Children born preterm or small for gestational age to mothers with multiple sclerosis: Do these children have an increased risk of infections in early life?

BACKGROUND: Mothers with multiple sclerosis are at increased risk of preterm birth and small for gestational age infants. Both conditions pose a risk of morbidity, including early-life infections. OBJECTIVE: This study aimed to assess the risk of infections in the first 3 years of life among children born preterm or small for gestational age to mothers with multiple sclerosis. METHODS: We used Danish national health registers to establish the study cohort of all births by women with MS born from 1995 to 2023. In Cox regression models, we estimated hazard ratios (HRs) of infections in preterm or small for gestational age children. RESULTS: Preterm children had an adjusted HR of 1.49 (95% confidence interval (95% CI) 1.15-1.93) for hospital-diagnosed infection and 0.88 (95% CI 0.72-1.06) for antibiotic prescriptions. Small for gestational age children had an adjusted HR of 0.81 (95% CI 0.54-1.22) for hospital-diagnosed infection and 1.07 (95% CI 0.82-1.38) for antibiotic prescriptions. CONCLUSION: Children born preterm to mothers with multiple sclerosis had an increased risk of hospital-diagnosed infections in the first 3 years of life, but not of mild-to-moderate infections evaluated on prescriptions. Children born small for gestational age did not have an increased risk of infections.

Paternal use of selective serotonin reuptake inhibitors and adverse health outcomes: A nationwide cohort study on 13,547 exposed children.

BACKGROUND: The use of selective serotonin reuptake inhibitors (SSRIs) has increased over time. Several studies indicate that paternal use of medication may adversely affect the developing fetus. Only a few studies have investigated the association between preconceptional paternal exposure to SSRIs and the risks of adverse health outcomes in children. OBJECTIVES: This study aimed to assess adverse birth outcomes and adverse early life events in children fathered by men using SSRIs prior to conception. MATERIALS AND METHODS: All live-born singleton children born in Denmark from 1997 until 2019 and their parents were included. The exposed cohort comprised all children fathered by men using SSRIs 3 months prior to conception and the unexposed cohort comprised all other children. We estimated the odds ratios for adverse birth outcomes: small for gestational age (SGA), preterm birth, low Apgar score, and major congenital malformations. Furthermore, we estimated the hazard ratios for adverse early life events of infections and hospitalizations within 1 year from birth. We also examined adverse birth outcomes and the adverse early life events according to SSRI subgroups. RESULTS: There was a statistically significantly increased odds ratio 1.15 (confidence interval, CI: 1.06-1.23) for preterm birth. No significant results were found for SGA, low Apgar score, and major congenital malformations. The adjusted hazard ratios for hospitalizations and infections were 1.06 (CI: 1.02-1.11) and 1.02 (CI: 0.97-1.07), respectively. There was a statistically significantly increased odds ratio for preterm birth with respect to the SSRI subgroups citalopram and escitalopram, and for hospitalizations with respect to citalopram. DISCUSSION AND CONCLUSION: Although the risks of certain adverse birth and adverse early life outcomes were statistically significantly increased, the ratios were small and may have limited clinical importance. Paternal use of SSRI was in general safe in the preconceptual period.

Neonatal outcomes in women with Multiple Sclerosis - Influence of disease activity: A Danish nationwide cohort study.

BACKGROUND: Maternal Multiple Sclerosis (MS) has been associated with an increased risk of adverse birth outcomes. We hypothesized that active disease during conception and pregnancy plays an important role in this context, which this study aims to address. METHODS: We used the Danish registers to conduct a nationwide cohort study. Information on maternal disease activity during pregnancy was retrieved using proxies from the linked registers (hospitalization, magnetic resonance imaging of the brain, and use of systemic corticosteroids during pregnancy). Neonates, exposed in utero to maternal disease activity constituted the exposed cohort and the unexposed cohort constituted neonates without in utero exposure to maternal disease activity. The examined outcomes were preterm birth, small for gestational age, low 5-minute Apgar score, and major congenital anomalies. In logistic regression models we estimated the odds ratios (OR) with adjustment for confounders such as maternal age, comorbidities, parity, smoking, calendar year of birth, and disease-modifying treatment. RESULTS: Among the study population of 2492 children of mothers with MS we identified 273 (11 %) neonates exposed to maternal disease activity during pregnancy, and 2219 (89 %) neonates without exposure to disease activity. The adjusted odds ratios (aOR) for preterm birth, small for gestational age, low 5-minute Apgar score, and major congenital anomalies among children born to women with disease activity during pregnancy were 0.92 (95 % confidence interval (95 % CI) 0.53-1.60), aOR 1.19 (95 % CI 0.62-2.26), aOR 2.57 (95 % CI 0.93-7.15) and aOR 0.93 (95 % CI 0.48-1.83), respectively. CONCLUSIONS: Women with MS having disease activity during pregnancy did not have a statistically significantly increased risk of adverse neonatal outcomes compared to women with MS without disease activity, which is overall reassuring results. We believe, that this will be useful knowledge for patients and clinicians in planning a pregnancy and preparing a birth plan.

