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

Peter Schielen,Rachel Carling,Laura Vilarinho,Martin Lindner,James Bonham,Roberto Cerone,Rolf Zetterstrom,Francois Boemer,Francois Eyskens,David Hougaard,Leifur Franzson

doi:10.3390/ijns4010008

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.

Highlights

Isovaleric acidaemia (IVA) is an autosomal recessive disorder of leucine metabolism
The questions included: (1) whether pivalate-containing medications contributed to false positive (FP) results when screening for isovaleric acidaemia (IVA); (2) if so, whether the contribution was suspected to arise mainly from the use of moisturising creams or antibiotics; (3) whether second tier testing was in place to identify pivaloyl carnitine in the blood spot sample prior to potential clinical referral; and (4) whether testing to identify pivaloyl carnitine was routinely available subsequent to clinical referral if this was indicated
Seven of the nine countries represented considered that pivalate within dried blood spots had been or was a significant confounding factor in the detection of IVA by newborn screening using C5 acylcarnitine alone as an indicator

Summary

Introduction

Isovaleric acidaemia (IVA) is an autosomal recessive disorder of leucine metabolism. In the acute neonatal form, patients are typically well at birth and present during the first two weeks of life with poor feeding, vomiting, lethargy, seizures, and progressive coma. While newborn screening has enabled the pre-symptomatic identification of IVA, prompt and appropriate treatment is required to ensure that the baby is protected and, as a result, rapid referral and assessment is advocated in screen positive cases. Pivaloylcarnitine can be present in blood due to maternal use of pivalic ester pro-drugs or pivalic acid derivatives used as emollients in some nipple creams. Common examples of such drugs include Pivmecillinam, the pivaloyloxymethyl ester of Mecillinam, and Pivampicillin, the pivaloylmethyl ester of Ampicillin. [4] reported 50 FP IVA results detected in Belgium during an 18-month period, which were subsequently investigated and found to be due to the use of a nipple fissure unguent containing pivalic acid derivatives. A recently published false positive case attributed to the use of the Neutrophil Elastase Inhibitor Sivelestat [6] in this respect is of note

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