Interferon-beta exposure in-utero and the risk of infections in early childhood.

BACKGROUND: Knowledge within the field of multiple sclerosis treatment during pregnancy is vital to ensure the most optimal clinical practice. Immunomodulatory treatment in pregnancy could in theory affect the normal development and maturation of the immune system of the fetus with a potential increased risk of infections, consequently. We therefore set out to investigate whether exposure to interferon-beta in utero affected the risk of acquiring infections in early childhood. METHODS: This retrospective matched cohort study utilized data from the Danish Multiple Sclerosis Registry linked with national Danish registries to identify all children born of mothers with MS in Denmark from 1998 to 2018. The study included 510 children exposed to interferon-beta in utero. The children were matched 1:1 on various of demographic characteristics with children born to mothers with untreated MS and 1:3 with children born to mothers without MS. Each child was followed for up to five years. Using individual-level data, we investigated all-cause mortality, rate of hospital admissions due to infections, and redeemed prescriptions of antibiotics. The primary statistical model applied was a negative binomial regression analysis. RESULTS: We found no differences in childhood mortality, for hospital admissions the rate ratio compared to healthy controls was 0.79 (0.62-1.00). Regarding antibiotic prescriptions, the results were similar (RR 1.00 (0.90-1.11). Furthermore, we found no certain dose-response relationship between interferon-beta exposure duration and hospital admission rate (P = 0.47) or redeemed antibiotic prescription (P = 0.71). CONCLUSION: Exposure to interferon-beta during gestation has little to no impact on the risk of acquiring significant infections during the first five years of childhood.

Pregnancy outcomes after early fetal exposure to injectable first-line treatments, dimethyl fumarate, or natalizumab in Danish women with multiple sclerosis.

BACKGROUND AND PURPOSE: Data on pregnancy outcomes following fetal exposure to disease-modifying drugs (DMDs) in women with multiple sclerosis (MS) are sparse although growing. METHODS: Data from the Danish Multiple Sclerosis Registry were linked with nationwide registries enabling an investigation of adverse pregnancy outcomes in newborns of women with MS following fetal exposure to injectable first-line treatments, dimethyl fumarate, glatiramer acetate, or natalizumab. Logistic regression models accounting for clustered data were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for individual and composite adverse outcomes after adjusting for relevant covariates. RESULTS: A total of 1009 DMD-exposed pregnancies were compared with 1073 DMD-unexposed pregnancies as well as 91,112 pregnancies from the general population. No association of an increased risk of any perinatal outcome was found when comparing newborns with fetal exposure with the general population, including preterm birth (OR = 1.19, 95% CI = 0.86-1.64), small for gestational age (OR = 1.38, 95% CI = 0.92-2.07), spontaneous abortion (OR = 1.04, 95% CI = 0.84-1.27), congenital malformation (OR = 0.99, 95% CI = 0.68-1.45), low Apgar score (OR = 0.62, 95% CI = 0.23-1.65), stillbirth (OR = 1.05, 95% CI = 0.33-3.31), placenta complication (OR = 0.53, 95% CI = 0.22-1.27), and any adverse event (OR = 1.10, 95% CI = 0.93-1.30). Similar results were found when comparing DMD-exposed pregnancies with DMD-unexposed pregnancies. CONCLUSIONS: We found no increased association of adverse pregnancy outcomes in newborns with fetal exposure to DMDs when compared with either DMD-unexposed pregnancies or the general population.

Pregnancy outcomes following maternal or paternal exposure to teriflunomide in the Danish MS population.

