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In an analysis of Danish health registry data, use of SSRIs during pregnancy was not associated with a significantly increased risk of autism spectrum disorders in children. A relative risk as high as 1.6 could not be ruled out, a finding suggesting the need for further research. Selective serotonin reuptake inhibitors (SSRIs) are increasingly used in the treatment of depression and anxiety disorders. Currently, SSRIs appear to provide the best balance between efficacy and safety and are the preferred first-line treatment. Depression is common during pregnancy, and given the risks of untreated depression to mother and fetus, 1 , 2 pharmacologic treatment is warranted, often with SSRIs. 3 However, SSRIs cross the placenta, and a number of safety concerns have been raised. 4 These include concerns about birth defects, adverse obstetrical and neonatal outcomes, and effects on cognitive and behavioral development in childhood. Recently, autism spectrum disorders have been linked to . . .

To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern. Register based cohort study. Sweden and Denmark from July 2013 to December 2016. A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists. The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 1.2, 1.16, 0.64 to 2.12). In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.

To explore the impact of COVID-19 lockdown on premature birth rates in Denmark, a nationwide register-based prevalence proportion study was conducted on all 31 180 live singleton infants born in Denmark between 12 March and 14 April during 2015–2020.The distribution of gestational ages (GAs) was significantly different (p=0.004) during the lockdown period compared with the previous 5 years and was driven by a significantly lower rate of extremely premature children during the lockdown compared with the corresponding mean rate for the same dates in the previous years (OR 0.09, 95% CI 0.01 to 0.40, p<0.001). No significant difference between the lockdown and previous years was found for other GA categories.The reasons for this decrease are unclear. However, the lockdown has provided a unique opportunity to examine possible factors related to prematurity. Identification of possible causal mechanisms might stimulate changes in clinical practice.

Full-term pregnancies reduce a woman’s long-term breast cancer risk, while abortions have been shown to have no effect. The precise minimal duration of pregnancy necessary to lower a woman’s breast cancer risk is, however, unknown. Here we provide evidence which point to the protective effect of pregnancy on breast cancer risk arising precisely at the 34th pregnancy week. Using a cohort of 2.3 million Danish women, we found the reduction in breast cancer risk was not observed for pregnancies lasting 33 weeks or less, but restricted to those pregnancies lasting 34 weeks or longer. We further found that parity, socioeconomic status, and vital status of the child at birth did not explain the association, and also replicated our finding in data from 1.6 million women in Norway. We suggest that a distinct biological effect introduced around week 34 of pregnancy holds the key to understand pregnancy-associated breast cancer protection. It is known that full-term pregnancies can reduce a woman’s breast cancer risk. Here, the authors interrogate data from 2.3 million Danish women, showing that this protective effect arises at precisely the 34th week of the pregnancy, and replicated this finding in 1.6 million women from Norway.

AbstractObjectiveTo assess the association between use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and risk of serious renal events in data from routine clinical practice.DesignCohort study using an active comparator, new user design and nationwide register data.SettingSweden, Denmark, and Norway, 2013-18.ParticipantsCohort of 29 887 new users of SGLT2 inhibitors (follow-up time: dapagliflozin 66.1%; empagliflozin 32.6%; canagliflozin 1.3%) and 29 887 new users of an active comparator, dipeptidyl peptidase-4 inhibitors, matched 1:1 on the basis of a propensity score with 57 variables. Mean follow-up time was 1.7 (SD 1.0) years.ExposuresSGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors, defined by filled prescriptions and analysed according to intention to treat.Main outcome measuresThe main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospital admission for renal events. Secondary outcomes were the individual components of the main outcome.ResultsThe mean age of the study population was 61.3 (SD 10.5) years; 11 108 (19%) had cardiovascular disease, and 1974 (3%) had chronic kidney disease. Use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a reduced risk of serious renal events (2.6 events per 1000 person years versus 6.2 events per 1000 person years; hazard ratio 0.42 (95% confidence interval 0.34 to 0.53); absolute difference −3.6 (–4.4 to −2.8) events per 1000 person years). In secondary outcome analyses, the hazard ratio for use of SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors was 0.32 (0.22 to 0.47) for renal replacement therapy, 0.41 (0.32 to 0.52) for hospital admission for renal events, and 0.77 (0.26 to 2.23) for death from renal causes. In sensitivity analyses in each of the Swedish and Danish parts of the cohort, the model was further adjusted for glycated haemoglobin and estimated glomerular filtration rate (Sweden and Denmark) and for blood pressure, body mass index, and smoking (Sweden only); in these analyses, the hazard ratio moved from 0.41 (0.26 to 0.66) to 0.50 (0.31 to 0.81) in Sweden and from 0.42 (0.32 to 0.56) to 0.55 (0.41 to 0.74) in Denmark.ConclusionsIn this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a significantly reduced risk of serious renal events.

AbstractObjectiveTo investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice.DesignCohort study using data from nationwide registers and an active-comparator new-user design.SettingDenmark, Norway, and Sweden, from April 2013 to December 2016.Participants20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score.Main outcome measuresPrimary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios.ResultsMean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death.ConclusionsIn this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.

