Newborn screening is the process by which infants are screened shortly after birth for a list of disorders that

are treatable, but difficult or impossible to detect clinically. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the jurisdiction. Newborn screening originated when Robert Guthrie developed a method to screen for phenylketonuria, a disorder which could be managed by dietary adjustment if diagnosed early. Whole blood samples are collected from the infant's heel on specially designed filter paper, and then tested for a panel of disorders. The disorders tested can vary from region to region, based on funding and the prevalence of a condition in the population.
Contents
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1 Goals 2 History 3 Disease qualification 4 Techniques

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4.1 Sample collection 4.2 Reporting results 5.1 Core panel 5.2 Secondary targets

5 Targeted disorders
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6 Projects 7 Expanded newborn screening 8 Controversies 9 See also 10 References 11 External links

[edit]Goals Universal newborn screening (NBS) aims to identify infants that appear healthy at birth, but are afflicted with conditions that can cause severe illness or

death.[1] With early detection, these conditions can be managed to prevent complications. [edit]History Robert Guthrie is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using blood samples onfilter paper obtained by pricking a newborn baby's heel on the second day of life to get a few drops of blood.[2] Congenital hypothyroidism was the second disease widely added in the 1970s.[3] The development of tandem mass spectrometry screening by Edwin Naylor and others in the early 1990s led to a large expansion of potentially detectable congenital metabolic diseases that affect blood levels of organic acids.[4] In 2006, the American College of Medical Genetics recommended a larger list of diseases be added for newborn screening across the country. The implementation of this panel across the United States meant all babies born would be screened for the same number of conditions. Prior to this, babies born in different states had received different levels of screening. On April 24, 2008, President George W. Bush signed into law the Newborn Screening Saves Lives Act of 2007. This act was enacted to increase awareness among parents, health professionals, and the public on testing newborns to identify certain disorders. It also sought to improve, expand, and enhance current newborn screening programs at the state level. [edit]Disease

qualification

Screening criteria used in newborn screening programs are based largely on criteria initially established by JMG Wilson and F. Jungner in 1968.[5] Their publication, Principles and practice of screening for disease proposed ten criteria that screening programs should meet before being used as a public health measure. The four criteria that are relied upon when making decisions for newborn screening programs are[5]: 1. having an acceptable treatment protocol in place that changes the outcome for patients diagnosed early with the disease 2. an understanding of the condition's natural history 3. an understanding about who will be treated as a patient

4. a NBS screening test that is reliable for both affected and unaffected patients and is acceptable to the public The HRSA [3] Secretary's Advisory Committee on Heritable Disorders in Newborns and Children is a national focal point for standardizing the newborn screen panel across states. The current list of tests by state can be found at the National Newborn Screening and Genetics Resource Center[6]. As diagnostic techniques have progressed, debates have arisen as to how screening programs should adapt. Tandem mass spectrometryhas greatly expanded the potential number of diseases that can be detected, even without satisfying all of the other criteria used for making screening decisions.[5][7] 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.[5] [edit]Techniques [edit]Sample

collection

Heel blood on a filter paper card for the newborn screening

Newborn screening tests are most commonly done from whole blood samples collected on specially designed filter paper. The filter paper is often attached to a form containing required information about the infant and parents. This includes date and time of birth, date and time of sample collection, the infant's weight and gestational age. The form will also have information about whether the baby has had a blood transfusion and any additional nutrition the baby may have received (total parenteral nutrition). Most newborn screening cards also include contact

information for the infant's physician in cases where follow up screening or treatment is needed. Ideally, newborn screening samples are collected from the infant between 24 hours and 7 days after birth. Samples can be collected at the hospital, or by midwives. If a sample is collected from an infant who is less than 24 hours old, the laboratory will often request a repeat specimen be taken after 24 hours. Samples are mailed daily to the laboratory responsible for testing. Most jurisdictions require samples to be collected for screening from all newborns, unless the parent or guardian opts out of the process in writing. In addition to the blood test, many regions also test newborns for hearing loss[8] and congenital heart failure using pulse oximetry.[9] [edit]Reporting

