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Mette Louise Andersen,1– 3 Line Riis Jølving,1,2 Egon Stenager,4,5 Torben Knudsen,4,6 Bente Mertz Nørgård1,2 1Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark; 2Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Gynecology and Obstetrics, University Hospital of Southern Jutland, Esbjerg, Denmark; 4Department of Regional Research, University of Southern Denmark, Odense, Denmark; 5Multiple Sclerosis Clinic Hospital of Southern Jutland, Aabenraa, University of Southern Denmark, Odense, Denmark; 6Department of Gastroenterology, University Hospital of Southern Jutland, Esbjerg, DenmarkCorrespondence: Mette Louise Andersen, Center for Clinical Epidemiology, Odense University Hospital, Kloevervaenget 30, Entrance 216, Odense, DK- 5000, Denmark, Email mette.louise.andersen@rsyd.dkObjective: To summarize the available literature and provide an overview of in utero exposure to maternal multiple sclerosis (MS) and the influence on offspring health outcomes.Methods: We conducted a systematic review by searching Embase, Medline and PubMed.gov databases, and we used covidence.org to conduct a thorough sorting of the articles into three groups; 1) women with MS and the influence on birth outcomes; 2) women with MS treated with disease-modifying therapy (DMT) during pregnancy and the influence on birth outcomes; and 3) women with MS and the influence on long-term health outcomes in the children.Results: In total, 22 cohort studies were identified. Ten studies reported on MS without DMT and compared with a control group without MS, and nine studies on women with MS and DMT prior to or during pregnancy met the criteria. We found only four studies reporting on long-term child health outcomes. One study had results belonging to more than one group.Conclusion: The studies pointed towards an increased risk of preterm birth and small for gestational age among women with MS. In terms of women with MS treated with DMT prior to or during pregnancy, no clear conclusions could be reached. The few studies on long-term child outcomes all had different outcomes within the areas of neurodevelopment and psychiatric impairment. In this systematic review, we have highlighted the research gaps on the impact of maternal MS on offspring health.Keywords: multiple sclerosis, pregnancy, neonatal outcomes, long-term health outcomes, reproduction

Bente Mertz Nørgård, 1–4 Michael Due Larsen, 1, 2 Sonia Friedman, 1–4 Jens Fedder 5, 6 1Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark; 2Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Crohn’s and Colitis Center, Brigham and Women’s Hospital, Boston, MA, USA; 4Harvard Medical School, Boston, MA, USA; 5Centre of Andrology and Fertility Clinic, Department D, Odense University Hospital, Odense, Denmark; 6Research Unit of Human Reproduction, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Bente Mertz NørgårdCenter for Clinical Epidemiology, Odense University Hospital, Sdr. Boulevard 29, Entrance 216, Odense C DK-5000, DenmarkTel +45 2133 3258Email bente.noergaard@rsyd.dkPurpose: Former studies have suggested that women with Crohn’s disease (CD) and ulcerative colitis (UC) have a decreased chance of a live born child after assisted reproductive technology (ART) treatment. It is debated whether corticosteroids before ART may improve outcomes, either by decreasing inflammatory bowel disease-related inflammation or increasing endometrial receptivity. We examined the efficacy of corticosteroids before embryo transfer in women with CD and UC.Patients and Methods: Our cohort study is based on nationwide Danish health registries, comprising women with CD and UC receiving an embryo transfer (1 January 2006 through 2017). Exposed cohorts constituted women with CD and UC who had received corticosteroids within three months before embryo transfer, and the unexposed cohorts women with CD and UC who did not receive corticosteroids. Our primary outcome was live birth. We controlled for multiple covariates in the analyses.Results: We examined 2408 embryo transfers. In patients with CD, 114 embryo transfers were preceded by a corticosteroid prescription, and 964 were not. The corresponding numbers in UC were 122 and 1208, respectively. The adjusted odds ratio (aOR) for live birth in women with CD receiving corticosteroids before embryo transfer, relative to women with CD not receiving corticosteroids, was 0.89 (95% CI 0.49– 1.63). The corresponding aOR in UC was 0.98 (95% CI 0.55– 1.74).Conclusion: Corticosteroids prior to ART in women with CD and UC did not increase the chance of a live born child. The exact impact of corticosteroids prior to embryo transfer in patients with CD and UC still remains to be determined.Keywords: corticosteroids, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, assisted reproductive technology, ART, assisted reproduction

