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.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.

Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS-and SQTS-associated mutations.

Background-In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results-The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers.When not taking ␤-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (Յ440 ms). A QTc Ͼ500 ms was associated with increased risk for cardiac events (ORϭ4.22; 95% CI, 1.12 to 15.80; Pϭ0.033). We also found that MCs with a heart rate Ͻ73 bpm were at significantly lower risk (ORϭ0.23; 95% CI, 0.06 to 0.86; Pϭ0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7Ϯ4 versus 13Ϯ9 years, both PϽ0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IK s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions-KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor. (Circulation. 2005;112:2602-2610.)

Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM.

Lower resting HR and "relatively low" BRS are protective factors in KCNQ1-A341V carriers. A plausible underlying mechanism is that blunted autonomic responses prevent rapid HR changes, arrhythmogenic when I(Ks) is reduced. These findings help understanding phenotypic heterogeneity in LQTS and identify a physiological risk modifier, which is probably genetically determined.

Objective To study the risk of adverse pregnancy outcomes in women with polycystic ovary syndrome (PCOS), and to examine the role of hyperandrogenaemia.Design Cohort study.Setting Singleton pregnancies in women with PCOS identified at a private fertility clinic during 1997-2010 and a background population including all singleton deliveries at Hvidovre Hospital, Denmark, in 2005.Population A cohort of 459 women with PCOS and a background population of 5409 women.Methods Obstetric outcomes were extracted from national Danish registries and odds ratios (ORs) were calculated by multiple logistic regression analysis, adjusting for age, parity, and body mass index.Main outcome measures Risk of pre-eclampsia, preterm delivery, and small for gestational age offspring in the entire PCOS population and in a subsample with hyperandrogenaemia.Results Women with PCOS had an increased risk of preterm delivery <37 weeks of gestation (OR 2.28; 95% confidence interval, 95% CI, 1.51-3.45; P < 0.0001). The elevated risk was confined to hyperandrogenic women with PCOS: preterm delivery before 37 weeks of gestation (OR 2.78; 95% CI 1.62-4.77; P < 0.0001), and was not seen in normoandrogenic women with PCOS (OR 1.35; 95% CI 0.54-3.39; P = 0.52). The overall risk of pre-eclampsia was not elevated (OR 1.69; 95% CI 0.99-2.88; P = 0.05) compared with the background population, but was significantly increased in the hyperandrogenic subsample (OR 2.41; 95% CI 1.26-4.58; P < 0.001). The risk of small for gestational age offspring was similar in all groups.Conclusion Women with PCOS had an increased risk of preterm delivery compared with the background population. The increased risk was confined to hyperandrogenic women with PCOS who had a two-fold increased risk of preterm delivery and pre-eclampsia.Keywords Hyperandrogenaemia, polycystic ovary syndrome, pre-eclampsia, preterm delivery.Please cite this paper as: Naver KV, Grinsted J, Larsen SO, Hedley PL, Jørgensen FS, Christiansen M, Nilas L. Increased risk of preterm delivery and pre-eclampsia in women with polycystic ovary syndrome and hyperandrogenaemia. BJOG 2014;121:575-581. IntroductionPolycystic ovary syndrome (PCOS) is the most common endocrinopathy among fertile women, affecting 5-10% in different ethnic populations. PCOS is a heterogeneous disorder and is associated with insulin resistance, dyslipidaemia, and increased long-term risk of type-II diabetes. The PCOS diagnosis according to the 2003 Rotterdam criteria includes any two or all three of the following features: menstrual irregularities; polycystic ovaries; and hyperandrogenism.1 As a consequence of anovulation, fertility treatment is often necessary to achieve a pregnancy. Recent studies indicate an increased risk of pregnancy complications such as pre-eclampsia, gestational diabetes, preterm delivery, and hypertension in PCOS pregnancies. 2 The pathophysiological explanation is debated, as several characteristics of the PCOS population, including obesity and the use of assisted reproductive techniques, are potential conf...