results

The goal is to report the results within a short period of time. If screens are normal, a paper report is sent to the submitting hospital and parents rarely hear about it. If an abnormality is detected, employees of the agency, usually nurses, begin to try to reach the physician, hospital, and/or nursery by telephone. They are persistent until they can arrange an evaluation of the infant by an appropriate specialist physician (depending on the disease). The specialist will attempt to confirm the diagnosis by repeating the tests by a different method or laboratory, or by performing other corroboratory or disproving tests. The confirmatory test varies depending on the positive results on the initial screen. Confirmatory testing will include analyte specific assays to confirm any elevations detected, functional studies to determine enzyme activity, and genetic testing to identify diseasecausing mutations. Depending on the likelihood of the diagnosis and the risk of delay, the specialist will initiate treatment and provide information to the family. Performance of the program is reviewed regularly and strenuous efforts are made to maintain a system that catches every infant with these diagnoses. Guidelines for newborn screening and follow up have been published by the American Academy of Pediatrics.[10] [edit]Targeted

disorders

The following list includes most of the disorders detected by the expanded or supplemental newborn screening by mass spectrometry. This expanded

screening is not yet universally mandated by most states, but may be privately purchased by parents or hospitals at a cost of approximately US$80. The same can also be purchased from other countries like Germany, Austria, Spain, Japan and India where more than 100 disorders are being tested based on a urine sample of the newborn. Perhaps one in 5,000 infants will be positive for one of the metabolic tests below (excluding the congenital infections). [edit]Core

panel

The following conditions and disorders were recommended as "core panel" by the 2005 report of the American College of Medical Genetics (ACMG).[11] The incidences reported below are from their report, pages 143-307, though the rates may vary in different populations. (WARNING: The file is a very large PDF.) Blood cell disorders

Sickle cell anemia (Hb SS) > 1 in 5,000; among African-Americans 1 in 400 Sickle-cell disease (Hb S/C) > 1 in 25,000 Hb S/Beta-Thalassemia (Hb S/Th) > 1 in 50,000

Inborn errors of amino acid metabolism

Tyrosinemia I (TYR I) < 1 in 100,000 Argininosuccinic aciduria (ASA) < 1 in 100,000 Citrullinemia (CIT) < 1 in 100,000 Phenylketonuria (PKU) > 1 in 25,000 Maple syrup urine disease (MSUD) < 1 in 100,000 Homocystinuria (HCY) < 1 in 100,000

Inborn errors of organic acid metabolism

Glutaric acidemia type I (GA I) > 1 in 75,000 Hydroxymethylglutaryl lyase deficiency (HMG) < 1 in 100,000 Isovaleric acidemia (IVA) < 1 in 100,000 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC) > 1 in 75,000 Methylmalonyl-CoA mutase deficiency (MUT) > 1 in 75,000 Methylmalonic aciduria, cblA and cblB forms (MMA, Cbl A,B) < 1 in 100,000

Beta-ketothiolase deficiency (BKT) < 1 in 100,000 Propionic acidemia (PROP) > 1 in 75,000 Multiple-CoA carboxylase deficiency (MCD) < 1 in 100,000

Inborn errors of fatty acid metabolism

Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) > 1 in 75,000 Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) > 1 in 25,000 Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD) > 1 in 75,000 Trifunctional protein deficiency (TFP) < 1 in 100,000 Carnitine uptake defect (CUD) < 1 in 100,000

Miscellaneous multisystem diseases

Cystic fibrosis (CF) > 1 in 5,000 Congenital hypothyroidism (CH) > 1 in 5,000 Biotinidase deficiency (BIOT) > 1 in 75,000 Congenital adrenal hyperplasia (CAH) > 1 in 25,000 Classical galactosemia (GALT) > 1 in 50,000

Newborn screening by other methods than blood testing

Congenital deafness (HEAR) > 1 in 5,000

[edit]Secondary

targets

The following disorders are additional conditions that may be detected by screening. Many[11] are listed as "secondary targets" by the 2006 ACMG report. Some states are now screening for more than 50 congenital conditions. Many of these are rare and unfamiliar to pediatricians and other primary health care professionals.[11] Blood cell disorders

Variant hemoglobinopathies (including Hb E)[11] Glucose-6-phosphate dehydrogenase deficiency (G6PD)