Children and Adolescents Diagnosed With Inflammatory Bowel Disease Are at Increased Risk of Developing Diseases With a Possible Autoimmune Pathogenesis.

BACKGROUND: The development of diseases with a possible autoimmune pathogenesis is common in adults with inflammatory bowel disease (IBD). In early onset IBD, it may differ but the evidence is sparse. We aimed to investigate the risk and time span from IBD diagnosis to outcomes with different associated disorders with possible autoimmune pathogenesis. METHODS: A register-based study included all Danish patients with early onset of IBD (≤18 years) between 1980 and 2021 and 50 matched references without IBD for each case. We examined the risk of type 1 and type 2 diabetes, celiac disease, thyroid disease, rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis in Cox regression models. RESULTS: In total, 6822 patients with IBD were identified, and 337 728 matched references. The median age at the time of IBD diagnosis or index date for the matched references was 16 years (25-75 percentile: 13-18 years), and the median age at the time of an outcome or at the end of follow-up was 28.1 years (25-75 percentile: 21.5-37.0 years). According to the cumulative incidence plots psoriatic arthritis, and spondyloarthritis was diagnosed approximately 10 years after the IBD onset, and the remaining outcomes later. The adjusted hazard ratio after full follow-up was 4.72 (95% CI, 3.85-5.80) for psoriatic arthritis, 5.21 (95% CI, 4.17-6.50) for spondyloarthritis, 2.77 (95% CI, 1.92-4.00) for celiac disease, 2.15 (95% CI, 1.54-3.01) for rheumatoid arthritis, 1.69 (95% CI, 1.23-2.32) and 1.64 (95% CI, 1.21-2.21) for type 1 and type 2 diabetes, respectively. For thyroid disease, it was 1.16 (95% CI, 0.97-1.40). CONCLUSIONS: The risk estimates were significantly increased for all outcomes at the end of follow-up, except for thyroid disease, but according to the cumulative incidence plots, only psoriatic arthritis and spondyloarthritis occurred earlier in the IBD cohort than in the matched references.

Children and adolescents diagnosed with inflammatory bowel disease are at increased risk of developing several diseases with possible autoimmune pathogenesis compared with a matched reference group. Cumulative incidence curves showed that psoriatic arthritis and spondyloarthritis debut in young adulthood when compared with a matched reference group without IBD.

Paternal preconception exposure to non-steroid anti-inflammatory drugs or opioids and adverse birth outcomes: A nationwide registry-based cohort study.

BACKGROUND AND AIM: Paternal use of analgesics during the time of conception and adverse birth outcomes are poorly studied. We investigated the association between paternal exposure to non-steroid anti-inflammatory drugs and opioids within 3 months before the date of conception and the risk of adverse birth outcomes (preterm birth, small for gestational age, low Apgar score, and major congenital malformations). METHODS: We used nationwide data from the Danish health registers. We included information on all singleton live births, and their fathers and mothers from 1997 to 2018. We created two exposed cohorts, children with preconception paternal exposure to (1) non-steroid anti-inflammatory drugs and (2) opioids. The unexposed cohort was children without preconception paternal exposure to non-steroid anti-inflammatory drugs or opioids, and we performed a sub-analysis against paternal use of acetaminophen (paracetamol). We used logistic regression models to estimate the odds ratios of adverse birth outcomes including 95% confidence intervals. RESULTS: We identified 1,260,934 children, 45,667 children with paternal exposure to non-steroid anti-inflammatory drugs, 10,086 children with paternal exposure to opioids, and 1,205,181 unexposed children. The adjusted odds ratio for preterm birth was 1.08 (95% confidence interval, 1.03-1.13) after paternal exposure to non-steroid anti-inflammatory drugs and 1.21 (95% confidence interval, 1.08-1.35) after paternal exposure to opioids. The adjusted odds ratio for small for gestational age was 1.09 (95% confidence interval, 1.03-1.17) after paternal exposure to non-steroid anti-inflammatory drugs, and 1.03 (95% confidence interval, 0.88-1.21) after paternal exposure to opioids. We found null-associations for a low Apgar score and major congenital malformations. Estimates were attenuated when compared against paternal paracetamol exposure. CONCLUSIONS: Overall, we found null-associations across the comparisons made. Weak associations were found for paternal exposure to non-steroid anti-inflammatory drugs or opioids and preterm birth and small for gestational age, but not with low Apgar score or major congenital malformation. All associations were attenuated when compared against an active comparator of paternal paracetamol exposure. The effect sizes were small and less likely to be of clinical relevance.

