Minimizing false positives in newborn screening is a critical priority.

Newborn screening represents one of public health's greatest success stories, allowing for early detection and intervention of rare but serious conditions that could otherwise lead to severe disability or death. However, the effectiveness of these programs hinges not only on identifying affected infants but also on minimizing false positive results. Recent research in the field, including studies published in the International Journal of Neonatal Screening [1,2], demonstrates that advances in screening technology are making significant strides in reducing false positive rates.

The true impact of false positives

When a newborn screening test incorrectly flags a healthy baby as potentially having a serious condition ( a “false positive” result), it often triggers a cascade of consequences that extend far beyond the initial screening result. These false positives can create substantial burdens for healthcare systems, laboratories, and most importantly, families.

For clinical laboratories, each false positive necessitates confirmatory testing, additional staff time, and resources that could otherwise be directed toward truly affected infants. This represents a significant operational challenge in systems already managing high testing volumes with finite resources.

For families, the hidden costs are primarily emotional but no less significant. Parents receiving notification of an abnormal screening result often experience intense psychological distress, including anxiety, depression, and disrupted bonding with their newborn. Even after confirmatory testing reveals their child is healthy, studies show that some parents continue to perceive their child as vulnerable or fragile for months or even years afterward [3,4]. Research has found that mothers who received false positive results showed higher stress levels than those who received normal results, with effects persisting even after the false positive was resolved [5,6].

Understanding the causes of false positives

False positive results in newborn screening stem from multiple factors, most of which are inherent to the screening process rather than reflecting any deficiency in laboratory practices:

• Biological variability: Newborns naturally exhibit wide variations in metabolite levels during the first days of life, particularly as they transition from fetal to independent metabolism [7].
• Timing of sample collection: Samples collected too early (before 24 hours of age) may show transitional metabolic patterns that mimic pathological states [8].
• Prematurity and low birth weight: Premature infants often display different metabolic profiles that can trigger flags in screening algorithms designed primarily for full-term newborns [9].
• Maternal conditions: Certain maternal health conditions or medications can affect newborn metabolite levels without indicating disease in the infant [10].
• Technical limitations: All screening methodologies have inherent technical limitations and established cutoff values that balance sensitivity against specificity.

Understanding these factors helps contextualize false positives as an inherent challenge in screening rather than a reflection of laboratory performance.

The economic burden

The financial impact of false positives can be substantial. Each false positive result often triggers a series of follow-up procedures:

• Immediate recall of the infant for confirmatory testing
• Consultations with specialists
• Additional specialized laboratory analyses
• Potential hospital admissions for observation
• Parental lost work time and travel expenses

A single false positive can cost the healthcare system in unnecessary follow-up care, while simultaneously reducing parents' productivity and increasing their out-of-pocket expenses during an already challenging time. An economic analysis stated that a reduction of false positive results had the largest impact on costs, and that “besides the financial impact and psychosocial impact, a reduction in false positives also prevents an unnecessary burden on the pediatric and laboratory healthcare system” [11].

Technological advancements reducing false positives

Recent research, including a study published in the International Journal of Neonatal Screening [1], highlights significant progress in reducing false positive rates through advanced screening technologies. The research examined various approaches and platforms noting that some had improvements in false positive rates while still maintaining necessary clinical sensitivity. For example, the study showed that screening for Tyrosinemia type 1 by measuring succinylacetone (as opposed to tyrosine) lowers both false positive and false negative rates, and that using the NeoBase 2 Non-derivatized MSMS kits provided the lowest false positive rates compared to any other analytical assay tested.

By employing sophisticated algorithms and improved analytical methods, modern screening approaches maintain excellent clinical sensitivity while reducing the number of healthy infants flagged for unnecessary follow-up. This represents a crucial advancement in newborn screening technology that benefits laboratories, healthcare systems, and families alike.

Balancing sensitivity and specificity

The challenge in newborn screening has always been maintaining the delicate balance between identifying affected infants (sensitivity) while minimizing false alarms (specificity). Missing a diagnosis can have devastating consequences, but having an excessive number of false positives, can also prove challenging. Contemporary screening approaches use advanced statistical methods and machine learning to optimize cutoff values, improving the precision of abnormal result identification [12]. This represents a significant evolution from earlier screening methodologies that often erred heavily on the side of sensitivity at the expense of specificity.

The path forward

As newborn screening programs continue to expand to include more conditions, providing low false positive rates becomes increasingly critical. Technological advancements point toward a future where newborn screening can achieve both comprehensive condition coverage and high accuracy.

For program administrators and laboratory directors, selecting solutions with demonstrated lower false positive rates should be a key consideration in program planning. The benefits extend beyond laboratory efficiency to include improved patient care, reduced healthcare costs, and protection of the parent-infant relationship during a critical developmental period.

As a trusted partner to laboratories worldwide, Revvity is committed to supporting accurate and efficient testing processes. We work diligently to help laboratories minimize false positives [1] and deliver reliable results, enabling healthcare providers to share important information with families about their newborns' health.