrecht, The Netherlands
- Academic Center of Inflammunity, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - E P van Puijenbroek
- Netherlands Pharmacovigilance Centre Lareb, 's Hertogenbosch, The Netherlands
| | - M Kapur
- Utrecht University of Medical Sciences, Utrecht, The Netherlands
| | - H J M J Crijns
- Medicines Evaluation Board (MEB), Graadt van Roggenweg 500, 3531 AH, Utrecht, The Netherlands
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Wijnsma KL, Ter Heine R, Wetzels JFM, van de Kar NCAJ, Brüggemann RJ. Author's Reply to Liu et al.: "Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab". Clin Pharmacokinet 2020; 59:1645-1646. [PMID: 33118148 DOI: 10.1007/s40262-020-00952-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2020] [Indexed: 11/30/2022]
Affiliation(s)
- Kioa Lente Wijnsma
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Science, Amalia Children's Hospital, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Rob Ter Heine
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jack F M Wetzels
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nicole C A J van de Kar
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Science, Amalia Children's Hospital, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Roger J Brüggemann
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
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Abstract
The disease course of autoimmune diseases such as rheumatoid arthritis is altered during pregnancy, and a similar modulatory role of pregnancy on inflammatory bowel disease (IBD) has been proposed. Hormonal, immunological, and microbial changes occurring during normal pregnancy may interact with the pathophysiology of IBD. IBD consists of Crohn's disease and ulcerative colitis, and because of genetic, immunological, and microbial differences between these disease entities, they may react differently during pregnancy and should be described separately. This review will address the pregnancy-induced physiological changes and their potential effect on the disease course of ulcerative colitis and Crohn's disease, with emphasis on the modulation of epithelial barrier function and immune profiles by pregnancy hormones, microbial changes, and microchimerism.
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The impact of pregnancy on biologic therapies for the treatment of inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2020; 44-45:101670. [PMID: 32359682 DOI: 10.1016/j.bpg.2020.101670] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 01/31/2023]
Abstract
Active inflammatory bowel disease during conception and pregnancy has been associated with adverse materno-fetal outcomes. Patients are often unduly concerned about the adverse effects of biologic medications on the growing fetus, however, continuing therapy is advised, with potential risks of therapy outweighed by the risks of active maternal disease. A number of physiological changes associated with pregnancy can alter the absorption, distribution and elimination of these therapies, which may impact on their safety and efficacy. We review the current evidence regarding the effects of pregnancy on the pharmacokinetics of biologic therapies, as well as drug concentration measurements during pregnancy and at time of delivery. A greater understanding of the impact of pregnancy on the pharmacokinetics of biologic therapies and the emerging utilisation of drug concentration monitoring during pregnancy may lead to improved materno-fetal outcomes in patients with inflammatory bowel disease.
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Tzanetakou V, Stergianou D, Giamarellos-Bourboulis EJ. Long-term safety of adalimumab for patients with moderate-to-severe hidradenitis suppurativa. Expert Opin Drug Saf 2020; 19:381-393. [PMID: 32098513 DOI: 10.1080/14740338.2020.1734560] [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: 02/06/2023]
Abstract
Introduction: Hidradenitis suppurativa (HS) is a chronic debilitating inflammatory skin disorder that affects regions rich in apocrine glands. Although the etiology of HS is not clear, inflammatory cytokines, like tumor necrosis factor (TNF)-α, participate in pathogenesis. Adalimumab (ADA), a human IgG1 monoclonal antibody that selectively targets TNFα, is the only EMA/FDA-approved biologic agent available for the therapy of moderate-to-severe HS.Areas covered: A comprehensive literature search was conducted to present existing studies with an emphasis on the safety profile of ADA for the treatment of moderate-to-severe HS. ADA is prescribed for more than 15 years for varied indications and has improved the therapeutic outcomes of many diseases. Clinical trials and real-life safety data from ADA administration in HS were presented, with particular attention to special populations, such as children, elderly, and pregnant women.Expert opinion: Existing data advise for limited safety concerns with long-term ADA treatment provided that patients are thoroughly screened for infections, latent tuberculosis, and history of malignancy before the start of treatment.