Line Riis Jølving,1,2 Michael Due Larsen,1,2 Jens Fedder,3,4 Sonia Friedman,1,2,5,6 Bente Mertz Nørgård1,2,5,61Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark; 2Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Centre of Andrology and Fertility Clinic, Department D, Odense University Hospital, Odense, Denmark; 4Research Unit of Human Reproduction, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Crohn’s and Colitis Center, Brigham and Women’s Hospital, Boston, MA, USA; 6Division of Gastroenterology, Hepatology and Endoscopy Research, Harvard Medical School, Boston, MA, USAPurpose: Women with thyroid disorders may have increased infertility and poor reproductive outcomes, but it is unclear if assisted reproductive technology (ART) is effective in this population. The aim of this study was to examine the chance of a pregnancy (biochemical and clinical), and a live birth after ART, in women with thyroid disorders undergoing ART treatment, compared to women without thyroid disorders. Among live-born children, we assessed the risk of congenital malformations.Patients and methods: In a nationwide cohort study of all women undergoing ART treatments in Denmark from 1 January 1994 throughout June 2017, we calculated the chance of a pregnancy and a live birth after embryo transfer. Women with thyroid disorders were stratified into two groups: those diagnosed with hypothyroid or hyperthyroid disorders. The adjusted OR (aOR) of a biochemical and a clinical pregnancy, a live born child and a congenital malformation was computed using multilevel logistic regression models.Results: In total, 199,674 embryo transfers were included in 2,101 women with thyroid disorders and in 65,526 women without thyroid disorders. The chance of a biochemical pregnancy was significantly reduced in women with hyperthyroidism (aOR=0.80, 95% CI 0.69–0.93), and the aOR of a live birth was 0.86, 95% CI 0.76–0.98. The aOR for a live birth in women with hypothyroidism was 1.03 (95% CI 0.94–1.12). Children of women with hypothyroidism, who were conceived after ART treatment, had a significantly increased risk of any congenital malformation (aOR=1.46 [95% CI 1.07–2.00]).Conclusion: Women with hyperthyroidism receiving ART treatment had a decreased chance of a live birth per embryo transfer compared to women without thyroid disorders. Women with hypothyroidism did not have a decreased chance of a live birth but their offspring had an increased risk of congenital malformation.Keywords: assisted reproductive technology, in vitro fertilization, hyperthyroidism, hypothyroidism, clinical epidemiology

Line Riis Jølving,1,2 Jan Nielsen,1,2 Ulrik Schiøler Kesmodel,3,4 Rasmus Gaardskær Nielsen,2,5 Bente Mertz Nørgård,1,2 Signe Sparre Beck-Nielsen6,7 1Center for Clinical Epidemiology, Odense University Hospital, 2Institute of Clinical Research, University of Southern Denmark, Odense C, 3Department of Obstetrics and Gynaecology, Herlev University Hospital, Herlev, 4Institute for Clinical Medicine, University of Copenhagen, København, 5Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense C, 6Department of Pediatrics Kolding, Hospital Lillebaelt, Kolding, 7Department of Regional Health Research, University of Southern Denmark, Odense C, Denmark Objective: Maternal thyroid disease (TD) during pregnancy is associated with adverse birth outcomes, but little is known on its long-term outcomes. We aimed to examine if children born to mothers with TD have increased disease risk during childhood and adolescence. Patients and methods: A register-based cohort study was conducted on all live born children in Denmark from 1989 to 2013, including the association between maternal TD during pregnancy and somatic and psychiatric diseases in the children. Cox proportional hazards models were used to compute hazard ratios (HRs) according to the type of maternal TD, Graves’ disease, and Hashimoto’s thyroiditis. Results: A total of 2,618 children were born to women with Graves’ disease, 760 to women with Hashimoto’s thyroiditis (exposed), and 1,557,577 to women without any TD (unexposed). The median follow-up time for children born to mothers with Graves’ disease was 9.3 years (25/75 percentile 5.4/13.9 years) and with Hashimoto’s thyroiditis was 4.8 years (25/75 percentile 2.5/8.2 years). In children exposed to maternal Graves’ disease in utero, the adjusted HR of TD was 12.83 (95% CI, 9.74–16.90), Graves’ disease was 34.3 (95% CI, 20.23–58.35), and type 1 was diabetes 2.47 (95% CI, 1.46–4.18). In children exposed to maternal Hashimoto’s thyroiditis, the adjusted HR of Hashimoto’s thyroiditis was 24.04 (95% CI, 5.89–97.94). Conclusion: Our data suggest that children born to women with Graves’ disease and Hashimoto’s thyroiditis have excess long-term morbidities in childhood and adolescence. We particularly found an increased risk of any TD and type 1 diabetes to be diagnosed in children exposed in utero to Graves’ disease. These novel findings are relevant for pediatricians, stressing the importance of history of maternal disease when evaluating children with suspected endocrine disorders. Keywords: thyroid disease, Graves’ disease, Hashimoto’s thyroiditis, reproduction, child morbidity, clinical epidemiology