Patients with multiple sclerosis: COVID-19 related disease activity and hospitalisations based on a nationwide cohort study.

BACKGROUND: It has not previously been clarified if COVID-19 triggers disease activity and increases the risk of hospitalisation with COVID-19 in patients with multiple sclerosis. We examined the association between COVID-19 and the use of systemic corticosteroids prescriptions and hospital contacts at neurological departments as proxies of disease activity among patients with multiple sclerosis. Furthermore, we examined whether patients with multiple sclerosis were more likely to be hospitalised with COVID-19 compared to references. METHODS: This study was based on nationwide health registries with data on the Danish population of 2,222,946 individuals with a positive COVID-19 PCR test. To study disease activity our study population consisted of all patients with multiple sclerosis and a positive COVID-19 PCR test. Our proxies for disease activity were compared after versus before a positive COVID-19 PCR test using a binomial regression model. Adjustments were made for age, sex, comorbidity, length of multiple sclerosis diagnosis, calendar period, vaccination, and immunomodulatory treatment. To study the risk of hospitalisation with COVID-19 in patients with multiple sclerosis our study population here consisted of all Danish citizens with a COVID-19 positive PCR test. In logistic regression models we estimated odds ratio (OR) for hospitalisation with COVID-19 in patients with multiple sclerosis relative to patients affected with other autoimmune diseases (inflammatory bowel disease/rheumatoid arthritis), and relative to individuals from the general population. Adjustments were made for age, sex, comorbidity, vaccination, and calendar period. To examine the impact of disease-modifying treatment, the risk of hospitalisation with COVID-19 was estimated in those with disease-modifying treatment versus those without any disease-modifying treatment. RESULTS: We included 7358 patients with multiple sclerosis and a positive COVID-19 PCR test. The adjusted incidence rate ratio (aIRR) for having corticosteroid prescriptions after COVID-19 in patients with multiple sclerosis was 0.93 (95 % CI 0.78 - 1.10), and the aIRR for hospital contacts at neurological departments/admissions with multiple sclerosis as primary diagnosis after COVID-19 infection was 1.10 (95 % 1.00-1.22). Adjusted OR (aOR) for hospitalisation with COVID-19 in the 30 days after a positive COVID-19 PCR test was 3.21 (95 % CI 2.75-3.74) compared to patients with other autoimmune diseases and the aOR was 5.34 (95 % CI 4.65-6.14) for patients with multiple sclerosis compared to all other individuals in the general population with a positive test. We found no increased risk of hospitalisations with COVID-19 in patients with multiple sclerosis using disease-modifying treatment 6 months prior to a positive COVID-19 PCR test compared to patients with multiple sclerosis without disease-modifying treatment (aOR 0.94 (95 % CI 0.69-1.27)). CONCLUSIONS: In this nationwide cohort of patients with multiple sclerosis, COVID-19 did not seem to trigger multiple sclerosis disease activity (based on proxy variables). We found a significantly increased risk of being hospitalised with COVID-19 in the first 30 days after a positive COVID-19 PCR test in patients with multiple sclerosis irrespective of the type of reference population. In patients with multiple sclerosis, the use of disease-modifying treatment did not increase the risk of hospitalisation with COVID-19.

A population-based nationwide study on total colectomy for ulcerative colitis and risk of ten prevalent inflammatory or autoimmune diseases.

