Paula Louise Hedley

Numerous circulating microRNAs (miRNAs) have been detected in maternal blood. Initial studies in third trimester demonstrated differential miRNA expression profiles between uncomplicated pregnancies and pregnancies complicated by pre-eclampsia (PE). Recently, studies in first trimester have shown similar differential profiles, however, these studies were often under-powered. We conducted a nested case-control study, in which serum samples, taken between 10 and 14 weeks gestation, were obtained from 413 singleton pregnant women, 126 of which later developed PE. Total RNAs were purified and a selection of 46 miRNAs plus two miRNA controls were quantitated by real time quantitative PCR. Seven of the miRNAs, hsa-miR-181b-5p, -323a-3p, -518b, -363-3p, -20a-5p, -29a-3p, and − 142-3p, could differentiate between uncomplicated pregnancies and pregnancies which develop PE, but only a single miRNA, hsa-miR-363-3p, could differentiate between mild and severe PE. A combination of all seven differentiating miRNAs was the best at discriminating between PE and uncomplicated pregnancies (AUC = 0.879). First trimester maternal serum miRNA expression profile could differentiate between uncomplicated pregnancies and pregnancies complicated by PE. These circulating miRNA markers have the potential to improve risk assessment of PE in the first trimester, weeks before the onset of symptoms.

This study aimed to identify reported causes of neonatal death across the European Economic Area (EEA) member states and Switzerland as of 1 January 2010 (hereafter referred to as the European Region) and, where possible, examine the cause-specific distribution of neonatal deaths over time. We conducted a two-pronged analysis: (1) database analysis using WHO public datasets (2000–2021) for 28 countries in the European Region and (2) a systematic review and meta-analysis of pertinent records from PubMed, Embase, Web of Science, Scopus, Cochrane, and Google Scholar, which were comprehensively reviewed against inclusion criteria up to 10 August 2024, following PRISMA guidelines. The average neonatal mortality rate (NMRs) between 2000 and 2021 in WHO data was 2.63 per 1000 live births, with a significant decline (−0.074 per year) across the region. Prematurity (41.2%) and congenital anomalies (28.9%) were the most common registered causes of neonatal death; however, WHO data lacked etiological detail to reliably analyze cause-specific trends. The systematic review identified 41 eligible studies, of which 15 were included in meta-analyses. Pooled estimates showed that congenital anomalies and prematurity accounted for 30% (95% CI 17–46) and 31% (95% CI 18–49) of deaths, respectively. Among extremely preterm neonates, infections, respiratory, and cardiovascular disorders were the most common reported causes of death.      Conclusion: NMRs across the European Region are declining, with prematurity and congenital anomalies being leading causes of neonatal death. Current reporting frameworks lack granularity, and a wider adoption of standardized classification systems is critical to improving surveillance and data comparability, especially for preterm infants. What is Known: • Neonatal mortality rates have declined across Europe over recent decades. • There are considerable regional disparities in both causes and rates of neonatal death. What is New: • Prematurity and congenital anomalies each account for ~30% of neonatal deaths. • Greater use of standardized classifications of neonatal death causes is urgently needed.

Aim: Congenital diaphragmatic hernia (CDH) is a severe malformation with high morbidity and mortality. This Danish study evaluated the birth prevalence, co‐occurring malformations, and temporal trends of CDH over nearly three decades. Methods: Nationwide data from the Danish Biobank Register were used to identify liveborn infants diagnosed with CDH from 1994 to 2021. They were classified as non‐syndromic or syndromic, based on co‐occurring structural malformations or genetic or syndromic anomalies. Poisson regression was used to estimate the prevalence, including annual percentage changes. Results: We found that 272 of the 1 696 357 liveborn infants were diagnosed with CDH, with a stable prevalence of 1.60 per 10 000 live births (95% confidence interval 1.42–1.81). The majority (89.3%) had non‐syndromic phenotypes: 79.4% of these had isolated CDH and 20.6% had CDH with co‐occurring malformations, predominantly cardiac malformations. Syndromic CDH was observed in 29 (10.7%) infants, and its prevalence declined significantly over the study period ( p < 0.03). Conclusion: Although the prevalence of liveborn Danish CDH births remained stable, there was a shift towards fewer syndromic cases, possibly due to improved prenatal screening and increased terminations. The high proportion of major, co‐occurring malformations emphasises the need for continued monitoring to address the healthcare needs of these patients.

