Metformin in pregnancy and risk of abnormal growth outcomes at birth: a register-based cohort study.

INTRODUCTION: We previously reported an increased risk of being small for gestational age (SGA) and a decreased risk of being large for gestational age (LGA) after in utero exposure to metformin compared with insulin exposure. This follow-up study investigated if these observations remain when metformin exposure (henceforth, metformin cohort) is compared with non-pharmacological antidiabetic treatment of gestational diabetes mellitus (GDM; naïve cohort), instead of insulin. RESEARCH DESIGN AND METHODS : This was a Finnish population register-based cohort study from singleton children born during 2004-2016. Birth outcomes from metformin cohort (n=3964) and the naïve cohort (n=82 675) were used in the main analyses. Additional analyses were conducted in a subcohort, restricting the metformin cohort to children of mothers with GDM only (n=2361). Results were reported as inverse probability of treatment weighted OR (wOR), with the naïve cohort as reference. RESULTS  : No difference was found for the outcome of SGA between the cohorts in the main analyses (wOR 0.97, 95% CI 0.73 to 1.27) or in the additional analyses (wOR 1.01, 95% CI 0.75 to 1.37). No difference between the cohorts was found for the risk of LGA (wOR 0.91, 95% CI 0.75 to 1.11) in the main analyses but a decreased risk was observed in the additional analyses (wOR 0.72, 95% CI 0.56 to 0.92). CONCLUSIONS : This follow-up study found no increase in the risk of SGA or LGA after in utero exposure to metformin, compared with drug-naïve GDM. The decreased risk of LGA in mothers with GDM may suggest residual confounding. The lack of increased SGA risk aligns with findings from studies using metformin in non-diabetic pregnancies. In contrast, lower birth weight and increased SGA birth risk were observed in GDM pregnancies for metformin versus insulin. Metformin should be avoided with emerging growth restriction in utero. The interplay of intrauterine hyperglycemia and pharmacological treatments needs further assessment.

Incidence of Aicardi-Goutières syndrome and KCNT1-related epilepsy in Denmark.

Objective: To estimate the incidence of Aicardi-Goutières syndrome (AGS) and potassium sodium-activated channel subfamily T member 1 (KCNT1)-related epilepsy in Denmark and to characterize the patients diagnosed with AGS and KCNT1-related epilepsy. Background: AGS and KCNT1-related epilepsy are 2 distinct rare genetic disorders. Due to the rarity of AGS and KCNT1-related epilepsy, the epidemiology remains unclear. The incidences for these diseases or the carriers with disease-related genetic variants remain unknown. Materials and methods: This is a retrospective, non-interventional, population-based study using aggregate data from the Danish population register and hospital-based patient-level data in Denmark to identify persons with genetically confirmed AGS between January 2010 to December 2020 and KCNT1-related epilepsies between January 2012 to December 2020. Cases of these disorders were identified from in-hospital databases, and pathogenic variants were identified and confirmed by Sanger and/or whole exome (panel-based) sequencing. The incidence of AGS and KCNT1-related epilepsy were estimated in separate statistical analyses. Results: A total of 7 AGS patients were identified. The mean age at AGS diagnosis was 19.4 months (median age 14 months). TREX1 (n < 5) and RNASEH2B (n ≥ 5) genes were reported with confirmed pathogenic variants. The birth incidence of AGS was <0.7600 per 100,000 live births. The average annual incidence rate was calculated as 0.0539 (95% CI: 0.0217-0.1111) per 100,000 persons per year in the total population < 18 years (n = 7); the average annual incidence rate was <0.7538 per 100,000 persons per year (n < 5) in the population < 12 months, and the average annual incidence rate in the population ≥ 12 months and < 18 years was <0.0406 per 100,000 persons per year (n < 5). A total of 14 KCNT1-related epilepsy cases were identified during the study period (n = 5 in 2016, remaining 9 cases in 2013 and 2015). The mean age at diagnosis was 20.6 years (median 19 years) for KCNT1 cases. A total of 8 cases (57.1%) were ≥ 18 years, and 6 (42.9%) were < 18 years at diagnosis. The phenotype autosomal dominant or sporadic sleep-related hypermotor epilepsy (ADSHE) (n = 10, 71.4%) was most reported; the remaining 4 cases had either epilepsy of infancy with migrating focal seizures (EIMFS) or an unclassifiable developmental and epileptic encephalopathy (DEE). The birth incidence of KCNT1-related epilepsy was ≤1.1205 per 100,000 live births. The average annual incidence rates per 100,000 persons per year during the study period were 0.0431 (95% confidence interval [CI]: 0.0236-0.0723; n = 14) in the overall population ≤ 50 years, 0.0568 (95% CI: 0.0209-0.1237; n = 6) in the population < 18 years, and 0.0365 (95% CI: 0.0157-0.0718; n = 8) in the population ≥ 18 and ≤ 50 years. There were 3 families with at least 2 cases diagnosed with KCNT1-related epilepsies (on average 3.3 cases per family), indicating 10 cases in total within the 3 families. All KCNT1 cases of ADSHE phenotype came from the 3 families. The higher incidence of older ages and ADSHE cases compared with previous KCNT1 studies is likely due to the capture of prevalent and familial previously undiagnosed cases. Excluding these family cases, the average annual incidence was 0.0123 (95% CI: 0.0034-0.0315, n = 4) per 100,000 persons per year in the population ≤ 50 years during 2012-2020. Conclusions: AGS and KCNT1-related epilepsy are particularly rare diseases. The annual average incidence rate of AGS was 0.0539 per 100,000 persons per year in the population < 18 years and birth incidence was <0.7600 per 100,000 live births during 2010-2020. The average annual incidence rate of KCNT1-related epilepsy was 0.0431 per 100,000 persons per year in the population ≤ 50 years and the birth incidence was ≤1.1205 per 100,000 live births during 2012-2020. Given similar healthcare systems and genetic pools, these findings may provide insight on the incidence of these rare diseases in the Nordics.