Background Teriflunomide (TFL) is an oral drug used for treatment of multiple sclerosis (MS). Due to possible teratogenicity it is contraindicated in women of childbearing potential. Additionally, a low risk of male-mediated embryo-fetal toxicity has been described as the drug can be transmitted via semen. This study investigated the association of adverse perinatal outcomes in newborns with either maternal or paternal exposure to TFL. Methods The Danish Multiple Sclerosis Registry was used to identify all patients treated with teriflunomide from 1st of September 2013 to 31st of December 2018. Data were merged with other nationwide national registries to identify all pregnancies with potential exposure to TFL. Exposure was defined as conception occurring after at least 30 consecutive days of treatment either during treatment or within two years of treatment discontinuation. Exposed pregnancies were matched 1:4 with controls from the general population. Individual outcomes of adverse perinatal events, namely preterm birth, congenital malformations, small for gestational age (SGA), stillbirth or low Apgar score were used to form a composite outcome, any adverse event, which was used for the analysis. Logistic regression was used to estimate the association of having any adverse event in newborns with either maternal or paternal exposure to TFL. Results A total of 112 TFL-exposed pregnancies were included of which 49 had maternal exposure and 63 paternal exposure. Among women, 21/49 pregnancies were terminated - 18 electively and three spontaneously. The remaining 28 pregnancies resulted in healthy newborns of which ≤3 were preterm. None of the newborns presented with malformations, being SGA or with low Apgar score. Among men, all 63 pregnancies resulted in birth of which 4/63 (6.3%) were preterm. Major malformations were registered in ≤3 event, and no newborn presented with low Apgar score or being SGA. No increased association of any adverse event was found in newborns with TFL exposure relative to controls (OR 1.03, 95% CI 0.50-2.13). Conclusion We did not find an increased prevalence of spontaneous abortion, preterm birth, congenital malformations, low Apgar score of being SGA in newborns with maternal or paternal exposure to TFL when compared with the general population. However, the sample was too small to draw firm conclusions.

Pregnancy in women with MS: Impact on long-term disability accrual in a nationwide Danish Cohort.

BACKGROUND: Pregnancy is considered to influence the disease course in women with multiple sclerosis (MS). OBJECTIVE: The aim of this study was to investigate the effect of pregnancy on long-term disability accrual in women with MS. METHODS: The Danish Multiple Sclerosis Registry (DMSR) was used to identify women diagnosed with clinically isolated syndrome or relapsing-remitting MS. Cox models with pregnancy as a time-dependent exposure and propensity score (PS) models were used to evaluate time to reach confirmed Expanded Disability Status Scale (EDSS) score of 4 and 6. RESULTS: A total of 425 women became parous and 840 remained nulliparous. When including pregnancy as a time-dependent exposure, a non-significant association with time to reach EDSS 4 (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.61-1.20) and EDSS 6 (HR 0.70, 95% CI 0.40-1.20) was found. Correspondingly, the PS model showed no association with pregnancy on time to reach EDSS 4 (HR 0.85, 95% CI 0.56-1.28). CONCLUSION: This study concludes that pregnancy does not affect long-term disability accumulation.

Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts.

INTRODUCTION: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. OBJECTIVE: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. METHODS: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients' sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed with weighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. RESULTS: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15-41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65-0.88); in those aged ≤ 38 years (0.64; 0.54-0.76); in those with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51). CONCLUSIONS: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity.

Pregnancy-Related and Perinatal Outcomes in Women With Multiple Sclerosis: A Nationwide Danish Cross-sectional Study.

OBJECTIVE: To investigate differences in pregnancy-related and perinatal outcomes in women with multiple sclerosis (MS) compared with the general population. METHODS: We conducted a cross-sectional study including pregnancies from January 1, 1997, to December 31, 2016, to women registered in the Danish Multiple Sclerosis Registry (the study cohort). Pregnancy-related and perinatal outcomes were compared with a randomly selected subcohort of pregnancies from the general population (the comparison cohort) using logistic regression adjusted for possible confounders. RESULTS: In total, 2,930 pregnancies were included in the study cohort and 56,958 pregnancies in the comparison cohort. No differences were found in pregnancy-related complications (preeclampsia/gestational diabetes or placenta complications), emergency caesarean section (c-section), instrumental delivery, low Apgar score, stillbirth, preterm birth, or congenital malformations. Elective c-section (odds ratio [OR] 1.89 [95% confidence interval (CI) 1.65-2.16]), induced delivery (OR 1.15 [95% CI 1.01-1.31]), and being born small for gestational age (SGA) (OR 1.29 [95 %CI 1.04-1.60]) had a higher prevalence in the study cohort, whereas the prevalence of signs indicating asphyxia was lower in the study cohort (OR 0.87 [95% CI 0.78-0.97]) relative to the comparison cohort. CONCLUSION: We found a higher prevalence of elective c-sections, induced delivery, and infants being SGA among newborns to women with MS, whereas the prevalence of asphyxia was lower in the study cohort. There were no significant differences in severe adverse perinatal outcomes when comparing women with MS and their newborns with those of the general population.