A bstract: Purpose: Despite considerable progress in reducing neonatal mortality, significant work remains. The regional differences in both the rates and causes of neonatal mortality, necessitates addressing this issue within a regional context. This study aimed to identify reported causes of neonatal death in the European Region and examine the cause-specific distribution of neonatal deaths over time. Methods: We conducted a two-pronged analysis: (1) database analysis using WHO public datasets (2000–2021) for 28 countries in the European Region and (2) a systematic review and meta-analysis of pertinent records from various databases which were comprehensively reviewed against inclusion criteria up to 10 ^th August 2024, following PRISMA guidelines. Results: The average neonatal mortality rate between 2000–2021 in WHO data was 2.63 per 1,000 live births, with a significant decline (-0.074 per year) across the European Region. Prematurity (41.2%) and congenital anomalies (28.9%) were the most common registered causes of neonatal death; no detailed etiological breakdown was available. The systematic review identified 41 eligible studies; 14 could be included in meta- analyses. Pooled estimates showed that congenital anomalies and prematurity each accounted for 30% of deaths. Among extremely preterm neonates, infections, respiratory and cardiovascular disorders were the most common reported causes of death. Conclusions: NMRs across the European Region is declining (rapidly) with prematurity and congenital anomalies being leading causes of neonatal death. Current mortality reporting frameworks inadequately capture the diagnostic complexity of neonatal death causes. Adoption of detailed, standardized classification systems is critical to improving surveillance and data comparability, especially for preterm infants. W hat is K nown: Neonatal mortality rates have declined across Europe over recent decades. There are considerable regional disparities in both causes and rates of neonatal death. W hat is N ew: Prematurity and congenital anomalies each account for ∼30% of neonatal deaths. In extremely preterm infants, infections and cardiorespiratory disorders predominate. Greater use of standardised classifications of neonatal death causes is urgently needed.

Background/Objectives: Maternal use of medication during pregnancy may have teratogenic effects, as seen with drugs like thalidomide, valproate, and phenytoin. Despite rigorous testing, both new and established drugs still pose a risk of teratogenesis, particularly if the teratogenic effects are probabilistic and not deterministic. Public health organizations maintain registers to centralize and evaluate adverse drug reactions (ADR). However, underreporting in these registries can obscure the signals of drug-related congenital malformations. This study aims to evaluate potential ADR-associated congenital malformations in Denmark over the past decade; Methods: An observational cross-sectional study was conducted using data from the national Danish Medicines Agency’s pharmacovigilance database, which includes all spontaneous ADR reports submitted to the Danish Medicines Agency from 1 July 2013 to 30 June 2023. Maternal antenatal drug use was identified, and reported ADRs were assessed for congenital malformations; Results: We identified reports of potential ADR-related congenital malformations in 75 children, with 92 diagnoses as classified by ICD-10. Eighty-five different drugs from 58 ATC codes were implicated. Only three diagnoses were reported in five or more children. The reports were generally sporadic, with no new signals detected; Conclusions: Public awareness is crucial when novel threats arise from medications, infections, or technologies, as these may pose risks to unborn children. Ongoing monitoring of potential ADR-related congenital malformations remains a critical component of public health. Given the potential underreporting, we encourage a low threshold for reporting ADRs based on suspicion alone, with final causality assessments made by health authorities.

Aims: In this study, we aimed to evaluate incidence trends and potential risk factors associated with Perthes’ disease in Denmark, using publicly available data.Methods: Our population-based case-control study used data from the Danish National Patient Register and Danish Civil Registration System, accessed through the publicly available Danish Biobank Register, to identify 1,924,292 infants born between 1985 and 2016. We estimated age-specific incidence rates for four birth periods of equal duration (1985 to 1992, 1993 to 2000, 2001 to 2008, and 2009 to 2016) and investigated associations with perinatal conditions, congenital malformations, coagulation defects, autism spectrum disorders (ASD), and attention deficit hyperactivity disorders (ADHD).Results: We identified 2,374 (81.6% male) diagnosed with Perthes’ disease aged between two and 12 years, corresponding to an overall incidence of 12.1 per 100,000 live births relative to the year of birth. The incidence declined across all four birth periods, irrespective of sex or age at diagnosis. Several perinatal conditions were associated with higher Perthes’ disease risk. Children with reported birth injuries (vs no reported injuries) exhibited the highest risk (relative risk (RR) 7.48 (95% CI 3.37 to 16.63)) followed by those with versus without coagulation defects (RR 4.77 (95% CI 1.79 to 12.69)). Children diagnosed with syndromic (RR 2.90 (95% CI 2.08 to 4.04)) or non-syndromic major congenital malformations (RR 1.86 (95% CI 1.55 to 2.23)) (vs those with no malformation diagnosis) were also associated with higher Perthes’ disease risk. The development of Perthes’ disease was positively associated with several ASD and ADHD diagnoses. However, once adjusting for the sex of the child and period of birth, the associations with ASD and ADHD were no longer significant.Conclusion: Using publicly available data, we observed a declining incidence of Perthes’ disease in Denmark over a 32-year study period. Our findings also confirm positive associations between Perthes’ disease and various perinatal conditions, coagulation defects, and congenital malformations, highlighting potential aetiological pathways for further investigation.Cite this article: Bone Joint J 2025;107-B(2):268–276.

