Comparative safety of infliximab and adalimumab on pregnancy outcomes of Women with Inflammatory Bowel Diseases: A Systematic Review & Meta-Analysis

Comparative safety of infliximab and adalimumab on pregnancy outcomes of Women with Inflammatory Bowel Diseases: A Systematic Review & Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative safety of infliximab and adalimumab on pregnancy outcomes of Women with Inflammatory Bowel Diseases: A Systematic Review & Meta-Analysis Han Wang, Yue Hu, Fang Chen, Mengdie Shen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2067249/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version 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 Crohn's disease, increasing the use of infliximab and adalimumab in clinical practice. However, it is unclear which biologics are more effective in 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. Conclusion Infliximab and adalimumab therapy did not show the difference of risk in adverse pregnancy outcomes such as congenital malformations and spontaneous abortion. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO , identifier: CRD 42021277869. Inflammatory bowel disease Adverse pregnancy outcomes Infliximab Adalimumab Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects most of the digestive tract [ 1 ]. According to the phenotypic manifestations, IBD can be divided into ulcerative colitis (UC) and Crohn's disease (CD). IBD affects people of all ages, including young patients in the reproductive stage. However, the cause of IBD is still unknown, but there is increasing evidence of familial susceptibility to transmittable intestinal antigens [ 2 ]. The peak age of CD diagnosis occurs during the childbearing years. Therefore, treatment of CD during pregnancy is very common [ 3 ]. However, the probable adverse effects of drugs on an unborn infant, complications after different delivery modes, lactation, predisposal to genetic diseases, and other beliefs may lead to intentional failure to have children [ 4 ]. Tumor necrosis factor (TNF)-α is a major proinflammatory and pathological cytokine having pleiotropic effects on various cell types [ 5 ]. Its plays a key role in the pathogenesis of systemic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Anti-TNF-α therapy was the first type of biotherapy approved to treat inflammatory bowel disease, which revolutionized IBD treatment [ 6 , 7 ]. At present, infliximab and adalimumab are the most widely used in clinical practice for IBD treatment. When compared with placebo, infliximab and adalimumab demonstrate similar clinical outcomes [ 6 , 8 – 11 ], including the requirements for corticosteroids, rates of remission, disease-related surgery, and hospitalizations. Of note, data on pregnant women are limited, and the differences between the study populations preclude determining comparative efficacy. Nevertheless, there is growing recognition of the need for studies on the comparative effectiveness of therapies for pregnant women to inform clinical practice accurately. Our previous study has shown that anti-TNF can be advocated for IBD women with pregnancy. With this current meta-analysis, our study aims to quantify the risk of adverse pregnancy outcomes (APOs) in IBD women exposed to infliximab and adalimumab. The outcome of this study will provide valuable evidence for guiding the best clinical decision-making. 2. Method The systematic evaluation was conducted using predefined protocols and reported according to the preferred reporting items of the system evaluation and the presentation of the system evaluation meta-analysis (PRISMA) incorporating health care interventions (PROSPERO registration number: CRD 42021277869). 2.1. Search strategy Medline, PubMed, Web of Science, Embase, and Cochrane Library were searched to identify relevant studies assessing the pregnancy outcomes in women with IBD who received infliximab or adalimumab at pregnancy. All studies and abstracts retrieved were presented at the meetings. There were no language restrictions. At the same time, we searched the reference list of the retrieved articles to carry out other relevant research as completely as possible. The database search was performed on 11th September 2021, and then updated on 12th July 2022. 2.2. Study selection Two reviewers independently reviewed the title and summary of each article to eliminate duplicates, annotations, case reports, and small case series (n < 10). We screened the titles and abstracts of published articles and excluded studies unrelated to this study. Full-text articles were obtained if at least one reviewer considered them qualified. Our analysis included RCTs, observational studies, and case-control studies. Infliximab and adalimumab received marketing authorization from the US Food and Drug Administration, or the European Medicines Agency were also considered in our research. In literature selection, any differences were resolved through discussion and consultation. Inclusion criteria: (1) Patients: Pregnancy in IBD patients older than 18 years who were taking infliximab or adalimumab; (2) Intervention: infliximab therapy at any stage of pregnancy; (3) Comparator: adalimumab therapy at any point during pregnancy; (4) Outcomes: the primary outcome was adverse pregnancy outcomes in patients with IBD pregnancy, including preterm birth, low birth weight, spontaneous abortion, and congenital malformations. Exclusion criteria: (1) trials evaluating any medical treatment protocol other than infliximab and adalimumab; (2) studies on the use of infliximab or adalimumab in pregnant women for an underlying disease other than IBD; (3) inadequate or absent control groups, information on birth outcomes was not available in full, provision of data obtained from other research, or trials assessing differences between combination therapy and monotherapy only. 2.3 Data extraction and Quality Assessment Two reviewers reviewed the full-text candidate articles to confirm the characteristics of the target population, disease treatment, medications used, the number of sample populations, and adverse results. The article's authors were contacted if the data were not available fully. Any dispute was settled through mutual discussion or negotiation with the third reviewer. The Newcastle Ottawa scale (NOS) was selected for assessing the literature qualities of selected case-control and cohort studies [ 12 ]. NOS is an assessment tool for the quality of observational research. It classified quality levels into three categories: group comparability, study group selection, exposure (case-control study), or result (cohort study). The research with 5 or more points in the 9-point system was rated as high-quality, while other studies were considered low-quality. Any differences between reviewers were discussed and resolved by negotiation. 2.4 Statistical analysis We used the Mantel Haenszel method to calculate the odds ratio (OR) and 95% confidence interval (CI). The selection of a random or fixed model was based on heterogeneity analysis [ 13 ]. I 2 statistics were used to evaluate heterogeneity, and a fixed-effect model was used for I 2 50% indicated significant heterogeneity in the study. For the evaluation of publication bias, we checked the asymmetry of the funnel chart, which was more conducive to determining whether small studies were effective [ 15 ]. All statistical analyses were performed using RevMan (version 5.3.0, Copenhagen, Denmark). 