Inborn errors of amino acid metabolism

Tyrosinemia II[11] Argininemia[11] Benign hyperphenylalaninemia Defects of biopterin cofactor biosynthesis[11] Defects of biopterin cofactor regeneration[11] Tyrosinemia III[11] Hypermethioninemia[11] Citrullinemia type II[11]

Inborn errors of organic acid metabolism

Methylmalonic acidemia (Cbl C,D)[11] Malonic acidemia[11] 2-Methyl 3-hydroxy butyric aciduria[11] Isobutyryl-CoA dehydrogenase deficiency[11] 2-Methylbutyryl-CoA dehydrogenase deficiency[11] 3-Methylglutaconyl-CoA hydratase deficiency[11] Glutaric acidemia type II HHH syndrome (Hyperammonemia, hyperornithinemia, homocitrullinuria syndrome) Beta-methyl crotonyl carboxylase deficiency Adenosylcobalamin synthesis defects

Inborn errors of fatty acid metabolism

Medium/short-chain L-3-hydroxy acyl-CoA dehydrogenase deficiency[11] Medium-chain ketoacyl-CoA thiolase deficiency[11] Dienoyl-CoA reductase deficiency[11] Glutaric acidemia type II[11] Carnitine palmityl transferase deficiency type 1[11] Carnitine palmityl transferase deficiency type 2[11] Short-chain acyl-CoA dehydrogenase deficiency (SCAD)[11] Carnitine/acylcarnitine Translocase Deficiency (Translocase)[11] Short-chain hydroxy Acyl-CoA dehydrogenase deficiency (SCHAD)

Long-chain acyl-CoA dehydrogenase deficiency (LCAD) Multiple acyl-CoA dehydrogenase deficiency (MADD)

Congenital infections

TORCH complex (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex, Syphilis etc.), if there are indicative symptoms or mothers who may have been exposed[12] HIV

Miscellaneous multisystem diseases

Galactokinase deficiency[11] Galactose epimerase deficiency[11] Maternal vitamin B12 deficiency

[edit]Projects Currently, National Institutes of Health (NIH) awarded a five-year, $4.5 million grant in April 2011 to fund the "Inborn Errors of Metabolism Collaborative" (IBEMC) project through NIH's R01 program, the agency's oldest grant mechanism. Newborn blood spot screening is a critical public health responsibility, but for most newborn-screened disorders there is no comprehensive, long-term assessment of outcomes. MPHI will serve as lead of the IBEMC. Thirteen clinic and university partners in ten states will collect longitudinal data to capture the clinical progress of persons affected with conditions identified by newborn screening (NBS), focusing on inborn errors of metabolism. Data will be used to explore survival rates, medical status, and longterm outcomes, and permit development of evidence-based treatment and management. The database will allow for investigation of:

The relationship between NBS values, genotype and early manifestations, and complications of inborn errors of metabolism Current interventions for treating children with metabolic disorders

The effectiveness of current interventions for specific metabolic disorders identified through newborn screening

The IBEMC will build on the work of the Health Resources and Services Administration-funded Region 4 Genetics Collaborative (www.region4genetics.org), housed in MPHI's Systems Reform program. The project will be developed in collaboration with other national efforts; work began in April 2012.[13] [edit]Expanded

newborn screening

The increasing availability and decreasing cost of tandem mass spectrometry (MS/MS) equipment greatly increased the number of diseases that could be detected from the standard newborn screening blood spot card. MS/MS screening to determine concentrations of amino acidsand acylcarnitines can be used to screen for a large number of inherited metabolic disorders.[13] Expanded newborn screening allowed a large number of disorders to be detected in a single test, previously newborn screening labs would have a single test for a single disease. [edit]Controversies Newborn screening tests have become a subject of political controversy in the last decade. Two California babies, Zachary Wyvill and Zachary Black, were both born with Glutaric acidemia type I. Wyvill's birth hospital only tested for the four diseases mandated by state law, while Black was born at a hospital that was participating in an expanded testing pilot program. Black's disease was treated with diet and vitamins; Wyvill's disease went undetected for over six months, and during that time the damage from the enzyme deficiency became irreversible. Birth-defects lobbyists pushing for broader and more universal standards for newborn testing cite this as an example of how much of an impact testing can have.[citation needed] Instituting MS/MS screening often requires a sizable up front expenditure. When states choose to run their own programs the initial costs for equipment, training and new staff can be significant. Moreover, MS/MS gives only the screening result and not the confirmatory result. The same has to be further done by higher