BACKGROUND: There is growing evidence to support a role of the gut microbiome in the development of chronic inflammatory and autoimmune disease (IAD). We used total colectomy (TC) for ulcerative colitis (UC) as a model for a significant disruption in gut microbiome to explore an association with subsequent risk of IAD. METHODS: We identified all patients with UC and no diagnosis of IAD prior to their UC diagnosis in Denmark from 1988 to 2015. Patients were followed from the date of UC to a diagnosis of IAD, death or end of follow-up, whichever occurred first. We used Cox regression to estimate hazard ratios (HRs) of IAD associated with TC, adjusting for age, sex, Charlson Comorbidity Index, and calendar year of UC diagnosis. RESULTS: 30,507 patients with UC (3,155 with TC and 27,352 without) were identified from the Danish National Patient Registry. During 43,266 person-years of follow-up, 2733 patients were diagnosed with an IAD. The risk of any IAD was higher for patients with TC compared to patients without (adjusted HR [aHR] 1.39 (95% CI: 1.24-1.57)). When the analyses were adjusted for exposure to antibiotics, immunomodulatory medicine and biologics (covering 2005-2018), the risk of IAD was still higher for patients with total colectomy (aHR = 1.41 (95% CI: 1.09;1.83)). Disease-specific analyses were weakened by a low number of outcomes. CONCLUSIONS: The risk of IAD was higher for patients who underwent TC for UC compared to patients who did not.KEY MESSAGESWhat is already known?o The gut microbiome plays an important role in host immune homeostasis, and changes in gut bacterial diversity and composition may change the individual's risk of inflammatory and autoimmune disease (IAD).What is new here?o Patients with ulcerative colitis who undergo total colectomy have a higher risk of being diagnosed with IAD, compared to patients with ulcerative colitis who do not undergo total colectomy.How can this study help patient care?o Future research can help uncover the mechanisms responsible for the higher risk of certain IADs after total colectomy. If the microbiome plays a role, modifying the gut microbiome could prove a viable therapeutic strategy to reduce the risk of developing IADs.

In this nationwide Danish cohort study of all Danish UC patients diagnosed in the period from 1988 to 2015, the risk of being diagnosed with inflammatory and autoimmune disease is higher for patients who underwent total colectomy compared to UC patients without total colectomy.

Assisted Reproductive Technology Results Using Donor or Partner Sperm: A Danish Nationwide Register-Based Cohort Study.

This was a nationwide cohort study based on Danish health registers focusing on assisted reproductive technology (ART) treatments in women using donor or partner sperm from 2007 to 2017. Women using donor sperm were subdivided into groups based on relationship status: women with male partners, single women, or women with female partners. The live birth adjusted odds ratios (aORs) after the IUI treatments in women using donor sperm compared with women using partner sperm were 1.48 (95% CI: 1.38-1.59) in women with male partners using donor sperm, 1.20 (95% CI: 1.13-1.28) in single women, and 1.46 (95% CI: 1.32-1.62) in women with female partners. The live birth aORs after IVF treatments in women using donor sperm compared with women using partner sperm were 1.16 (95% CI: 1.02-1.32) in women with male partners using donor sperm, 0.88 (95% CI: 0.80-0.96) in single women, and 1.20 (95% CI: 1.00-1.44), in women with female partners. The use of donor sperm was associated with a higher chance of a live birth after the IUI treatments, but there was no difference after the IVF treatments. Our study invites healthcare professionals to increase their attention toward the different needs and fertility issues of all women attending fertility clinics.

Adverse birth outcomes and early-life infections after in utero exposure to corticosteroids for inflammatory bowel disease: a Danish nationwide cohort study.