3. Results 3.1 Study selection The initial electronic and manual searches produced a total of 1449 studies. Among them, 94 studies met our research criteria, including 34 reports or small case series (n>10), 39 retrospective studies, and 21 prospective studies. Finally, 8 studies (4 prospective studies, 2 retrospective studies, and 2 both) with final compliance for selection criteria were included in the meta-analysis (Fig. 1 ). 3.2 Study characteristics A total of 527 cases were included in the 8 eligible studies. In addition, 343 pregnant women with IBD were treated with infliximab therapy and 184 with adalimumab therapy. These studies characteristics and pregnancy outcomes are summarized in Tables 1 and 2 , respectively. Table 1 Characteristics of the studies included on the use of Infliximab and Adalimumab during pregnancy Study Design Pregnancies (n) No. of pregnancies in infliximab-exposed group No. of pregnancies in adalimumab-exposed group Study quality C.J.Kiely[ 16 ] P 21 10 Infliximab 11 Adalimumab ☆☆☆☆☆☆ Fabian Schnitzler[ 17 ] P 42 35 Infliximab 7 Adalimumab ☆☆☆☆☆☆☆ M. Seirafi[ 18 ] P + R 128 86 Infliximab 42 Adalimumab ☆☆☆☆☆☆☆ M.J.Casanova[ 19 ] R 29 20 Infliximab 9 Adalimumab ☆☆☆☆☆☆☆ Mette Julsgaard[ 20 ] P 80 44 Infliximab 36 Adalimumab ☆☆☆☆☆☆ Razvan Arsenescu[ 21 ] R 10 8 Infliximab 2 Adalimumab ☆☆☆☆☆ Slama W[ 22 ] P 186 122 Infliximab 64 Adalimumab ☆☆☆☆☆ Zuzana Zelinkova[ 23 ] P + R 31 18 Infliximab 13 Adalimumab ☆☆☆☆☆☆ R: Retrospective; P: Prospective Table 2 Pregnancy outcomes (proportion of adverse outcome to number of exposed pregnancies) of included studies Outcomes Group preterm delivery low birth weight spontaneous abortion congenital malformations A B A B A B A B C.J.Kiely[ 16 ] 2/21 2/21 0/10 1/11* 0/21 Fabian Schnitzler[ 17 ] 8/42 6/42 6/35 1/7 0/35 1/7 M. Seirafi[ 18 ] 1/86 0/42 M.J.Casanova[ 19 ] 0/20 1/9 Mette Julsgaard[ 20 ] 3/80 6/80 2/44 1/36 Razvan Arsenescu[ 21 ] 1/8 0/2 0/10 Slama W[ 22 ] 1/122 1/64 3/122 1/64 Zuzana Zelinkova[ 23 ] 1/18 2/13 1/18 0/13 A: exposed to Infliximab B: exposed to Adalimumab * This patient underwent an emergency colectomy following failed treatment with adalimumab. The stillbirth occurred at week 21 gestation, 11 days following the colectomy. 3.3 Adverse pregnancy outcomes Eight studies reported the APOs associated with spontaneous abortion and congenital malformations after exposure to biological agents in pregnant women with IBD. The OR for the pooled crude rates of APOs was 0.74 (95% CI: 0.33, 1.66; P = 0.46), comparing infliximab (n = 343) with adalimumab (n = 184), without obvious heterogeneity ( P = 0.95, I 2 = 0%). Spontaneous abortion Five studies reported the outcome of spontaneous abortion in IBD pregnant women exposed to biological agents. The pooled OR for the crude rate of spontaneous abortion was 0.61 (95% CI: 0.19, 1.97; P = 0.41). There was no heterogeneity between studies when comparing infliximab (n = 193) and adalimumab (n = 97) ( P = 0.93, I 2 = 0%). Congenital malformations Six studies reported congenital malformation outcomes in IBD pregnant women exposed to anti TNF-α. The pooled OR for the crude rate of congenital malformations was 0.81 (95% CI: 0.29, 2.25; P = 0.69) comparing patients treated with infliximab (n = 325) and adalimumab (n = 171). There was no significant heterogeneity observed between studies ( P = 0.46, I 2 = 0%) (Fig. 2 ). 4. Sensitivity Analysis The sensitivity analysis with "leave-one-out " shows that our results were robust. In addition, we excluded each included study separately and found that the original research results did not change substantially. Among the 8 studies included, there was one with a large number of patients, so we removed this study[ 22 ] and evaluated again. Our results are as follow: Seven studies reported the APOs associated with spontaneous abortion and congenital malformations after exposure to biological agents in pregnant women with IBD. The OR for the pooled crude rates of APOs was 0.66 (95% CI: 0.26, 1.68; P = 0.38), comparing infliximab (n = 221) with adalimumab (n = 120), without obvious heterogeneity ( P = 0.92, I 2 = 0%). Spontaneous abortion Four studies reported the outcome of spontaneous abortion in IBD pregnant women exposed to biological agents. The pooled OR for the crude rate of spontaneous abortion was 0.63 (95% CI: 0.17, 2.29; P = 0.48). There was no heterogeneity between studies when comparing infliximab (n = 71) and adalimumab (n = 33) ( P = 0.85, I 2 = 0%). Congenital malformations Five studies reported congenital malformation outcomes in IBD pregnant women exposed to anti TNF-α. The pooled OR for the crude rate of congenital malformations was 0.66 (95% CI: 0.20, 2.12; P = 0.48) comparing patients treated with infliximab (n = 203) and adalimumab (n = 107). There was no significant heterogeneity observed between studies ( P = 0.38, I 2 = 0%) (Fig. 3 ). 5. Discussion The high incidence rate of inflammatory bowel disease (IBD) accounts for more than 0.3% of cases in North America and many European countries. Many patients are diagnosed with IBS as young adults, which affects the peak of fertility and family planning [ 24 ]. Many patients take 5-amino salicylate (5-ASA), corticosteroids, biologics, and immunosuppressants [ 25 , 26 ]. Female patients with active inflammatory bowel disease have an ascendant risk of developing adverse maternal and infant outcomes. Therefore, the best practice for both mothers and infants is to optimize disease control during pregnancy [ 27 , 28 ]. However, before or during pregnancy, women often reduce or stop prescribing drugs without discussing them with their physicians [ 29 ]. Most patients with IBD require long-term medication to control and maintain the disease [ 30 , 31 ]. All anti-TNF drugs effectively maintain clinical remission and mucosal healing in the case of infliximab and adalimumab therapy [ 32 ]. The Toronto [ 27 ] and ECCO[ 3 , 31 ] consensus statements showed that sustained remission is important for pregnancy success. At the same time, anti-TNF therapy does not lead to adverse maternal and infant outcomes. For 5-ASA, thiopurines, or anti-TNF-α, women with well-controlled medical maintenance therapy should continue treatment throughout pregnancy. Nevertheless, patient misconceptions and unsubstantiated fears of treatment teratogenicity contribute to medication non-adherence during pregnancy and breastfeeding [ 33 – 37 ]. Anti-TNF therapies are reported to be effective in many high-quality placebo-controlled trials, but data comparing the effectiveness of the two drugs in clinical practice are limited. Women with IBD already in the active phase before pregnancy have a higher risk of premature birth. This is also associated with poorer fetal outcomes, including the ascendant risk of small gestational age preterm delivery and low birth weight [ 38 ]. Therefore, it is necessary to study the comparative safety of therapies for pregnant women with IBD. The basis for selecting anti-TNF monoclonal antibodies is not clearly stated in the consensus. Moreover, there is no evidence on the safety of infliximab and adalimumab in pregnant women with inflammatory bowel disease. Although many regulatory bodies strongly encourage various studies to incorporate pregnant women and women of childbearing age in RCTs, pregnant and lactating women are often excluded from the trial due to unknown potential harm to the fetus. Therefore, treatment options during pregnancy often lack strong evidence-based recommendations. Safety information comes from voluntary reports of adverse events or uncontrolled observational studies during post-marketing monitoring. The current meta-analysis explored