The Effects of Marital Status, Fertility, and Bereavement on Adult Mortality in Polygamous and Monogamous Households: Evidence From the Utah Population Database.

Although the associations among marital status, fertility, bereavement, and adult mortality have been widely studied, much less is known about these associations in polygamous households, which remain prevalent across much of the world. We use data from the Utah Population Database on 110,890 women and 106,979 men born up to 1900, with mortality follow-up into the twentieth century. We examine how the number of wife deaths affects male mortality in polygamous marriages, how sister wife deaths affect female mortality in polygamous marriages relative to the death of a husband, and how marriage order affects the mortality of women in polygamous marriages. We also examine how the number of children ever born and child deaths affect the mortality of men and women as well as variation across monogamous and polygamous unions. Our analyses of women show that the death of a husband and the death of a sister wife have similar effects on mortality. Marriage order does not play a role in the mortality of women in polygamous marriages. For men, the death of one wife in a polygamous marriage increases mortality to a lesser extent than it does for men in monogamous marriages. For polygamous men, losing additional wives has a dose-response effect. Both child deaths and lower fertility are associated with higher mortality. We consistently find that the presence of other kin in the household-whether a second wife, a sister wife, or children-mitigates the negative effects of bereavement.

Cost and utility in immunocompromised subjects who developed herpes zoster during the randomized V212 inactivated varicella-zoster vaccine (ZVIN) trial.

Objectives: Immunocompromised subjects are at increased risk for herpes zoster (HZ) and HZ-related complications, such as post-herpetic neuralgia (PHN). We describe health utilities, health care resource utilization (HCRU), productivity loss and health care costs in recipients of autologous hematopoietic stem-cell transplantation (Auto-HSCT) who developed confirmed HZ in the phase 3 clinical trial. Methods: HCRU, costs, and EQ-5D-3L utility were assessed for 155 confirmed HZ cases observed after receiving inactivated varicella-zoster virus (VZV) vaccine (ZVIN) or placebo. In a prospective, longitudinal 6-month follow up, costs and utilities were analyzed for two health states, HZ without PHN and HZ with PHN. Results: There was a clinically relevant difference in utility between HZ without PHN (mean 0.814) and HZ with PHN (0.729). The disutility for HZ without PHN was estimated to -0.117 and to -0.186 for HZ with PHN. Direct costs (2017 USD) associated with a HZ without PHN episode and HZ with PHN episode was estimated at $3,412 and $3,711, respectively, of which hospitalizations accounted for 90% of the costs. Expert opinion: Both HZ and PHN are associated with considerable disutility in recipients of Auto-HSCT. Costs were comparable to published estimates in other immunocompromised subjects. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT01229267).