Highlight
Low Diagnostic Yield at Birth
LDL cholesterol (LDL-C) levels in umbilical cord blood show a wide overlap between newborns with genetically verified familial hypercholesterolaemia (FH) and those without, limiting the efficacy of birth-based screening.
High Discrimination After Infancy
From age one through twelve, LDL-C levels provide excellent discrimination between FH and non-FH children, with a 95th percentile cut-off identifying nearly 90% of cases.
Evidence-Based Screening Window
The study suggests that universal cholesterol-based screening for FH is not feasible at birth and should ideally be implemented from the age of one year onward.
The Clinical Context of Familial Hypercholesterolaemia
Familial Hypercholesterolaemia (FH) is one of the most common autosomal dominant genetic disorders, characterized by lifelong elevations in low-density lipoprotein cholesterol (LDL-C). If left untreated, individuals with FH face a significantly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Despite its prevalence—estimated at 1 in 250 to 1 in 311 in the general population—FH remains vastly underdiagnosed, with many patients identified only after their first cardiovascular event.
The quest for an effective universal screening strategy has led to significant debate. While cascade screening (testing relatives of an index patient) is highly cost-effective, it fails to identify ‘new’ families entering the healthcare system. Universal screening of children has been proposed as a solution. However, the optimal timing for such screening—whether at birth using umbilical cord blood or later in childhood—has remained a point of scientific contention due to a lack of data comparing genetically verified FH cases against non-FH controls in an unbiased population.
Study Design and Methodology
A recent study published in the European Heart Journal by Bogsrud et al. (2025) addressed this gap using data from the Norwegian national family cascade screening programme. Spanning from 1998 to 2023, the researchers analyzed cholesterol levels in two distinct groups: newborns (n = 113) using umbilical cord blood and children aged 1–12 years (n = 1346) using venous blood. Unlike previous studies that often only performed genetic testing on children who already presented with high LDL-C levels, this study utilized unique data where the genetic status was known for all participants, allowing for a true assessment of the overlap in LDL-C levels.
Population and Comparators
The study compared variant-positive children (confirmed FH) with variant-negative children (non-FH siblings). This methodology is crucial because it accounts for the genetic and environmental ‘background’ within families, providing a clearer picture of how the FH mutation itself influences lipid levels at different developmental stages.
Key Findings: The Diagnostic Gap in Newborns
The results regarding newborns were particularly illuminating. While the mean LDL-C was statistically higher in FH newborns compared to non-FH newborns (1.22 mmol/L vs. 0.68 mmol/L, P < .001), the individual values overlapped so extensively that clinical utility was severely compromised.
Screening Efficacy at Birth
When applying potential screening cut-offs, the researchers found that:
1. A cut-off level at the 95th percentile would identify only 55.7% of newborns with FH.
2. Even a more inclusive cut-off at the 85th percentile would still miss nearly 25% of FH cases (75.4% sensitivity).
Furthermore, the study found that screening efficacy at birth did not improve when looking at subgroups, such as sex, gene type (LDLR vs. APOB), or mutation severity (null vs. non-null variants). Neither total cholesterol nor non-HDL cholesterol offered better diagnostic performance than LDL-C in the neonatal period.
The Shift at Age One: Improved Screening Efficacy
The diagnostic landscape changed dramatically once children reached the age of one. In the 1–12 year age group, LDL-C levels became a highly sensitive marker for the presence of an FH mutation. The overlap between the two groups narrowed significantly, allowing for much clearer discrimination.
Screening Efficacy in Childhood (1–12 Years)
For children in this age bracket, the diagnostic yield was far superior:
1. A 95th percentile LDL-C cut-off identified 88.4% of children with FH.
2. An 85th percentile cut-off identified 94.1% of children with FH.
This suggests that by the time a child is one year old, the metabolic pathways regulating cholesterol are sufficiently mature, and the genetic influence of the FH mutation has become the dominant driver of LDL-C levels, independent of the maternal-fetal environment.
Expert Commentary and Biological Plausibility
Why is LDL-C so much less reliable at birth? Clinical experts point toward several biological factors. During pregnancy, the fetus relies on placental transfer of cholesterol, and the fetal liver’s LDL receptor activity is regulated differently than in later life. Furthermore, the umbilical cord blood profile can be influenced by maternal lipid levels and the physiological stress of delivery. By the age of one, these confounding factors have largely dissipated, and the child’s diet and internal homeostasis provide a more stable environment for assessing genetic lipid disorders.
Addressing Study Limitations
The authors note that while this is the first study to show the ‘true’ overlap by utilizing a national cascade programme, it is based on a Norwegian population which may have specific genetic clusters. However, the fundamental biological findings regarding the maturation of lipid metabolism are likely generalizable to other populations.
Conclusion: Implications for Public Health
The implications of this study for health policy are clear. Universal screening for FH at birth using cord blood is likely to result in a high rate of false negatives, potentially providing a false sense of security to families. Conversely, universal screening starting at age one—perhaps integrated into routine pediatric check-ups or vaccinations—offers a highly effective window for identification.
Early identification remains the cornerstone of FH management. While pharmacological intervention with statins usually begins later in childhood (typically age 8-10), early diagnosis allows for dietary education, the initiation of family cascade screening, and the establishment of long-term cardiovascular monitoring. By deferring universal screening until after the first year of life, healthcare systems can maximize diagnostic accuracy and ensure that children with FH are identified and treated before the onset of atherosclerotic damage.
References
Bogsrud MP, Stava TT, Berge KE, Strøm TB, Retterstøl K, Holven KB. LDL-cholesterol in newborns and children with genetically verified familial hypercholesterolaemia: implications for cholesterol-based screening. Eur Heart J. 2025 Dec 22;46(48):5261-5269. doi: 10.1093/eurheartj/ehaf815. PMID: 41127896.