the risk of adverse pregnancy outcomes (we collected the data on preterm delivery, low birth weight, spontaneous abortion, and congenital malformations) following the infliximab and adalimumab therapy in women with IBD. 343 pregnant women with IBD who received infliximab were compared with 184 pregnant women who received adalimumab. In our study, the ORs for adverse pregnancy outcomes in IBD patients taking infliximab therapy during pregnancy compared with those taking adalimumab were 0.74 (95% CI: 0.33, 1.66). The OR of pooled crude rates of congenital malformations and spontaneous abortion were 0.81 (95% CI: 0.29, 2.25) and 0.61 (95% CI: 0.19, 1.97), respectively. However, no significant difference was observed between infliximab and adalimumab in the risk of APOs. A retrospective analysis of "real" data from 3205 patients showed that infliximab was superior to adalimumab and certolizumab in treating CD [ 39 ]. In contrast, a series of recent studies in Austria showed that infliximab and adalimumab were equally effective in treating CD [ 40 ]. These results were neither uniform nor different. During pregnancy, the pharmacodynamics and pharmacokinetics of many drugs changes. Infliximab and adalimumab are complete IgG1 anti-TNF monoclonal antibodies with strong anti-inflammatory effects. They are actively transferred through the placenta in exponential form through the Fc receptor from the second trimester of pregnancy. In one small study by Seow et al[ 41 ], 15 pregnant women treated with infliximab and 10 pregnant women treated with adalimumab increased infliximab levels while adalimumab levels remained stable. IgG1 is transported across the placenta more readily than other IgG subclasses, with passage increasing exponentially toward the later stages of pregnancy [ 42 ]. Several cohort studies, systematic reviews, and meta-analyses have reported no adverse effects of infliximab, adalimumab, or certolizumab during pregnancy. There was no increased risk of congenital malformations, preterm birth, spontaneous abortion, or low birth weight [ 19 , 43 – 49 ]. These observations were consistent with our study, which shows that pregnant women with IBD on infliximab and adalimumab therapy did not show the difference in the risk of APOs. Like other anti-TNFs, infliximab and adalimumab are classified as pregnancy category B (no documented human toxicity) by the US Food and Drug Administration. Infliximab is a murine/human chimeric anti-TNF- α Monoclonal antibody containing murine variable and human IgG1 constant regions. Infliximab contains 25% murine sequences, which may be related to the occurrence of adverse reactions. Adalimumab is a completely humanized anti-TNF- α Monoclonal antibody with no difference from normal human IgG1 [ 5 , 50 ]. (Fig. 4 ). Infliximab and adalimumab can efficiently cross the placenta in the second and third trimesters due to their specific FcRn receptor-mediated mechanisms [ 42 , 51 ]. Our study had some limitations. First, the conclusions of the expert group were based on the opinions of experts and the interpretation of existing evidence. However, the evidence for certain scenarios included in the study was limited. We attempted to obtain the data on preterm delivery and low birth weight. However, some articles did not clearly distinguish between the infliximab and adalimumab groups. Thus we analyzed the risk of congenital malformations and spontaneous abortion. Secondly, our results did not rule out other factors, such as patient compliance, local drug access, or lack through the local medical level. Inevitably, clinicians need to consider the best treatment for a particular patient, considering the numerous associated factors. Although good control of disease activity during pregnancy is beneficial for a better outcome, there is no strong evidence to prove the safety of drug exposure to developing fetuses. Therefore, clinicians should be very cautious. There are still many aspects that need optimization in this field. Thus, larger prospective trials involving pregnant patients are required to establish a drug safety database. Additionally, larger RCTs research outcomes will help promote the clinical decision-making of the treatment of women with inflammatory bowel disease of childbearing age to optimize the pregnancy outcome. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. Competing interests All authors declare that there is no conflict of interest. Funding No financial support. Authors' contributions FC and YH independently reviewed the title, abstract, or full text of all the identified articles. MS contacted to collect missing data or assess eligibility. Any disagreements regarding the eligibility of a study were resolved by mutual discussion (HW) or consultation with MS. All authors contributed to the article and approved the submitted version. Acknowledgements Not applicable. Authors' information 1 Department of gynecology and obstetrics, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, P.R. China 2 Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, Zhejiang Province, P.R. China 3 Department of Gastroenterology, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, 310006, Zhejiang Province, P.R. China 4 Department of Internal Medicine, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, P.R. China References Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L: Crohn's disease . Lancet 2017, 389 (10080):1741-1755. Keighley MR, Stockbrugger RW: Inflammatory bowel disease . Aliment Pharmacol Ther 2003, 18 Suppl 3 :66-70. Gionchetti P, Dignass A, Danese S, Magro Dias FJ, Rogler G, Lakatos PL, Adamina M, Ardizzone S, Buskens CJ, Sebastian S et al : 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 2: Surgical Management and Special Situations . J Crohns Colitis 2017, 11 (2):135-149. 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Malek A, Sager R, Kuhn P, Nicolaides KH, Schneider H: Evolution of maternofetal transport of immunoglobulins during human pregnancy . Am J Reprod Immunol 1996, 36 (5):248-255. Mahadevan U, McConnell RA, Chambers CD: Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease . Gastroenterology 2017, 152 (2):451-462.e452. Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Llurba E, Gris JM: Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review . Clin Rev Allergy Immunol 2017, 53 (1):40-53. Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, Ullman T, Glover S, Valentine JF, Rubin DT et al : Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease . Clin Gastroenterol Hepatol 2013, 11 (3):286-292; quiz e224. Kanis SL, de Lima-Karagiannis A, van der Ent C, Rizopoulos D, van der Woude CJ: Anti-TNF Levels in Cord Blood at Birth are Associated with Anti-TNF Type . J Crohns Colitis 2018, 12 (8):939-947. Marchioni RM, Lichtenstein GR: Tumor necrosis factor-α inhibitor therapy and fetal risk: a systematic literature review . World J Gastroenterol 2013, 19 (17):2591-2602. Deepak P, Stobaugh DJ: Maternal and foetal adverse events with tumour necrosis factor-alpha inhibitors in inflammatory bowel disease . Aliment Pharmacol Ther 2014, 40 (9):1035-1043. Lichtenstein GR, Feagan BG, Mahadevan U, Salzberg BA, Langholff W, Morgan JG, Safdi M, Nissinen R, Taillard F, Sandborn WJ et al : Pregnancy Outcomes Reported During the 13-Year TREAT Registry: A Descriptive Report . Am J Gastroenterol 2018, 113 (11):1678-1688. Sedger LM, McDermott MF: TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future . Cytokine Growth Factor Rev 2014, 25 (4):453-472. Kane SV, Acquah LA: Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy . Am J Gastroenterol 2009, 104 (1):228-233. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 17 Oct, 2022 Reviews received at journal 23 Sep, 2022 Reviewers agreed at journal 23 Sep, 2022 Reviewers agreed at journal 22 Sep, 2022 Reviewers invited by journal 22 Sep, 2022 Editor assigned by journal 22 Sep, 2022 Editor invited by journal 22 Sep, 2022 Submission checks completed at journal 22 Sep, 2022 First submitted to journal 15 Sep, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2067249","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":138763330,"identity":"51066488-adea-4245-a897-a9d7b9cd8c07","order_by":0,"name":"Han Wang","email":"","orcid":"","institution":"Women's Hospital, School of Medicine, Zhejiang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Wang","suffix":""},{"id":138763331,"identity":"d7b8b303-a58e-45f1-af72-da815d7ca551","order_by":1,"name":"Yue Hu","email":"","orcid":"","institution":"First Affiliated Hospital of Zhejiang Chinese Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Hu","suffix":""},{"id":138763332,"identity":"a2d7c938-75dc-4b09-9962-73555c63f1bf","order_by":2,"name":"Fang Chen","email":"","orcid":"","institution":"Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Chen","suffix":""},{"id":138763333,"identity":"a0497371-f91d-4a0e-8f94-53bf2a9403cc","order_by":3,"name":"Mengdie Shen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIie3RvQrCMBDA8SuBuKR2zWR9hIijPkxc2klwEseI4CS4Bhx8Bt/g5KAupbODg5Ozo+AHtg6ONm6C+W0H9ycHAfC8X8TY7nqbPFoAWE7cJWlwLUWO3S+SSLRlOMeBeU0uSTwToCQ/pOtpruA8JohW5nOiKEStxGk4NbkKbEEgD1iTsKZGLdlwBrli4ZzKN3XtYR2DiqW8Su4uCZDoBkaTFlUSuCSKeMIAk46FbLRdFKmQ+7rDlpSx4NGPY0ub42Xca0W27rA3ia/PFK77pch8sex5nvdXnjd/Qnd1bOyhAAAAAElFTkSuQmCC","orcid":"","institution":"Women's Hospital, School of Medicine, Zhejiang University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mengdie","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2022-09-15 05:59:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2067249/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2067249/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":26968138,"identity":"dc8e0a06-3df7-466c-9c6b-47419746b2a4","added_by":"auto","created_at":"2022-09-26 13:33:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":69446,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eStudy flow diagram. Records were identified through database searches and grey literature. A total of 94 articles met the criteria for full-text review, and 8 of them were finally included in the meta-analysis.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2067249/v1/97e16cf3ffba854d709af050.png"},{"id":26967814,"identity":"4f38be2e-72a1-43c0-bad7-cbecf3b26c4e","added_by":"auto","created_at":"2022-09-26 13:28:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":257651,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of APOs in pregnant women treated with infliximab and adalimumab for IBD.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2067249/v1/07fa218ab3129ac733803a55.png"},{"id":26968692,"identity":"5d5d43a2-2c02-44fa-9313-28e9c1b38bfd","added_by":"auto","created_at":"2022-09-26 13:38:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":244454,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of APOs in pregnant women treated with infliximab and adalimumab for IBD (sensitivity analysis).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2067249/v1/4733dfb959c006b11c034f1b.png"},{"id":26967817,"identity":"5cafc943-5b9b-424b-a74f-8bf1b0a3b729","added_by":"auto","created_at":"2022-09-26 13:28:11","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":64608,"visible":true,"origin":"","legend":"\u003cp\u003eSimplified diagrams of the molecular structures of two TNF antagonists.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-2067249/v1/2de0cbb349b4860271892d0e.png"},{"id":26968693,"identity":"de9886e2-3051-43ec-af54-e128813b77b1","added_by":"auto","created_at":"2022-09-26 13:38:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2153083,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2067249/v1/785631d0-eb61-49c6-b996-289a8b2d3115.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative safety of infliximab and adalimumab on pregnancy outcomes of Women with Inflammatory Bowel Diseases: A Systematic Review \u0026 Meta-Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eInflammatory bowel disease (IBD) is a chronic inflammatory disease that affects most of the digestive tract [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. According to the phenotypic manifestations, IBD can be divided into ulcerative colitis (UC) and Crohn's disease (CD). IBD affects people of all ages, including young patients in the reproductive stage. However, the cause of IBD is still unknown, but there is increasing evidence of familial susceptibility to transmittable intestinal antigens [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The peak age of CD diagnosis occurs during the childbearing years. Therefore, treatment of CD during pregnancy is very common [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, the probable adverse effects of drugs on an unborn infant, complications after different delivery modes, lactation, predisposal to genetic diseases, and other beliefs may lead to intentional failure to have children [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTumor necrosis factor (TNF)-α is a major proinflammatory and pathological cytokine having pleiotropic effects on various cell types [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Its plays a key role in the pathogenesis of systemic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Anti-TNF-α therapy was the first type of biotherapy approved to treat inflammatory bowel disease, which revolutionized IBD treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. At present, infliximab and adalimumab are the most widely used in clinical practice for IBD treatment. When compared with placebo, infliximab and adalimumab demonstrate similar clinical outcomes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], including the requirements for corticosteroids, rates of remission, disease-related surgery, and hospitalizations. Of note, data on pregnant women are limited, and the differences between the study populations preclude determining comparative efficacy. Nevertheless, there is growing recognition of the need for studies on the comparative effectiveness of therapies for pregnant women to inform clinical practice accurately. Our previous study has shown that anti-TNF can be advocated for IBD women with pregnancy. With this current meta-analysis, our study aims to quantify the risk of adverse pregnancy outcomes (APOs) in IBD women exposed to infliximab and adalimumab. The outcome of this study will provide valuable evidence for guiding the best clinical decision-making.\u003c/p\u003e"},{"header":"2. Method","content":"\u003cp\u003eThe systematic evaluation was conducted using predefined protocols and reported according to the preferred reporting items of the system evaluation and the presentation of the system evaluation meta-analysis (PRISMA) incorporating health care interventions (PROSPERO registration number: CRD 42021277869).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Search strategy\u003c/h2\u003e \u003cp\u003eMedline, PubMed, Web of Science, Embase, and Cochrane Library were searched to identify relevant studies assessing the pregnancy outcomes in women with IBD who received infliximab or adalimumab at pregnancy. All studies and abstracts retrieved were presented at the meetings. There were no language restrictions. At the same time, we searched the reference list of the retrieved articles to carry out other relevant research as completely as possible. The database search was performed on 11th September 2021, and then updated on 12th July 2022.