Background—Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort.Methods and Results—In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51–4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23–10.6, and relative risk, 3.49; 95% confidence interval, 2.91–4.13, respectively; P=0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74–13.8).Conclusions—The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.

Objective To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).Design Nationwide register based cohort study.Setting Denmark, 1996Denmark, -2011 Participants 999 378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30 091; maternal use after birth, n=21 557; use in infants, n=6591), surgery for IHPS, and potential confounders.Main outcome measures Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth.Results 880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and −0.11 (−0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (−0.31 to 0.50) and 0.67 (−0.06 to 2.02).Conclusions Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.

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Background: The mechanism behind the cardiovascular protection observed with human GLP-1 RA (glucagon-like peptide-1 receptor agonists) in type 2 diabetes is unknown. We hypothesized that treatment with the GLP-1 RA liraglutide had a positive effect on vascular inflammation. Methods: LIRAFLAME (Effect of liraglutide on vascular inflammation in type-2 diabetes: A randomized, placebocontrolled, double-blind, parallel clinical PET/CT trial) was a double-blind, randomized controlled trial performed at a single university hospital clinic in Denmark. Patients with type 2 diabetes were via computer-generated randomization list assigned (1:1) liraglutide up to 1.8 mg or placebo once daily for 26 weeks. The primary end point was change in vascular inflammation over 26 weeks assessed by [ 18 F]-fluorodeoxyglucose positron emission tomography/computed tomography. Analyses were based on intention-to-treat. Key secondary outcomes included change in other indices of atherosclerosis. Results: Between October 26, 2017, and August 16, 2019, 147 patients were screened and 102 were randomly assigned to liraglutide (n=51) or placebo (n=51) and 99 (97%) completed the trial. Change in the [ 18 F]-fluorodeoxyglucose positron emission tomography measure of vascular inflammation (active-segment target-to-background ratio) did not differ between treatment groups: change from baseline to 26 weeks was −0.04 (95% CI, −0.17 to 0.08) in the liraglutide group compared with −0.09 (−0.19 to 0.01) in the placebo group (mean difference, 0.05 [95% CI, −0.11 to 0.21], P =0.53). Secondary analyses restricted to [ 18 F]-fluorodeoxyglucose positron emission tomography of the carotid arteries as well as other indices of atherosclerosis confirmed the primary result. We performed an explorative analysis of interaction between treatment group and history of cardiovascular disease ( P =0.052). Conclusions: In this low to moderate risk population with type 2 diabetes, liraglutide did not change vascular inflammation assessed as [ 18 F]-fluorodeoxyglucose uptake compared with placebo. An explorative analysis indicated a possible effect in persons with history of cardiovascular disease, in line with current guidelines where liraglutide is recommended to patients with history of cardiovascular disease. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03449654.