technologies or procedure like GC/MS, Enzyme Assays or DNA Tests. This in effect adds more cost burden and makes physicians lose precious time. To avoid at least a portion of the up front costs, some states such as Mississippi have chosen to contract with private labs for expanded screening. Others have chosen to form Regional Partnerships sharing both costs and resources. But for many states, screening is an integrated part of the department of health which can not or will not be easily replaced. Thus the initial expenditures can be difficult for states with tight budgets to justify. Screening fees have also increased in recent years as health care costs rise and more states add MS/MS screening to their programs. (See Report of Summation of Fees Charged for Newborn Screening, 20012005) Dollars spent for these programs may reduce resources available to other potentially lifesaving programs. It has been recommended that one disorder, Short Chain Acyl-coenzyme A Dehydrogenase Deficiency, or SCAD, be eliminated from screening programs, due to a "spurious association between SCAD and symptoms.[14] However, recent studies suggest that expanded screening is cost effective (see ACMG report page 94-95 and articles published in Pediatrics[15]'.[16] Advocates are quick to point out studies such as these when trying to convince state legislatures to mandate expanded screening. Expanded newborn screening is also opposed by among some health care providers who are concerned that effective follow-up and treatment may not be available, that false positive screening tests may cause harm, and issues of informed consent.[17] 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. The results from this study also reveal that parents found newborn screening to be a beneficial and necessary tool to prevent treatable diseases.[18] To address the false positive issue, researchers from the University of Maryland, Baltimoreand Genetic Alliance established a check-list to assist health care providers communicate with parents about a screen-positive result.[19] Controversy has also erupted in some countries over collection and storage of blood or DNA samples by government agencies during the routine newborn blood screen. It was revealed that in Texas the state had collected and stored blood and DNA samples on millions of newborns without the parents knowledge

or consent. These samples were then used by the state for genetic experiments and to set up a database to catalog all of the samples/newborns. Samples obtained without parent's consent were destroyed.[20]

Food groups
Main article: Food groups [edit]Carbohydrates Carbohydrates are a source of energy that can be transformed into glucose, the form of sugar that is transported and used by the body, more quickly than proteins or fats. A diet too high in carbohydrates can upset the delicate balance of a body's blood sugar level, resulting in fluctuations in energy and mood that leave one feeling irritated and tired.[citation needed] [edit]Vegetables A vegetable is a part of a plant consumed by humans that is generally savory but is not sweet. A vegetable is not considered a grain, fruit, nut, spice, or herb. For example, the stem, root, flower, etc., may be eaten as vegetables. Vegetables contain many vitamins and minerals; however, different vegetables contain different spreads, so it is important to eat a wide variety of types. For example, green vegetables typically contain vitamin A, dark orange and dark green vegetables contain vitamin C,and vegetables like broccoli and related plants contain iron and calcium. Vegetables are very low in fats and calories, but cooking can often add these. [edit]Fruits In terms of food (rather than botany), fruits are the sweet-tasting seed-bearing parts of plants, or occasionally sweet parts of plants which do not bear seeds. These include apples, oranges,plums, bananas, etc. Fruits are low in calories and fat and are a source of natural sugars, fiber and vitamins. Processing fruits when canning or making into juices may add sugars and remove nutrients. The fruit food group is sometimes combined with the vegetable food group. Note that many foods considered fruits in botany because they bear seeds are not considered fruits in cuisine because they lack the characteristic sweet taste, e.g., tomatos or avocados.