Purpose: Omphalocele is a congenital abdominal wall defect associated with a high risk of morbidity and mortality, with co-occurring congenital malformations often being the most important prognostic factor. High rates of spontaneous and medical terminations have been reported among pregnancies with omphalocele and co-occurring malformations. Few studies have focused on co-occurring malformations, particularly non-gastrointestinal malformations among live births. This study examined birth prevalence of omphalocele and co-occurring major malformations among a 25-year Danish liveborn cohort. Methods: This nationwide retrospective prevalence study used data from the Danish National Patient Register and Danish Civil Registration System for infants who were delivered in Denmark during 1997–2021 and included in the Danish neonatal screening biobank. Diagnoses of omphalocele and co-occurring malformations were ascertained and prevalence estimated using Poisson regression. Results: Among 1,498,685 live births, 147 infants with omphalocele were identified, yielding a combined and stable prevalence (per 10,000 infants) of 0.98 (95% CI 0.83–1.15). Over one-half (53.7%) presented with one or more major malformations, and an additional 17.0% were diagnosed with a syndrome. Conclusions: Omphalocele birth prevalence in Denmark was stable over a recent 25-year period. The proportion of infants with co-occurring major malformations or diagnosed syndrome has important implications for long-term healthcare demands.

Objective: To evaluate the association between maternal BMI and congenital heart defects (CHDs) in the offspring when including live births, stillbirths, aborted and terminated pregnancies and to investigate if maternal interpregnancy weight changes between the first and second pregnancy influences the risk of foetal CHDs. Methods: A nationwide cohort study of all singleton pregnancies in Denmark from 2008 to 2018. Data were retrieved from the Danish Foetal Medicine Database, which included both pre- and postnatal diagnoses of CHDs. Children or foetuses with chromosomal aberrations were excluded. Odds ratios were calculated with logistic regression models for CHDs overall, severe CHDs and five of the most prevalent subtypes of CHDs. Results: Of the 547 105 pregnancies included in the cohort, 5 442 had CHDs (1.0%). Risk of CHDs became gradually higher with higher maternal BMI; for BMI 25-29.9 kg/m², adjusted odds ratio (aOR) 1.17 (95% CI 1.10-1.26), for BMI 30-34.9 kg/m², aOR 1.21 (95% CI 1.09-1.33), for BMI 35-39.9 kg/m², aOR 1.29 (95% CI 1.11-1.50) and for BMI ≥ 40 kg/m², aOR 1.85 (95% CI 1.54-2.21). Data was adjusted for maternal age, smoking status and year of estimated due date. The same pattern was seen for the subgroup of severe CHDs. Among the atrioventricular septal defects (n = 231), an association with maternal BMI ≥ 30 kg/m² was seen, OR 1.67 (95% CI 1.13-2.44). 109 654 women were identified with their first and second pregnancies in the cohort. Interpregnancy BMI change was associated with the risk of CHDs in the second pregnancy (BMI 2 to < 4 kg/m²: aOR 1.29, 95% CI 1.09-1.53; BMI ≥ 4 kg/m²: aOR 1.36, 95% CI 1.08-1.68). Conclusion: The risk of foetal CHDs became gradually higher with higher maternal BMI and interpregnancy weight increases above 2 BMI units were also associated with a higher risk of CHDs.

Background: Congenital talipes equinovarus (clubfoot) is a common musculoskeletal anomaly, with a suspected multifactorial etiopathogenesis. Herein, we used publicly available data to ascertain liveborn infants with clubfoot delivered in Denmark during 1994–2021, and to classify co-occurring congenital anomalies, estimate annual prevalence, and compare clubfoot occurrence with maternal smoking rates, a commonly reported risk factor. Characterizing this nationwide, liveborn cohort provides a population-based resource for etiopathogenic investigations and life course surveillance. Methods: This case-cohort study used data from the Danish National Patient Register and Danish Civil Registration System, accessed through the publicly available Danish Biobank Register, to identify 1,315,282 liveborn infants delivered during 1994–2021 in Denmark to Danish parents. Among these, 2,358 infants (65.1% male) were ascertained with clubfoot and classified as syndromic (co-occurring chromosomal, genetic, or teratogenic syndromes) and nonsyndromic (isolated or co-occurring multiple congenital anomalies [MCA]). Annual prevalence estimates and corresponding 95% confidence intervals (CIs) for children with nonsyndromic clubfoot were estimated using Poisson regression and compared with population-based, maternal annual smoking rates obtained from publicly available resources. Results: Infants most often presented with nonsyndromic clubfoot (isolated = 88.6%; MCA = 11.4%); limb and heart anomalies were the most frequently identified MCAs. Prevalence (per 1,000 liveborn infants) was 1.52 (CI 1.45–1.58) for isolated and 0.19 (CI 0.17–0.22) for MCA clubfoot. Prevalence estimates for both isolated and MCA clubfoot remained relatively stable during the study period, despite marked decreases in population-based maternal smoking rates. Conclusions: From 1994 to 2021, prevalence of nonsyndromic clubfoot in Denmark was relatively stable. Reduction in population-level maternal smoking rates did not seem to impact prevalence estimates, providing some support for the suspected multifactorial etiopathogenesis of this anomaly. This nationwide, liveborn cohort, ascertained and clinically characterized using publicly available data from the Danish Biobank Register, provides a population-based clinical and biological resource for future etiopathogenic investigations and life course surveillance.