BACKGROUND: Systemic corticosteroids are often used to treat inflammatory bowel disease (IBD) flares during pregnancy as maintenance of disease remission is crucial to optimize pregnancy outcomes. However, there is little data regarding the effect of in utero exposure to corticosteroids on the risk of adverse birth outcomes and early-life infections in the offspring. METHODS: We used the Danish national registries to establish a nationwide cohort of all singleton live births in women with IBD from 1995 to 2015. Outcomes in children exposed in utero to corticosteroids were compared to those who were not exposed. In logistic and Cox proportional hazard regression models, we adjusted the outcomes (major congenital malformation, preterm birth, small for gestational age, low 5-min Apgar score, and infections) for confounders such as body mass index, smoking, comorbidity, and additional medical IBD treatment. RESULTS: After in utero exposure to corticosteroids at any time between 30 days prior to conception through the first trimester (n = 707), the adjusted hazard ratio of major congenital malformation was 1.28 (95% CI: 0.82-2.00) compared to children born to women with IBD, but not exposed to corticosteroids in utero (n = 9371). After in utero exposure to corticosteroids at any time during pregnancy (n = 1336), the adjusted odds ratios for preterm birth, small for gestational age, and low 5-min Apgar score were 2.45 (95% CI: 1.91-3.13), 1.21 (95% CI: 0.76-1.90), and 0.91 (95% CI: 0.33-2.52), respectively. Finally, the adjusted hazard ratio of overall infections in the first year of life was 1.14 (95% CI: 0.94-1.39). CONCLUSIONS: This nationwide cohort study suggests that children of women with IBD exposed to corticosteroids in utero had an almost 2.5-fold increased risk of preterm birth. Use of corticosteroids is closely related to disease activity and we cannot adjust for the independent role of disease activity. It is however reassuring that the other examined birth and early-life outcomes were not statistically significantly increased.

Maternal Multiple Sclerosis and Health Outcomes Among the Children: A Systematic Review.

Objective: 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.

Increased Risk of Postpartum Infections After Caesarian and Vaginal Delivery in Women With Inflammatory Bowel Disease: A Danish Nationwide Cohort Study.

BACKGROUND: There is lack of knowledge concerning postpartum infections in women with inflammatory bowel disease (IBD). Our aim is to determine the 30-day postpartum infectious complications in women with and without IBD who have a caesarian section, normal vaginal delivery, or assisted vaginal delivery. METHODS: We used Danish national registries to establish a study population of liveborn, singleton births from January 1, 1997, through December 31, 2015. We examined 30-day postpartum maternal infectious complications in women with and without IBD, according to the mode of delivery. Statistical models were adjusted for multiple confounders. RESULTS: In all, 3255 women with and 207 608 without IBD had a caesarian section. Within 30 days postpartum, 4.5% of women with and 3.7% without IBD had an infectious complication. Increased infectious complications included overall infections (adjusted OR [aOR], 1.83; 95% confidence interval [CI], 1.35-2.47), infections of the gastrointestinal tract (aOR, 4.36, 95% CI 2.34-8.10), and infections of the skin and subcutaneous tissue (aOR, 4.45; 95% CI, 2.30-8.50). Other puerperal infections, urological and gynecological, and other infections were increased, although not significantly. For vaginal deliveries, 1.6% of 5771 women with IBD and 1.3% of 793 110 women without IBD had an infectious complication, and the aOR of infections of the gastrointestinal tract was 3.17 (95% CI, 1.47-6.85). There were too few outcomes to calculate the risk of infections after assisted vaginal delivery. CONCLUSIONS: The risk of a 30-day postpartum infectious complication is increased in women with IBD. Physicians should carefully monitor their patients postpartum to prevent these adverse outcomes.

Women with inflammatory bowel disease who have a caesarean section or a vaginal delivery are at increased risk for infections within the 30-day postpartum period. Physicians should be aware of this increased risk and work to minimize infectious complications after delivery.

Adverse Birth and Child Outcomes in Children Fathered by Men Treated with Antidiabetics Prior to Conception: A Nationwide Cohort Study.

BACKGROUND: The safety of fathers' use of antidiabetic drugs in terms of child outcomes is an important clinical question. We aimed to assess the risk of adverse birth and early childhood outcomes after fathers' use of antidiabetics prior to conception. METHODS: A nationwide cohort study based on Danish health registries. The study comprised all live born singleton children in Denmark (1997 through 2018). Children were categorized according to fathers' filled prescriptions for antidiabetic drugs three months prior to conception. Exposed cohorts: children born after paternal use of insulin or non-insulin anti-hyperglycemic agents. The unexposed constituted children born by fathers not treated with antidiabetics prior to conception. We examined adverse birth outcomes (preterm birth, small for gestational age (SGA)), and adverse childhood outcomes in the first year of life (major congenital malformations (MCMs), and infections diagnosed at a hospital). RESULTS: A total of 1,318,684 children were included. In all, 5527 children were born after paternal use of insulin, 2121 after use of non-insulin anti-hyperglycemic agents, and 1,311,036 were unexposed. After fathers' use of insulin we did not find increased risk of adverse outcomes. After fathers' use of metformin, the adjusted OR of MCMs was 1.40 (95% CI 1.11-1.76). After fathers' use of sulfonylureas, the adjusted OR of SGA was 1.80 (95% CI 1.11-2.93), and for child gastrointestinal infections the adjusted HR was 1.76 (95% CI 1.04-2.99). CONCLUSIONS: Fathers' use of insulin was reassuring. Metformin and sulfonylureas were associated with selected adverse outcomes. Our findings suggest an additional 14 MCMs per 1000 fathers exposed to metformin prior to conception. As there is no meaningful supporting biological rationale, these findings should be confirmed in a different population prior to clinical consequences being drawn.