Low-cost methods for monitoring fetal development could improve prenatal care, especially in low-resource settings. By measuring the levels of certain placental RNA transcripts in maternal blood, Ngo et al. developed two noninvasive blood tests that provide a window into the progression of individual pregnancies. In a small proof-of-concept study, the first blood test predicted fetal age and delivery date with an accuracy comparable to that of ultrasound. The second blood test, also examined in a small pilot study, discriminated women at risk of preterm delivery from those who delivered at full term. The next step will be to assess the reliability of the tests in large, blinded clinical trials. Science , this issue p. 1133 In pilot studies of pregnant women, RNA-based tests of maternal blood predicted delivery date and risk of early childbirth. Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (25 full-term and 13 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.

Maternal infections are common during pregnancy, but it is unclear how they impact the cognitive outcome of the offspring, with many studies suggesting adverse effects. Using long-term follow-up of a nationwide sibling cohort in Denmark with information on maternal antimicrobial prescriptions in community pharmacies and in-patient hospitalizations for infection, we aimed to estimate the effect of maternal infections during pregnancy on offspring school grades and intelligence test results in adolescence. From population-based national registries we defined a cohort of all full-siblings, born from January 1, 1996 to December 31, 2,003 in Denmark, and linked them to maternal filled prescription for antimicrobial pharmaceuticals and maternal hospitalizations for infection during pregnancy. Standardized examination grades in language and mathematics at the final year of compulsory schooling, in addition to intelligence test scores (calculated as IQ) for a nested sub-cohort of full brothers, were used as outcomes. Among 274,166 children in the full-sibling cohort, 80,817 (29.5%) had a mother who during her pregnancy filled a prescription for a systemic antimicrobial, while 5,628 (2.1%) had a mother who during her pregnancy was hospitalized due to an infection. We found no consistent difference in school grades in language (z-score difference, 0.0, 95% confidence interval [CI] [-0.0,0.0]; p = 0.920) and mathematics (z-score difference, -0.0, 95% CI [-0.0,-0.0]; p = 0.042), and in IQ (IQ-difference, 0.3, 95% CI [-0.2,0.7]; p = 0.217), in children whose mother filled one antimicrobial prescription compared with children whose mother did not fill any, when taking shared family factors into account, while many associations were consistently significant when not taking shared family factors into account. Furthermore, we found no indication of an impact of maternal in-patient hospitalizations for infections during pregnancy on school grades (z-score difference for language, -0.0, 95% CI [-0.1,0.0]; p = 0.103; z-score difference for mathematics, 0.0, 95% CI [-0.0,0.0]; p = 0.809) or IQ (IQ-difference, 0.4, 95% CI [-0.8,1.6]; p = 0.545), when also taking shared family factors into account. Similar findings were found when considering infections in bi-weekly exposure periods during gestation. The main limitations of the study were lacking information on within hospital pharmaceutical prescriptions and the underlying pathogenic microorganisms. Our study does not support major effects of common maternal infections during pregnancy on offspring cognitive outcomes, and support the safety of commonly prescribed antimicrobials during pregnancy with respect to the long-term cognitive outcomes of the offspring.

Some 5%-15% of all women experience postpartum depression (PPD), which for many is their first psychiatric disorder. The purpose of this study was to estimate the incidence of postpartum affective disorder (AD), duration of treatment, and rate of subsequent postpartum AD and other affective episodes in a nationwide cohort of women with no prior psychiatric history. Linking information from several Danish national registers, we constructed a cohort of 457,317 primiparous mothers with first birth (and subsequent births) from 1 January 1996 to 31 December 2013 (a total of 789,068 births) and no prior psychiatric hospital contacts and/or use of antidepressants. These women were followed from 1 January 1996 to 31 December 2014. Postpartum AD was defined as use of antidepressants and/or hospital contact for PPD within 6 months after childbirth. The main outcome measures were risk of postpartum AD, duration of treatment, and recurrence risk. We observed 4,550 (0.6%) postpartum episodes of AD. The analyses of treatment duration showed that 1 year after the initiation of treatment for their first episode, 27.9% of women were still in treatment; after 4 years, 5.4%. The recurrence risk of postpartum AD for women with a PPD hospital contact after first birth was 55.4 per 100 person-years; for women with postpartum antidepressant medication after first birth, it was 35.0 per 100 person-years. The rate of postpartum AD after second birth for women with no history of postpartum AD was 1.2 per 100 person-years. After adjusting for year of birth and mother's age, women with PPD hospital contact after first birth had a 46.4 times higher rate (95% CI 31.5-68.4) and women with postpartum antidepressant medication after their first birth had a 26.9 times higher rate (95% CI 21.9-33.2) of a recurrent postpartum episode after their second birth compared to women with no postpartum AD history. Limitations include the use of registry data to identify cases and limited confounder control. In this study, an episode of postpartum AD was observed for 0.6% of childbirths among women with no prior psychiatric history. The observed episodes were characterized by a relatively short treatment duration, yet the women had a notably high rate of later AD and recurrent episodes of postpartum AD. The recurrence risk of postpartum AD was markedly higher among women with PPD hospital contact after first birth compared to women with postpartum antidepressant medication after first birth. Our results underline the necessity of measures targeted at specific vulnerable groups, such as women who experience PPD as a first psychiatric episode.

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients ( P  = 1.76 × 10 −6 ). This finding is replicated in an independent cohort of early-onset lone AF patients ( n  = 399; odds ratio = 36.8; P  = 4.13 × 10 −6 ). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF. Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2 -mutant zebrafish.