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Affiliation(s)
- Vassiliki Tzanetakou
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Stergianou
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Rottenstreich A, Bar-Gil Shitrit A. Preconception counseling of females with inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2020; 44-45:101666. [PMID: 32359680 DOI: 10.1016/j.bpg.2020.101666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel diseases (IBD) are commonly diagnosed in women of childbearing age. As such, pregnancy is often encountered in this subset of patients. Management of pregnancy in IBD patients poses numerous challenges as ensuring the safety of the mother and the fetus is required. Disease remission prior to pregnancy is a key determinant of both the course of IBD throughout gestation and pregnancy outcome. Thus, adequate preconception care is of paramount importance in order to achieve optimal maternal and perinatal outcomes and maintain disease quiescence throughout gestation. In addition, preconception care has a major role in improving patient's knowledge, concerns and misbeliefs related to reproductive-health issues among IBD patients. In this review, we discuss the various aspects involved in the preconception care of IBD patients.
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Affiliation(s)
- Amihai Rottenstreich
- Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ariella Bar-Gil Shitrit
- IBD MOM Unit, Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Medical School, Hebrew University, Jerusalem, Israel.
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Luu M, Benzenine E, Barkun A, Doret M, Michiels C, Degand T, Quantin C, Bardou M. Safety of first year vaccination in children born to mothers with inflammatory bowel disease and exposed in utero to anti-TNFα agents: a French nationwide population-based cohort. Aliment Pharmacol Ther 2019; 50:1181-1188. [PMID: 31617226 DOI: 10.1111/apt.15504] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/30/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Children born to mothers with IBD may be exposed to anti-TNFα agents antenatally. Current European guidelines recommend postponing live vaccines until after 6 months of life in this population. Data on the safety of live vaccines administration in the first year of life of these children are sparse with one reported fatality following bacillus Calmette-Guerin (BCG) administration. AIMS To describe the use and safety of vaccines administered in children born to mothers with IBD and exposed antenatally to anti-TNFα agents METHODS: Data from children born to mothers with IBD between 2013 and 2014 were collected retrospectively from the French Health Insurance Database. Vaccines recommended before or at 1 year of age were considered. RESULTS Among 4741 children, 670 (14.1%) were exposed to anti-TNFα agents antenatally, with concomitant thiopurines in 16.0% (n = 107) and steroids in 19.3% (n = 214). Among these 670 children, 315 (47%) were exposed up to delivery. Exposed children were less likely than non-exposed to receive BCG (88/670, 13.1% vs 780/4071, 19.2% respectively, P < .05) and received it later in life (months, mean ± SD, 4.3 ± 3.9 and 2.4 ± 2.9 respectively, P < .001). In exposed children, 64/88 (73%) received BCG vaccination before 6 months of age, but with no BCG-related severe adverse event observed during the first year. Uptake of other vaccines recommended before 6 months was above 85% in both groups. CONCLUSION In children exposed antenatally to anti-TNFα agents, vaccinations are often not postponed in keeping with the recommendations, but no BCG-related severe adverse events were reported in children vaccinated before 6 months of life.