The impact of medical therapies and factors related to treatment procedures in women with rheumatoid arthritis and inflammatory bowel disease receiving assisted reproduction: a nationwide cohort study.

OBJECTIVE: To examine whether medications used to treat rheumatoid arthritis (RA)/chronic inflammatory bowel disease (IBD), or factors related to the assisted reproductive technology (ART) procedures, impact the success of ART. In women with RA/IBD, initial studies have shown a reduced chance of a live-born child after ART. DESIGN: Cohort study. SETTING: Nationwide Danish health registries. PATIENTS: All Danish women with a fresh embryo transfer from January 1, 2006, through 2018. The cohorts comprised 1,824 embryo transfers in women with RA/IBD and 97,191 embryo transfers in women without RA/IBD. INTERVENTIONS: Observational, noninterventional study. MAIN OUTCOME MEASURE: Live birth per fresh embryo transfer. RESULTS: The chance of a live birth in women with RA/IBD receiving ART, compared with other women receiving ART, had an adjusted odds ratio (OR) of 0.79 (95% confidence interval [CI], 0.68-0.91). Prescribed corticosteroids before embryo transfer were positively associated with a live-born child (adjusted OR, 1.21; 95% CI, 1.12-1.31), while the use of antiinflammatory/immunosuppressive agents did not have significant importance. Intracytoplasmic sperm injection was associated with a reduced chance (adjusted OR, 0.94; 95% CI, 0.90-0.97). Type of hormone treatment protocol did not have significant importance, and transfer at the blastocyst stage was positively associated with a live-born child (adjusted OR, 1.54; 95% CI, 1.46-1.62). CONCLUSIONS: In women with RA and/or IBD, prescribed corticosteroid before embryo transfer and embryo transfer at the blastocyst stage were associated with successful ART. Intracytoplasmic sperm injection was associated with a slightly reduced chance. Antiinflammatory/immunosuppressive agents and type of hormone protocols did not have significant importance.

The risk of chronic diseases and congenital malformations during childhood and adolescence after in utero exposure to thiopurines.

BACKGROUND: Women with autoimmune diseases, particularly inflammatory bowel disease (IBD), often need to continue immunomodulatory therapies during pregnancy. While the evidence of birth and short-term outcomes in children exposed in utero to these medicines is reassuring, long-term safety data are lacking. AIM: To assess any association between in utero exposure to thiopurines and diagnoses of chronic diseases (type 1 diabetes, coeliac disease, thyroid disease, rheumatoid arthritis, IBD and asthma) and congenital malformations during childhood and adolescence. METHODS: This nationwide cohort study was based on information using Danish registers and comprised all live-born children from 1995 to 2015 (N = 1 308 778). Children exposed in utero to thiopurines were followed for a median of 8.9 years (25%-75% percentiles 5.5-12.4 years); children not exposed were followed for 13.9 years (25%-75% percentiles 8.7-19.0 years). Analyses were adjusted for a number of confounders including the type of maternal underlying disease. RESULTS: A total of 1047 children had been exposed to thiopurines in utero; 96 developed a chronic disease and 126 were diagnosed with congenital malformations during follow-up. The adjusted hazard ratio for rheumatoid arthritis was 0.78 (95% CI 0.35-1.73); for IBD, it was 1.45 (95% CI 0.64-3.27); for asthma 0.94 (95% CI 0.73-1.21), and for congenital malformations, it was 0.95 (95% CI 0.78-1.15). For type 1 diabetes, coeliac disease, thyroid disease and ulcerative colitis, we had insufficient data to perform adjusted analysis. CONCLUSION: We found no increased risk of seven common chronic diseases or congenital malformations during childhood and adolescence after gestational exposure to thiopurines.