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Study selection\u003c/h2\u003e \u003cp\u003eTwo reviewers independently reviewed the title and summary of each article to eliminate duplicates, annotations, case reports, and small case series (n\u0026thinsp;\u0026lt;\u0026thinsp;10). We screened the titles and abstracts of published articles and excluded studies unrelated to this study. Full-text articles were obtained if at least one reviewer considered them qualified. Our analysis included RCTs, observational studies, and case-control studies. Infliximab and adalimumab received marketing authorization from the US Food and Drug Administration, or the European Medicines Agency were also considered in our research. In literature selection, any differences were resolved through discussion and consultation.\u003c/p\u003e \u003cp\u003eInclusion criteria: (1) Patients: Pregnancy in IBD patients older than 18 years who were taking infliximab or adalimumab; (2) Intervention: infliximab therapy at any stage of pregnancy; (3) Comparator: adalimumab therapy at any point during pregnancy; (4) Outcomes: the primary outcome was adverse pregnancy outcomes in patients with IBD pregnancy, including preterm birth, low birth weight, spontaneous abortion, and congenital malformations.\u003c/p\u003e \u003cp\u003eExclusion criteria: (1) trials evaluating any medical treatment protocol other than infliximab and adalimumab; (2) studies on the use of infliximab or adalimumab in pregnant women for an underlying disease other than IBD; (3) inadequate or absent control groups, information on birth outcomes was not available in full, provision of data obtained from other research, or trials assessing differences between combination therapy and monotherapy only.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data extraction and Quality Assessment\u003c/h2\u003e \u003cp\u003eTwo reviewers reviewed the full-text candidate articles to confirm the characteristics of the target population, disease treatment, medications used, the number of sample populations, and adverse results. The article's authors were contacted if the data were not available fully. Any dispute was settled through mutual discussion or negotiation with the third reviewer.\u003c/p\u003e \u003cp\u003eThe Newcastle Ottawa scale (NOS) was selected for assessing the literature qualities of selected case-control and cohort studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. NOS is an assessment tool for the quality of observational research. It classified quality levels into three categories: group comparability, study group selection, exposure (case-control study), or result (cohort study). The research with 5 or more points in the 9-point system was rated as high-quality, while other studies were considered low-quality. Any differences between reviewers were discussed and resolved by negotiation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eWe used the Mantel Haenszel method to calculate the odds ratio (OR) and 95% confidence interval (CI). The selection of a random or fixed model was based on heterogeneity analysis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e statistics were used to evaluate heterogeneity, and a fixed-effect model was used for \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;50%, while a random-effect model was used for \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u0026ge;\u0026thinsp;50% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% indicated significant heterogeneity in the study. For the evaluation of publication bias, we checked the asymmetry of the funnel chart, which was more conducive to determining whether small studies were effective [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. All statistical analyses were performed using RevMan (version 5.3.0, Copenhagen, Denmark).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study selection\u003c/h2\u003e \u003cp\u003eThe initial electronic and manual searches produced a total of 1449 studies. Among them, 94 studies met our research criteria, including 34 reports or small case series (n\u0026gt;10), 39 retrospective studies, and 21 prospective studies. Finally, 8 studies (4 prospective studies, 2 retrospective studies, and 2 both) with final compliance for selection criteria were included in the meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Study characteristics\u003c/h2\u003e \u003cp\u003eA total of 527 cases were included in the 8 eligible studies. In addition, 343 pregnant women with IBD were treated with infliximab therapy and 184 with adalimumab therapy. These studies characteristics and pregnancy outcomes are summarized in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the studies included on the use of Infliximab and Adalimumab during pregnancy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDesign\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePregnancies (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo. of pregnancies in infliximab-exposed group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo. of pregnancies in adalimumab-exposed group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eStudy quality\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC.J.Kiely[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFabian Schnitzler[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM. Seirafi[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM.J.Casanova[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMette Julsgaard[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRazvan Arsenescu[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlama W[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e122 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZuzana Zelinkova[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eP\u0026thinsp;+\u0026thinsp;R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e☆☆☆☆☆☆\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eR: Retrospective; P: Prospective\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePregnancy outcomes (proportion of adverse outcome to number of exposed pregnancies) of included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcomes Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003epreterm delivery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003elow birth weight\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003espontaneous abortion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c11\" namest=\"c8\"\u003e \u003cp\u003econgenital malformations\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC.J.Kiely[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2/21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e2/21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0/10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1/11*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003e0/21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFabian Schnitzler[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e8/42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6/42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6/35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0/35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e1/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM. Seirafi[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1/86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e0/42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM.J.Casanova[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0/20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e \u003cp\u003e1/9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMette Julsgaard[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3/80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6/80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e2/44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e1/36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRazvan Arsenescu[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c11\" namest=\"c8\"\u003e \u003cp\u003e0/10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlama W[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1/122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1/64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3/122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e \u003cp\u003e1/64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZuzana Zelinkova[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2/13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e \u003cp\u003e0/13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eA: exposed to Infliximab B: exposed to Adalimumab\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003e* This patient underwent an emergency colectomy following failed treatment with adalimumab. The stillbirth occurred at week 21 gestation, 11 days following the colectomy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Adverse pregnancy outcomes\u003c/h2\u003e \u003cp\u003eEight studies reported the APOs associated with spontaneous abortion and congenital malformations after exposure to biological agents in pregnant women with IBD. The OR for the pooled crude rates of APOs was 0.74 (95% CI: 0.33, 1.66; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.46), comparing infliximab (n\u0026thinsp;=\u0026thinsp;343) with adalimumab (n\u0026thinsp;=\u0026thinsp;184), without obvious heterogeneity (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.95, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e \u003cp\u003e \u003cem\u003eSpontaneous abortion\u003c/em\u003e \u003c/p\u003e \u003cp\u003eFive studies reported the outcome of spontaneous abortion in IBD pregnant women exposed to biological agents. The pooled OR for the crude rate of spontaneous abortion was 0.61 (95% CI: 0.19, 1.97; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.41). There was no heterogeneity between studies when comparing infliximab (n\u0026thinsp;=\u0026thinsp;193) and adalimumab (n\u0026thinsp;=\u0026thinsp;97) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.93, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e \u003cp\u003e \u003cem\u003eCongenital malformations\u003c/em\u003e \u003c/p\u003e \u003cp\u003eSix studies reported congenital malformation outcomes in IBD pregnant women exposed to anti TNF-α. The pooled OR for the crude rate of congenital malformations was 0.81 (95% CI: 0.29, 2.25; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.69) comparing patients treated with infliximab (n\u0026thinsp;=\u0026thinsp;325) and adalimumab (n\u0026thinsp;=\u0026thinsp;171). There was no significant heterogeneity observed between studies (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.46, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Sensitivity Analysis","content":"\u003cp\u003eThe sensitivity analysis with \"leave-one-out \" shows that our results were robust. In addition, we excluded each included study separately and found that the original research results did not change substantially.\u003c/p\u003e \u003cp\u003eAmong the 8 studies included, there was one with a large number of patients, so we removed this study[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and evaluated again. Our results are as follow:\u003c/p\u003e \u003cp\u003eSeven studies reported the APOs associated with spontaneous abortion and congenital malformations after exposure to biological agents in pregnant women with IBD. The OR for the pooled crude rates of APOs was 0.66 (95% CI: 0.26, 1.68; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.38), comparing infliximab (n\u0026thinsp;=\u0026thinsp;221) with adalimumab (n\u0026thinsp;=\u0026thinsp;120), without obvious heterogeneity (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.92, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e \u003cp\u003e \u003cem\u003eSpontaneous abortion\u003c/em\u003e \u003c/p\u003e \u003cp\u003eFour studies reported the outcome of spontaneous abortion in IBD pregnant women exposed to biological agents. The pooled OR for the crude rate of spontaneous abortion was 0.63 (95% CI: 0.17, 2.29; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.48). There was no heterogeneity between studies when comparing infliximab (n\u0026thinsp;=\u0026thinsp;71) and adalimumab (n\u0026thinsp;=\u0026thinsp;33) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.85, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e \u003cp\u003e \u003cem\u003eCongenital malformations\u003c/em\u003e \u003c/p\u003e \u003cp\u003eFive studies reported congenital malformation outcomes in IBD pregnant women exposed to anti TNF-α. The pooled OR for the crude rate of congenital malformations was 0.66 (95% CI: 0.20, 2.12; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.48) comparing patients treated with infliximab (n\u0026thinsp;=\u0026thinsp;203) and adalimumab (n\u0026thinsp;=\u0026thinsp;107). There was no significant heterogeneity observed between studies (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.38, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"5. Discussion","content":"\u003cp\u003eThe high incidence rate of inflammatory bowel disease (IBD) accounts for more than 0.3% of cases in North America and many European countries. Many patients are diagnosed with IBS as young adults, which affects the peak of fertility and family planning [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Many patients take 5-amino salicylate (5-ASA), corticosteroids, biologics, and immunosuppressants [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Female patients with active inflammatory bowel disease have an ascendant risk of developing adverse maternal and infant outcomes. Therefore, the best practice for both mothers and infants is to optimize disease control during pregnancy [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, before or during pregnancy, women often reduce or stop prescribing drugs without discussing them with their physicians [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Most patients with IBD require long-term medication to control and maintain the disease [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. All anti-TNF drugs effectively maintain clinical remission and mucosal healing in the case of infliximab and adalimumab therapy [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The Toronto [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and ECCO[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] consensus statements showed that sustained remission is important for pregnancy success. At the same time, anti-TNF therapy does not lead to adverse maternal and infant outcomes. For 5-ASA, thiopurines, or anti-TNF-α, women with well-controlled medical maintenance therapy should continue treatment throughout pregnancy. Nevertheless, patient misconceptions and unsubstantiated fears of treatment teratogenicity contribute to medication non-adherence during pregnancy and breastfeeding [\u003cspan additionalcitationids=\"CR34 CR35 CR36\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Anti-TNF therapies are reported to be effective in many high-quality placebo-controlled trials, but data comparing the effectiveness of the two drugs in clinical practice are limited. Women with IBD already in the active phase before pregnancy have a higher risk of premature birth. This is also associated with poorer fetal outcomes, including the ascendant risk of small gestational age preterm delivery and low birth weight [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Therefore, it is necessary to study the comparative safety of therapies for pregnant women with IBD. The basis for selecting anti-TNF monoclonal antibodies is not clearly stated in the consensus. Moreover, there is no evidence on the safety of infliximab and adalimumab in pregnant women with inflammatory bowel disease.