[edit]Oils The food pyramid advises that fats be consumed sparingly. Butter and oils are examples of fats. Healthy sources of fat can be found in fish, nuts, and certain fruits and vegetables, such as avocados. [edit]Dairy Dairy products are produced from the milk of mammals, most usually but not exclusively cattle. They include milk, yogurt and cheese. Milk and its derivative products are a rich source of dietary calcium, but also provide protein, phosphorus, vitamin A, and vitamin D. However, many dairy products are high in saturated fat and cholesterol compared to vegetables, fruits and whole grains, which is why skimmed products are available as an alternative. For adults, three cups of dairy products are recommended per day.[8][9] [edit]Meat and beans Meat is the tissue usually muscle of an animal consumed by humans. Since most parts of many animals are edible, there is a vast variety of meats. Meat is a major source of protein, as well as iron, zinc, and vitamin B12. Meats, poultry, and fish include beef, chicken,pork, salmon, tuna, shrimp, and eggs. The meat group is one of the major compacted food groups in the food guide pyramid. Many of the same nutrients found in meat can also be found in foods like eggs, dry beans, and nuts, such foods are typically placed in the same category as meats, as meat alternatives. These include tofu, products that resemble meat or fish but are made with soy, eggs, and cheeses. For those who do not consume meat or animal products (see Vegetarianism, veganism and Taboo food and drink), meat analogs, tofu, beans, lentils, chick peas, nuts and other high-protein vegetables are also included in this group. The food guide pyramid suggests that adults eat 23 servings per day. One serving of meat is 4 oz (110 g), about the size of a deck of cards. [edit]Controversy Many nutritional experts, like Harvard nutritionist Dr. Walter Willett, believe the 1992 pyramid does not reflect the latest research on dietetics.[10] Certain dietary

choices that have been linked to heart disease, such as three cups of whole milk and an 8 oz (230 g). serving of hamburger daily, were technically permitted under the pyramid. The pyramid also lacked differentiation within the protein-rich group ("Meat, Poultry, Fish, Dry Beans, Eggs, and Nuts").[11] Some of the recommended quantities for the different types of food in the old pyramid have also come under criticism for lack of clarity. For instance, the pyramid recommends two to three servings from the protein-rich group, but this is intended to be a maximum. The pyramid recommends two to four fruit servings, but this is intended to be the minimum.[12] The fats group as a whole have been put at the tip of the pyramid, under the direction to eat as little as possible, which is largely problematic. Under the guide, one would assume to avoid fats and fatty foods, which can lead to health problems. For one, fat is essential in a person's general sustainability.[13][14][15] Unsaturated fats from a natural source can actually aid in weight loss, reduce heart disease risk,[16] lower blood sugar, and even lower cholesterol.[17][18][19] These fats can be found in olive oil,[20][21] nuts,[22][23] pesto,[24] seafood (including fish, shrimp, squid, and krill among many more)[25][26] and avocados.[27][28] Also, they are very long sustaining, and help keep blood sugar at a steady level.[29][30] On top of that, these fats help brain function as well.[31] Several books have recently claimed that food and agricultural associations exert undue political power on the USDA.[32][33] Food industries, such as milk companies, have been accused of influencing the United States Department of Agriculture into making the colored spots on the newly created food pyramid larger for their particular product. The milk section has been claimed to be the easiest to see out of the six sections of the pyramid, making individuals believe that more milk should be consumed on a daily basis compared to the others.[34]Furthermore, the inclusion of milk as a group unto itself implies that is an essential part of a healthy diet, despite the many people who are lactose intolerant and choose to abstain from dairy, and a number of cultures that have historically consumed little if any dairy products with the exception of breastfeeding.

These controversies prompted the creation of pyramids for specific audiences, particularly some Vegetarian Diet Pyramids.[35][36][37] [edit]Alternatives The Harvard School of Public Health proposes the Healthy eating pyramid, which includes calcium and multi-vitamin supplements as well as moderate amounts of alcohol, as an alternative to the Food Guide Pyramid. Many observers[who?] believe that the Harvard pyramid follows the results of nutrition studies published in peer-reviewed scientific journals more closely. In their book Fantastic Voyage: Live Long Enough to Live Forever, published in 2004, Ray Kurzweil and Terry Grossman M.D., point out that the guidelines provided in the Harvard Pyramid fail to distinguish between healthy and unhealthy oils. In addition, whole-grain foods are given more priority than vegetables, which should not be the case, as vegetables have a lower glycemic load. Other observations are that fish should be given a higher priority due to its high omega-3 content, and that high fat dairy products should be excluded. As an alternative, the authors postulate a new food pyramid, emphasising low glycemicload vegetables, healthy fats, such as avocados, nuts and seeds, lean animal protein, fish, and extra virgin olive oil. The University of Michigan Integrative Medicines Healing Foods Pyramid emphasizes plant-based choices, variety and balance. It includes sections for seasonings and water as well as healthy fats.