The Efficacy of Assisted Reproduction in Women with a Wide Spectrum of Chronic Diseases - A Review.

Assisted reproductive technology (ART) treatments in women with underlying chronic diseases have become increasingly frequent. The objective of this review is to provide an overview of the literature examining the chance of having a live born child after ART in women with chronic diseases, compared to other women receiving ART. We focused on some of the most prevalent chronic diseases in women during their reproductive years, ie ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, epilepsy, hyperthyroidism, hypothyroidism, and diabetes mellitus. Secondly, we studied the chance of successful implantation. The literature search was performed in the database Pubmed.gov. including all studies published before October 2020. Title and abstracts of 58 papers were reviewed, 37 papers were excluded and other 8 studies were excluded after full-text evaluation. Only 13 papers were eligible for review. Results indicate that women with ulcerative colitis, Crohn's disease, rheumatoid arthritis, hyperthyroidism, and diabetes mellitus type 2 might have problems with low implantation rate or early embryo development during ART. On the contrary, the few studies on women with hypothyroidism, diabetes mellitus type 1, and epilepsy suggest an equivalent chance of a live birth compared to other women undergoing ART. A possible explanation behind these differences could reside in the disease-specific dysregulation of the innate or adaptive immune system. To our knowledge, this is the first review on ART in women with chronic diseases, and it has disclosed that the evidence in this area is indeed sparse. We encourage others to examine live birth after ART in women with chronic diseases.

The Danish National Register of assisted reproductive technology: content and research potentials.

The Danish National Register of assisted reproductive technology (ART) was initially established in 1994. The register comprises complete information on all ART procedures in public and private clinics in Denmark from 2013 and onwards, including baseline information on the cause of infertility and a number of health-related patient characteristics. The register enables monitoring and research on infertility treatment and reproductive topics in single women or couples seeking assisted reproduction, and the register is thus a key component of the Danish health information system within human reproduction. We aimed to provide an updated description of the register including advantages and pitfalls when using the register for reproductive epidemiological research, and a description of the accessibility for researchers. The Danish ART register is a valuable tool for epidemiological research. However, the inherent strengths and limitations ought to be in perspective when designing studies and interpreting the study results. Reports with annually aggregated data on ART treatments, can be accessed on the Danish Health Data Authority web page and researchers may obtain access to individual pseudonomized data via secure servers at the Danish Health Data Authority and Statistics Denmark.

Hospitalization for COVID-19 in patients treated with selected immunosuppressant and immunomodulating agents, compared to the general population: A Danish cohort study.

AIMS: In the Danish population, we examined whether patients treated with thiopurines, methotrexate, systemic corticosteroids, anti-tumour necrosis factor (TNF)-α agents, anti-interleukin therapeutic agents, selective immunosuppressive agents and cyclosporine/tacrolimus had an increased risk of hospitalization for COVID- 19, compared to the background population. METHODS: A nationwide cohort study including all people alive in Denmark on 1 March 2020. Exposed patients constituted those exposed to thiopurines (n = 5484), methotrexate (n = 17 977), systemic corticosteroids (n = 55 868), anti-TNF-α agents (n = 17 857), anti-interleukin therapeutic agents (n = 3744), selective immunosuppressive agents (n = 3026) and cyclosporine/tacrolimus (n = 1143) in a period of 12 months prior to 1 March 2020 (estimated time of outbreak in Denmark). We estimated the adjusted risk of hospitalization for COVID-19 for patients treated with the above-mentioned categories of medications, compared to the rest of the population. RESULTS: The adjusted odds ratios of hospitalization in patients treated with corticosteroids and cyclosporine/tacrolimus were 1.64 (95% confidence interval [CI] 1.35 to 2.00) and 4.75 (95% CI 1.96 to 11.49), respectively. The risks of hospitalization in patients treated with thiopurines, methotrexate, and anti-TNF-α agents, were 1.93 (95% CI 0.91 to 4.08), 0.74 (95% CI 0.43 to 1.28), 1.00 (95% CI 0.52 to 1.94), respectively. The number of outcomes in patients treated with anti-interleukin therapeutic agents and selective immunosuppressive agents was too small for analysis. CONCLUSION: Patients treated with systemic corticosteroids and cyclosporine/tacrolimus had a significantly increased risk of being hospitalized for COVID-19. Our study does not uncover whether the increased risk is related to the drug itself, the underlying condition for which the patient is treated or other factors.

