NBS started with the discovery that the amino acid disorder phenylketonuria (PKU) could be treated by dietary adjustment, and that early intervention was required for the best outcome.

Infants with PKU appear normal at birth, but are unable to metabolize the essential amino acid phenylalanine, resulting in irreversible intellectual disability.

In the 1960s, Robert Guthrie developed a simple method using a bacterial inhibition assay that could detect high levels of phenylalanine in blood shortly after a baby was born.

Guthrie also pioneered the collection of blood on filter paper which could be easily transported, recognizing the need for a simple system if the screening was going to be done on a large scale.

Bedside tests for hearing loss using automated auditory brainstem response and congenital heart defects using pulse oximetry are included in some NBS programs.

Robert Guthrie is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using a bacterial inhibition assay (BIA) to measure phenylalanine levels in blood samples obtained by pricking a newborn baby's heel on the second day of life on filter paper.

[3] The development of tandem mass spectrometry (MS/MS) screening in the early 1990s led to a large expansion of potentially detectable congenital metabolic diseases that can be identified by characteristic patterns of amino acids and acylcarnitines.

[4] In many regions, Guthrie's BIA has been replaced by MS/MS profiles, however the filter paper he developed is still used worldwide, and has allowed for the screening of millions of infants around the world each year.

[7][8] Duchenne muscular dystrophy is a disease that has been added to screening programs in several jurisdictions around the world, despite the lack of evidence as to whether early detection improves the clinical outcome for a patient.

[7] Newborn screening is intended as a public health program to identify infants with treatable conditions before they present clinically, or suffer irreversible damage.

Phenylketonuria (PKU) was the first disorder targeted for newborn screening, being implemented in a small number of hospitals and quickly expanding across the United States and the rest of the world.

Medium chain acyl-CoA dehydrogenase deficiency (MCADD), which had been implicated in several cases of sudden infant death syndrome[16][17][18] was one of the first conditions targeted for inclusion.

[11] Population based studies in Germany, the United States and Australia put the combined incidence of fatty acid oxidation disorders at 1:9300 among Caucasians.

Elevated 17α-hydroxyprogesterone (17α-OHP) is the primary marker used when screening for CAH, most commonly done using enzyme-linked immunosorbant assays, with many programs using a second tier tandem mass spectrometry test to reduce the number of false positive results.

As per the clinical practice guideline issued by the Endocrine Society in 2018, employing LC-MS/MS to measure 17α-OHP and other adrenal steroid hormones (such as 21-deoxycortisol and androstenedione) is recommended as a supplementary screening approach to enhance the accuracy of positive predictions.

[citation needed] Cystic fibrosis (CF) was first added to newborn screening programs in New Zealand and regions of Australia in 1981, by measuring immunoreactive trypsinogen (IRT) in dried blood spots.

Samples with an elevated IRT value were then analyzed with molecular methods to identify the presence of disease causing mutations before being reported back to parents and health care providers.

[24] Disorders of the distal urea cycle, such as citrullinemia, argininosuccinic aciduria and argininemia are included in newborn screening programs in many jurisdictions that using tandem mass spectrometry to identify key amino acids.

Their data showed an increased incidence from what was expected in the population, and also a number of late onset forms of disease, which are not typically the target for newborn screening programs.

[32] Undiagnosed hearing loss in a child can have serious effects on many developmental areas, including language, social interactions, emotions, cognitive ability, academic performance and vocational skills, any combination of which can have negative impacts on the quality of life.

[33] Newborn hearing testing is done at the bedside using transiently evoked otoacoustic emissions, automated auditory brainstem responses, or a combination of both techniques.

[citation needed] Severe combined immunodeficiency (SCID) caused by T-cell deficiency is a disorder that was recently added to newborn screening programs in some regions of the United States.

At various times since 1978, DMD has been included (often as a pilot study on a small subset of the population) in newborn screening programs in Edinburgh, Germany, Canada, France, Wales, Cyprus, Belgium and the United States.

As mass spectrometry became more widely available, the technology allowed rapid determination of a number of acylcarnitines and amino acids from a single dried blood spot.

Initial studies using Robert Guthrie's test for PKU reported high false positive rates that were attributed to a poorly selected type of filter paper.

In most regions, the newborn screening card (which contains demographic information as well as attached filter paper for blood collection) is supplied by the organization carrying out the testing, to remove variations from this source.

By August, 2004, the California state budget law had passed requiring the use of tandem mass spectroscopy to test for more than 30 genetic illnesses and provided funding.

[60] A recent study by Genetic Alliance and partners suggests that communication between health care providers and parents may be key in minimizing the potential harm when a false positive test occurs.

[61] To address the false positive issue, researchers from the University of Maryland, Baltimore and Genetic Alliance established a check-list to assist health care providers communicate with parents about a screen-positive result.

[citation needed] In the United States, it was revealed that Texas had collected and stored blood and DNA samples on millions of newborns without the parents' knowledge or consent.