\u003c/p\u003e \u003cp\u003eAlthough many regulatory bodies strongly encourage various studies to incorporate pregnant women and women of childbearing age in RCTs, pregnant and lactating women are often excluded from the trial due to unknown potential harm to the fetus. Therefore, treatment options during pregnancy often lack strong evidence-based recommendations. Safety information comes from voluntary reports of adverse events or uncontrolled observational studies during post-marketing monitoring. The current meta-analysis explored the risk of adverse pregnancy outcomes (we collected the data on preterm delivery, low birth weight, spontaneous abortion, and congenital malformations) following the infliximab and adalimumab therapy in women with IBD. 343 pregnant women with IBD who received infliximab were compared with 184 pregnant women who received adalimumab. In our study, the ORs for adverse pregnancy outcomes in IBD patients taking infliximab therapy during pregnancy compared with those taking adalimumab were 0.74 (95% CI: 0.33, 1.66). The OR of pooled crude rates of congenital malformations and spontaneous abortion were 0.81 (95% CI: 0.29, 2.25) and 0.61 (95% CI: 0.19, 1.97), respectively. However, no significant difference was observed between infliximab and adalimumab in the risk of APOs.\u003c/p\u003e \u003cp\u003eA retrospective analysis of \"real\" data from 3205 patients showed that infliximab was superior to adalimumab and certolizumab in treating CD [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In contrast, a series of recent studies in Austria showed that infliximab and adalimumab were equally effective in treating CD [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. These results were neither uniform nor different. During pregnancy, the pharmacodynamics and pharmacokinetics of many drugs changes. Infliximab and adalimumab are complete IgG1 anti-TNF monoclonal antibodies with strong anti-inflammatory effects. They are actively transferred through the placenta in exponential form through the Fc receptor from the second trimester of pregnancy. In one small study by Seow et al[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], 15 pregnant women treated with infliximab and 10 pregnant women treated with adalimumab increased infliximab levels while adalimumab levels remained stable. IgG1 is transported across the placenta more readily than other IgG subclasses, with passage increasing exponentially toward the later stages of pregnancy [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Several cohort studies, systematic reviews, and meta-analyses have reported no adverse effects of infliximab, adalimumab, or certolizumab during pregnancy. There was no increased risk of congenital malformations, preterm birth, spontaneous abortion, or low birth weight [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44 CR45 CR46 CR47 CR48\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. These observations were consistent with our study, which shows that pregnant women with IBD on infliximab and adalimumab therapy did not show the difference in the risk of APOs. Like other anti-TNFs, infliximab and adalimumab are classified as pregnancy category B (no documented human toxicity) by the US Food and Drug Administration. Infliximab is a murine/human chimeric anti-TNF- α Monoclonal antibody containing murine variable and human IgG1 constant regions. Infliximab contains 25% murine sequences, which may be related to the occurrence of adverse reactions. Adalimumab is a completely humanized anti-TNF- α Monoclonal antibody with no difference from normal human IgG1 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Infliximab and adalimumab can efficiently cross the placenta in the second and third trimesters due to their specific FcRn receptor-mediated mechanisms [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOur study had some limitations. First, the conclusions of the expert group were based on the opinions of experts and the interpretation of existing evidence. However, the evidence for certain scenarios included in the study was limited. We attempted to obtain the data on preterm delivery and low birth weight. However, some articles did not clearly distinguish between the infliximab and adalimumab groups. Thus we analyzed the risk of congenital malformations and spontaneous abortion. Secondly, our results did not rule out other factors, such as patient compliance, local drug access, or lack through the local medical level. Inevitably, clinicians need to consider the best treatment for a particular patient, considering the numerous associated factors. Although good control of disease activity during pregnancy is beneficial for a better outcome, there is no strong evidence to prove the safety of drug exposure to developing fetuses. Therefore, clinicians should be very cautious. There are still many aspects that need optimization in this field. Thus, larger prospective trials involving pregnant patients are required to establish a drug safety database. Additionally, larger RCTs research outcomes will help promote the clinical decision-making of the treatment of women with inflammatory bowel disease of childbearing age to optimize the pregnancy outcome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that there is no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFC and YH independently reviewed the title, abstract, or full text of all the identified articles. MS contacted to collect missing data or assess eligibility. Any disagreements regarding the eligibility of a study were resolved by mutual discussion (HW) or consultation with MS. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Department of gynecology and obstetrics, Women\u0026rsquo;s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, P.R. China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003e Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006,\u0026nbsp;Zhejiang Province,\u0026nbsp;P.R. China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003e Department of Gastroenterology, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, 310006,\u0026nbsp;Zhejiang Province,\u0026nbsp;P.R. China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003e Department of Internal Medicine, Women\u0026rsquo;s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, P.R. China\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTorres J, Mehandru S, Colombel JF, Peyrin-Biroulet L: \u003cstrong\u003eCrohn\u0026apos;s disease\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2017, \u003cstrong\u003e389\u003c/strong\u003e(10080):1741-1755.