The efficacy of assisted reproductive treatment in women with epilepsy.

RESEARCH QUESTION: The question of interest for this study was to examine the chance of a live birth following assisted reproductive technology (ART) treatment in women with epilepsy compared with women without epilepsy. In sub-analyses, the chance of biochemical and clinical pregnancies, and the impact of antiepileptic drugs (AED) treatment prior to embryo transfer, was analysed. DESIGN: This register-based cohort study was based on the Danish ART register comprising all women who underwent embryo transfer during 2006 to 2017, which included 730 ART treatments in 264 women with a history of epilepsy, and 128,387 ART treatments in 42,938 women without epilepsy. Adjustments were made for comorbidity, women's age, calendar year, type of infertility treatment and cause of infertility. A possible impact of AED use at the time of embryo transfer was studied in a sub-analysis. The primary outcome was live birth within a period of 140-308 days after the date of embryo transfer. RESULTS: The adjusted odds ratio for a live birth per embryo transfer in women with epilepsy, relative to women without epilepsy, was 1.06 (95% confidence interval [CI] 0.88-1.28). The adjusted odds ratio for a live birth among users of an AED was 1.22 (95% CI 0.77-1.92) relative to women who had stopped the use of AED prior to embryo transfer. CONCLUSIONS: The chances of a live birth per embryo transfer were similar in women with and without epilepsy. These are novel and reassuring findings on the efficacy of infertility treatment in women with epilepsy.

Live-born children after assisted reproduction in women with type 1 diabetes and type 2 diabetes: a nationwide cohort study.

AIMS/HYPOTHESIS: Type 1 and type 2 diabetes are among the most prevalent chronic diseases in women in the fertile years and women with diabetes may experience several reproductive issues. We aimed to examine the chance of biochemical pregnancy, clinical pregnancy and live birth after assisted reproductive technology (ART) treatment in women with type 1 and type 2 diabetes and whether obesity per se influenced the results. METHODS: This nationwide register-based cohort study is based on the Danish ART Registry comprising 594 women with either type 1 diabetes or type 2 diabetes from 2006 to 2017. RESULTS: Relative to women without diabetes, the adjusted OR (95% CI) of a live birth per embryo transfer was 0.50 (0.36, 0.71) in women with type 2 diabetes and 1.10 (0.86, 1.41) in women with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our data on the efficacy of ART treatment in women with type 1 and type 2 diabetes is the first in this field. When compared with women without diabetes, women with type 1 diabetes had an equivalent chance of a live birth per embryo transfer whereas women with type 2 diabetes had a reduced chance. The findings in women with type 2 diabetes did not seem to be driven by obesity per se as the same pattern was seen in both normal-weight and obese women. Graphical abstract.

Long-term Motor and Cognitive Function in the Children of Women With Inflammatory Bowel Disease.

INTRODUCTION: Research on long-term outcomes of children exposed to inflammatory bowel disease [IBD] in utero is lacking. Maternal inflammation, IBD medications, or other factors may increase the risk of developmental disabilities in the offspring. METHODS: We used the Danish National Birth Cohort, an ongoing prospective study that includes 100 419 pregnancies of 92 274 women, in conjunction with the Danish National Registries, to evaluate cognitive and motor development of the children of women with and without IBD. We analysed basic measures of childhood development at 6-month and 18-month interviews with the mother and with validated questionnaires filled out by the parents when the child was 7 years old. We adjusted for multiple confounders, including preterm birth. RESULTS: At 6 months, we included 484 children of women with IBD and 69 571 unexposed children; at 18 months, 471 exposed and 66 018 unexposed; at 7 years, 391 exposed and 54 356 unexposed. At 18 months, exposed children were significantly less likely to 'use word-like sounds' but there was no difference between use of 'sentences of 2 words'. At 6 and 18 months, there were no other obvious differences in language and motor development. At 7 years, cognitive scores [emotional, conduct, hyperactivity, peer, and social scores] and motor development [gross/fine motor skills and general coordination] were similar between the two groups. CONCLUSIONS: Children exposed to IBD in utero and unexposed children scored similarly on survey-based tools assessing basic measures of neurodevelopment over 7 years. These results are reassuring for current and future parents with IBD.