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Affiliation(s)
- Maxime Luu
- Clinical Investigation Center (INSERM 1432), Dijon - Bourgogne University Hospital, Dijon, France.,UFR Sciences Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Eric Benzenine
- Biostatistics and Bioinformatics Department, Dijon Bourgogne University Hospital, Dijon, France
| | - Alan Barkun
- The McGill University Health Centre, Montreal General Hospital, McGill University, Montreal, Canada
| | - Muriel Doret
- Hôpital Femme-Mère-Enfant Service de Gynécologie Obstétrique, Bron, France
| | - Christophe Michiels
- Division of Gastroenterology, Dijon Bourgogne University Hospital, Dijon, France
| | - Thibault Degand
- Division of Gastroenterology, Dijon Bourgogne University Hospital, Dijon, France
| | - Catherine Quantin
- Biostatistics and Bioinformatics Department, Dijon Bourgogne University Hospital, Dijon, France.,Biostatistics, Biomathematics, Pharmacoepidemiology and Infectious Diseases (B2PHI), UVSQ, Institut Pasteur, Université Paris-Saclay, INSERM, Paris, France
| | - Marc Bardou
- Clinical Investigation Center (INSERM 1432), Dijon - Bourgogne University Hospital, Dijon, France.,UFR Sciences Santé, Université Bourgogne Franche-Comté, Dijon, France
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48
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Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee B, Lomer MCE, Parkes GC, Selinger C, Barrett KJ, Davies RJ, Bennett C, Gittens S, Dunlop MG, Faiz O, Fraser A, Garrick V, Johnston PD, Parkes M, Sanderson J, Terry H, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen R, Hawthorne AB. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019; 68:s1-s106. [PMID: 31562236 PMCID: PMC6872448 DOI: 10.1136/gutjnl-2019-318484] [Citation(s) in RCA: 1510] [Impact Index Per Article: 251.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/10/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
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Affiliation(s)
- Christopher Andrew Lamb
- Newcastle University, Newcastle upon Tyne, UK
- Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Nicholas A Kennedy
- Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
- University of Exeter, Exeter, UK
| | - Tim Raine
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
| | - Philip Anthony Hendy
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
- Imperial College London, London, UK
| | - Philip J Smith
- Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
| | - Jimmy K Limdi
- The Pennine Acute Hospitals NHS Trust, Manchester, UK
- University of Manchester, Manchester, UK
| | - Bu'Hussain Hayee
- King's College Hospital NHS Foundation Trust, London, UK
- King's College London, London, UK
| | - Miranda C E Lomer
- King's College London, London, UK
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Gareth C Parkes
- Barts Health NHS Trust, London, UK
- Barts and the London School of Medicine and Dentistry, London, UK
| | - Christian Selinger
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
- University of Leeds, Leeds, UK
| | | | - R Justin Davies
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
- University of Cambridge, Cambridge, UK
| | - Cathy Bennett
- Systematic Research Ltd, Quorn, UK
- Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | | | - Malcolm G Dunlop
- University of Edinburgh, Edinburgh, UK
- Western General Hospital, Edinburgh, UK
| | - Omar Faiz
- Imperial College London, London, UK
- St Mark's Hospital, Harrow, UK
| | - Aileen Fraser
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | | | | | - Miles Parkes
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
| | - Jeremy Sanderson
- King's College London, London, UK
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - Daniel R Gaya
- Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| | - Tariq H Iqbal
- Queen Elizabeth Hospital Birmingham NHSFoundation Trust, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - Stuart A Taylor
- University College London, London, UK
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Melissa Smith
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
- Brighton and Sussex Medical School, Brighton, UK
| | - Matthew Brookes
- Royal Wolverhampton NHS Trust, Wolverhampton, UK
- University of Wolverhampton, Wolverhampton, UK
| | - Richard Hansen
- Royal Hospital for Children Glasgow, Glasgow, UK
- University of Glasgow, Glasgow, UK
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Abstract
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
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50
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A Pharmacological Approach to Managing Inflammatory Bowel Disease During Conception, Pregnancy and Breastfeeding: Biologic and Oral Small Molecule Therapy. Drugs 2019; 79:1053-1063. [PMID: 31183768 DOI: 10.1007/s40265-019-01141-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The inflammatory bowel diseases commonly affect individuals during their peak reproductive years. Patients are often concerned about the impact of medical therapies on their ability to conceive, effect on the fetus, as well as the ability to breastfeed, which has led to poor medical adherence during pregnancy. However, most medications are safe, and discontinuation may lead to active disease, which is associated with adverse materno-fetal outcomes. The anti-TNF biologic therapies, infliximab and adalimumab have been extensively studied in the context of pregnancy. They are actively transferred to the placenta during the second and third trimesters; these have not been associated with an increased rate of congenital abnormalities or fetal death. The minimal amounts of drug that are transferred to breast milk are proteolyzed by the infant's digestive system with no reported short- or long-term adverse effects. There is a paucity of clinical data for the other approved anti-TNF agents or newer anti-integrin (vedolizumab) and anti-interleukin (ustekinumab) therapies used in the management of inflammatory bowel disease; however, no significant safety signals have been documented thus far. The new oral small molecule therapy, tofacitinib is teratogenic in animal models and is contra-indicated in patients attempting pregnancy. It is important that patients, as well as physicians managing patients with these conditions, be aware of the impact of these medical therapies during pregnancy.
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