Raising Awareness of False Positive Newborn Screening Results Arising from Pivalate-Containing Creams and Antibiotics in Europe When Screening for Isovaleric Acidaemia

Abstract

While the early and asymptomatic recognition of treatable conditions offered by newborn screening confers clear health benefits for the affected child, the clinical referral of patients with screen positive results can cause significant harm for some families. The use of pivalate-containing antibiotics and more recently the inclusion of neopentanoate as a component within moisturising creams used as nipple balms by nursing mothers can result in a significant number of false positive results when screening for isovaleric acidaemia (IVA) by measuring C5 acylcarnitine. A recent survey conducted within centres from nine countries indicated that this form of contamination had been or was a significant confounding factor in the detection of IVA in seven of the nine who responded. In three of these seven the prominent cause was believed to derive from the use of moisturising creams and in another three from antibiotics containing pivalate; one country reported that the cause was mixed. As a result, four of these seven centres routinely perform second tier testing to resolve C5 isobars when an initial C5 result is elevated, and a fifth is considering making this change within their national programme. The use of creams containing neopentanoate by nursing mothers and evolving patterns in the prescription of pivalate-containing antibiotics during pregnancy require those involved in the design and operation of newborn screening programmes used to detect IVA and the doctors who receive clinical referrals from these programmes to maintain an awareness of the potential impact of this form of interference on patient results.

Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS

“…After surveying mothers, it was concluded that the FP results were caused by the use of a nipple fissure cream used by lactating mothers. These findings were also reported by other European neonatal screening programs [ 34 ]. After the implementation of 2TT for C5 isomers, the number of FPs for IVA decreased to zero ( Table 6 ), which makes the impact of the secondary biomarker clear.…”

Personalised metabolic whole-body models for newborns and infants predict growth and biomarkers of inherited metabolic diseases

“…66 For instance, the personalised infant-WBMs could support newborn screening for IVA, which is suffering from an increasing number of false-positive screening results, due to antibiotics given to pregnant women to treat urinary tract infections 74 and pivalate-containing creams. 75 Moreover, drug dosage determination for children is very important as their immature drug metabolism is often associated with drug toxicity 76 and the pharmacokinetics and pharmacodynamics of drugs are often different in children and adults. 77, 78 However, almost 50% of prescription drugs lack age-appropriate dosing guidelines 76 and the paediatric drug clearance data is less attainable, which is probably due to the difficulties associated with conducting paediatric clinical trials.…”

Neonatal screening for isovaleric aciduria: Reducing the increasingly high false‐positive rate in Germany

“…It is known that exogenous sources of pivalic acid and the subsequently formed isomeric compound pivaloylcarnitine can cause a false‐positive result, 7 and therefore, methods to differentiate pivaloyl‐ from isovalerylcarnitine in NBS both for derivatized 8,9 and nonderivatized 10,11 samples have been suggested in the past. Pivalic acid containing antibiotics have caused trouble in NBS before and problems in other parts of Europe have been reported 11,12 . Similar to antibiotics and as well for pharmacokinetic reasons, leukocyte elastase inhibitors have been bound to pivalic acid and have caused false‐positive IVA screening 13 .…”

“…Pivalic acid containing antibiotics have caused trouble in NBS before and problems in other parts of Europe have been reported. 11 , 12 Similar to antibiotics and as well for pharmacokinetic reasons, leukocyte elastase inhibitors have been bound to pivalic acid and have caused false‐positive IVA screening. 13 Pivalic acid derivatives are also used by the cosmetic industry as emollient under the term “neopentanoate” and neopentanoate‐esters in a nipple‐fissure unguent that was routinely provided to breastfeeding mothers resulted in a high number of false‐positive screening cases in Belgium.…”