\u003c/li\u003e\n\u003cli\u003eKeighley MR, Stockbrugger RW: \u003cstrong\u003eInflammatory bowel disease\u003c/strong\u003e. \u003cem\u003eAliment Pharmacol Ther \u003c/em\u003e2003, \u003cstrong\u003e18 Suppl 3\u003c/strong\u003e:66-70.\u003c/li\u003e\n\u003cli\u003eGionchetti P, Dignass A, Danese S, Magro Dias FJ, Rogler G, Lakatos PL, Adamina M, Ardizzone S, Buskens CJ, Sebastian S\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003e3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn\u0026apos;s Disease 2016: Part 2: Surgical Management and Special Situations\u003c/strong\u003e. \u003cem\u003eJ Crohns Colitis \u003c/em\u003e2017, \u003cstrong\u003e11\u003c/strong\u003e(2):135-149.\u003c/li\u003e\n\u003cli\u003eSchulze H, Esters P, Dignass A: \u003cstrong\u003eReview article: the management of Crohn\u0026apos;s disease and ulcerative colitis during pregnancy and lactation\u003c/strong\u003e. \u003cem\u003eAliment Pharmacol Ther \u003c/em\u003e2014, \u003cstrong\u003e40\u003c/strong\u003e(9):991-1008.\u003c/li\u003e\n\u003cli\u003eTracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP: \u003cstrong\u003eTumor necrosis factor antagonist mechanisms of action: a comprehensive review\u003c/strong\u003e. \u003cem\u003ePharmacol Ther \u003c/em\u003e2008, \u003cstrong\u003e117\u003c/strong\u003e(2):244-279.\u003c/li\u003e\n\u003cli\u003eHanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMaintenance infliximab for Crohn\u0026apos;s disease: the ACCENT I randomised trial\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2002, \u003cstrong\u003e359\u003c/strong\u003e(9317):1541-1549.\u003c/li\u003e\n\u003cli\u003eTargan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ: \u003cstrong\u003eA short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn\u0026apos;s disease. 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An Updated and Comprehensive Review\u003c/strong\u003e. \u003cem\u003eClin Rev Allergy Immunol \u003c/em\u003e2017, \u003cstrong\u003e53\u003c/strong\u003e(1):40-53.\u003c/li\u003e\n\u003cli\u003eMahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, Ullman T, Glover S, Valentine JF, Rubin DT\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePlacental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease\u003c/strong\u003e. \u003cem\u003eClin Gastroenterol Hepatol \u003c/em\u003e2013, \u003cstrong\u003e11\u003c/strong\u003e(3):286-292; quiz e224.\u003c/li\u003e\n\u003cli\u003eKanis SL, de Lima-Karagiannis A, van der Ent C, Rizopoulos D, van der Woude CJ: \u003cstrong\u003eAnti-TNF Levels in Cord Blood at Birth are Associated with Anti-TNF Type\u003c/strong\u003e. \u003cem\u003eJ Crohns Colitis \u003c/em\u003e2018, \u003cstrong\u003e12\u003c/strong\u003e(8):939-947.\u003c/li\u003e\n\u003cli\u003eMarchioni RM, Lichtenstein GR: \u003cstrong\u003eTumor necrosis factor-\u0026alpha; inhibitor therapy and fetal risk: a systematic literature review\u003c/strong\u003e. \u003cem\u003eWorld J Gastroenterol \u003c/em\u003e2013, \u003cstrong\u003e19\u003c/strong\u003e(17):2591-2602.\u003c/li\u003e\n\u003cli\u003eDeepak P, Stobaugh DJ: \u003cstrong\u003eMaternal and foetal adverse events with tumour necrosis factor-alpha inhibitors in inflammatory bowel disease\u003c/strong\u003e. \u003cem\u003eAliment Pharmacol Ther \u003c/em\u003e2014, \u003cstrong\u003e40\u003c/strong\u003e(9):1035-1043.\u003c/li\u003e\n\u003cli\u003eLichtenstein GR, Feagan BG, Mahadevan U, Salzberg BA, Langholff W, Morgan JG, Safdi M, Nissinen R, Taillard F, Sandborn WJ\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePregnancy Outcomes Reported During the 13-Year TREAT Registry: A Descriptive Report\u003c/strong\u003e. \u003cem\u003eAm J Gastroenterol \u003c/em\u003e2018, \u003cstrong\u003e113\u003c/strong\u003e(11):1678-1688.\u003c/li\u003e\n\u003cli\u003eSedger LM, McDermott MF: \u003cstrong\u003eTNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future\u003c/strong\u003e. \u003cem\u003eCytokine Growth Factor Rev \u003c/em\u003e2014, \u003cstrong\u003e25\u003c/strong\u003e(4):453-472.\u003c/li\u003e\n\u003cli\u003eKane SV, Acquah LA: \u003cstrong\u003ePlacental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy\u003c/strong\u003e. \u003cem\u003eAm J Gastroenterol \u003c/em\u003e2009, \u003cstrong\u003e104\u003c/strong\u003e(1):228-233.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Inflammatory bowel disease, Adverse pregnancy outcomes, Infliximab, Adalimumab","lastPublishedDoi":"10.21203/rs.3.rs-2067249/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2067249/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eInflammatory 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 Crohn's disease, increasing the use of infliximab and adalimumab in clinical practice. However, it is unclear which biologics are more effective in pregnant women with IBD.\u003c/p\u003e\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eWe conducted a systematic review and meta-analysis for the risk of adverse pregnancy outcomes following treatment with infliximab and adalimumab in women with IBD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBibliographic databases were retrieved from their inception to July 2022. The results were adverse pregnancy outcomes, including congenital malformations and spontaneous abortion.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA 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.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eInfliximab and adalimumab therapy did not show the difference of risk in adverse pregnancy outcomes such as congenital malformations and spontaneous abortion.\u003c/p\u003e\u003ch2\u003eSystematic Review Registration:\u003c/h2\u003e \u003cp\u003e \u003cspan class=\"ExternalRef\"\u003e \u003cspan class=\"RefSource\"\u003ehttp://www.crd.york.ac.uk/PROSPERO\u003c/span\u003e \u003cspan address=\"http://www.crd.york.ac.uk/PROSPERO\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e \u003c/span\u003e, identifier: CRD 42021277869.\u003c/p\u003e","manuscriptTitle":"Comparative safety of infliximab and adalimumab on pregnancy outcomes of Women with Inflammatory Bowel Diseases: A Systematic Review \u0026amp; Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-26 13:28:09","doi":"10.21203/rs.3.rs-2067249/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-10-17T08:21:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-09-23T12:59:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5eb7db5b-b1e5-49e6-9d8e-29f7208a3498","date":"2022-09-23T04:34:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8a091405-1ec6-4c59-8404-d07af3d2658f","date":"2022-09-23T03:33:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-09-23T01:24:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-09-23T01:16:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-09-22T12:16:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-09-22T12:14:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2022-09-15T05:56:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f13b90a4-7bc1-44cd-9f16-3e909507d87e","owner":[],"postedDate":"September 26th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-11-07T07:59:29+00:00","versionOfRecord":[],"versionCreatedAt":"2022-09-26 13:28:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2067249","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2067249","identity":"rs-2067249","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}