Pregnancy Outcomes in Men and Women Treated With Teriflunomide. A Population-Based Nationwide Danish Register Study.

Background: The majority of persons diagnosed with multiple sclerosis (MS) experience their first MS symptoms in the reproductive age. Teriflunomide (TFL, Aubagio), was first released in Denmark for relapsing-remitting MS in December 2013. TFL treatment is contraindicated in women of childbearing potential who are not using reliable contraception. TFL can be transmitted via semen and a low risk of male-mediated embryo-fetal toxicity is described. Objective: To report pregnancy outcomes of TFL-treated women and partners to TFL-treated men: gestation week. Methods: Prospective cohort study comparing pregnancy outcomes of TFL-treated men and women, matched on age at conception, 1:4 with controls from the general population. Data on TFL-treated patients treated 1st of January 2014-31st of December 2016 for at least 30 consecutive days prior to conception, and with conception occurring latest 2 years after treatment discontinuation were extracted from The Danish Multiple Sclerosis Registry and merged with several national reproductive registries. Logistic regression was used to analyse the association between TFL exposure and any adverse event. Results: A total of 31 pregnancies were recorded, 13 women and 18 of partners to a TFL-treated man. All 18 partners of TFL-treated men completed their pregnancies: livebirth (18), gestation time >37 weeks (17), gestation time 33-36 weeks (1), normal birth weight (18), spontaneous and elective abortion (0), congenital malformation (plagiocephali) (1), normal delivery (14), induced delivery (2), cesarean section (2), Apgar score ≥7 (18). Among the 13 pregnancies in women exposed to TFL: elective abortion (11), spontaneous abortion (0), livebirth (2), gestation time >37 weeks (2), normal birth weight (2), congenital malformations (0), normal delivery (1), induced delivery (1), Apgar score ≥7 (2). The TFL group was associated with a 22% reduction in the odds of any adverse event relative to controls, although this association was not significant (OR 0.78; 95% CI 0.16-3.72, p = 0.753). Conclusion: Pregnancy outcomes were consistent with those of the general population. The malformation reported of the partner to a TFL-treated man is comparable to the rate of plagiocephaly reported in Denmark.

Mental health among children of mothers with multiple sclerosis: A Danish cohort and register-based study.

BACKGROUND: Multiple sclerosis is associated with an increased risk of developing physical, cognitive, and mental health problems. Current studies have demonstrated variating outcomes of parental multiple sclerosis mental health problems and their children's mental health development. OBJECTIVE: The purpose of this study was to investigate whether maternal multiple sclerosis is associated with the mental health status of their child. METHODS: Data from the Danish National Birth Cohort (DNBC) were merged with information from the Danish Multiple Sclerosis Registry. Two proxies, total difficulties score and prediction of any psychiatric diagnosis based on the strengths and difficulties questionnaire, were used to measure the mental health status of the children. The two groups were compared using Mann-Whitney and logistic regression analyses. RESULTS: For the total difficulties score the control and exposed group consisted of respectively n = 42,016 and n = 40, and for the prediction of any psychiatric diagnosis respectively n = 16,829 and n = 17. We found no statistically significant association between maternal multiple sclerosis and mental health status on neither of the proxies. CONCLUSION: Maternal multiple sclerosis did not show any association with the mental health status of their children at age eleven. On the contrary, other studies conclude that there is an association between maternal multiple sclerosis and the child's mental health status, one especially mediated by the maternal mental health status.