Vlad Dima
Department of Neonatology, Filantropia Clinical Hospital, Bucharest, Romania;
Correspondence to: Vlad Dima, MD, Ph.D., Neonatology, dima.vlad@yahoo.com
Abstract
Neonatal screening has proven its usefulness over time by discovering conditions that can profoundly affect the quality of life and the incidence of mortality and morbidity in the pediatric age. Neonatal screening methods differ, with no international consensus. Current neonatal screening in Romania consists of metabolic screening (congenital hypothyroidism, phenylketonuria and mucoviscidosis), screening for hearing loss and screening for congenital hip dislocation. A separate category is represented by premature babies and newborns who were admitted to neonatal intensive care, and they are also subjected to retinopathy screening.
Neonatal metabolic screening has helped in the early detection of inborn errors of metabolism. Even though since the middle of the 20th century, simple and effective test methods for the detection of metabolic diseases have been identified, until now no worldwide consensus has been found regarding the content of neonatal metabolic screening panels. There are large differences between countries in terms of the number of metabolic diseases identified through the national metabolic screening program, the number varied from zero to several dozen, the most frequent testing being done for phenylketonuria and congenital hypothyroidism (including in Romania). Given that rare diseases have been identified in recent decades that can be treated effectively, reducing the financial burden on the health system, we can count on their introduction into the national neonatal metabolic screening program.
Keywords: neonatal screening, hearing loss, retinopathy, congenital dislocation of the hip, inborn errors of metabolism, costs, consensus, extension
History of neonatal screening
Metabolic tests - The most significant event in the history of neonatal screening was the discovery of phenylketonuria (PKU) by Dr. Asbjørn Folling in 1934. The discovery of phenylketonuria was the first biochemical explanation for mental retardation.(1,2)
Guthrie and Susi developed a simple, inexpensive, and effective metabolic test to determine whether newborns have phenylketonuria (PKU) in the mid-20th century.
With the passage of time, new laboratory tests have been developed for the detection of additional diseases, among which we should emphasize congenital hypothyroidism (ChT). Phenylketonuria and congenital hypothyroidism are the diseases most commonly tested for in neonatal metabolic screening programs, and there is substantial variation in the other diseases that are included in national screening programs. (3,4)
Screening for Congenital Hearing Loss - The use of some form of hearing testing as a screening for all newborns was first pioneered by Larry Fisch in 1957, and by the end of the 20th-century hearing loss screening had become standard in most countries. (5)
Hearing loss has been recognized as a factor inducing significant morbidity, which has prevented affected children from reaching their full social, cognitive and economic potential. The effect of early hearing loss was documented in the Ebers papyrus around 1534 BC. Deafness is described as follows: "When deaf, the mouth cannot be opened, that is, it cannot speak" (6). In the 16th and 17th centuries, in monasteries and later in the secular world there were developed various forms of sign language as instructional methods for the severely deaf child. Throughout the world, in the 19th and 20th centuries, special schools were established to educate deaf children.
There have been a number of attempts to create a hearing test device. Three of the first attempts were made by Hartmann in 1878 and in 1879 by Hughes, Richardson and Bell. All of these used a vibration source, for example, a tuning fork and AG Bell's telephone receiver. (7,8,9,10)
Screening for retinopathy - Since it was first described in 1942, ROP has become recognized as the leading cause of childhood blindness. Historically, there have been global epidemic periods of ROP and ROP-induced blindness. (11,12,13)
The first epidemic was seen in the late 1940s and early 1950s when ROP occurred due to unrestricted use of oxygen without adequate monitoring. During this period, the mean birth weight (BW) of ROP infants was 1,370 g (range, 934–1,843 g) and 1,354 g (range, 770–3,421 g) in the United Kingdom (UK) and the United States. (USA), respectively. ( 6,7) The second epidemic began in the late 1960s and early 1970s when the survival of smaller and less mature children increased with the many advances in neonatal care in industrialized countries with well-developed neonatal units. (14,15)
In the early 1990s, it became apparent that an epidemic of ROP blindness was emerging in developing middle-income countries with neonatal intensive care, referred to as the third epidemic. (16,17)
Screening for congenital hip dislocation - In 1936 Ortolani described a simple test that could help establish the diagnosis of congenital hip dysplasia. Unfortunately, his innovation was published in an Italian medical journal that was not widely disseminated, and his method was little known outside Italy. In 1948, von Rosen and his colleagues began using the Ortolani method for examining the newborn hip in Sweden. In 1958, von Rosen and Andren reported that the use of the simple test invented by Ortolani was sufficient for the diagnosis of congenital hip dysplasia. A study by Barlow et al. (1962) examined the early diagnosis and treatment outcomes of a cohort of 9289 newborns with unstable hips identified through a universal clinical screening program at a single institution in the United Kingdom. (18) In 1994, Marks et al. evaluated whether ultrasound screening for hip instability in newborns could prevent or mitigate dislocations with late presentation to the physician.(19)
In the early 1980s, Graf introduced the diagnosis of congenital hip dysplasia by ultrasonography. This avoids radiological exposure, a procedure that is not sensitive in the diagnosis of hip dysplasia in newborns and reveals features undetectable with the Ortolani-Barlow maneuver.(20,21)
Current neonatal screening in Romania
Currently, in 2022, four categories of newborn screening are used: metabolic screening (national testing for phenylketonuria, congenital hypothyroidism and cystic fibrosis; there is also a pilot program for testing for spinal amyotrophy but not yet expanded nationally), screening for congenital hearing loss, screening for congenital dislocation of the hip and screening for retinopathy (for premature newborns and those requiring a long neonatal intensive care stay).
Even if initially the only form of screening for newborns in Romania was metabolic testing, later the other tests were gradually introduced in order to detect early the conditions that can influence the psychosomatic development of children.
The neonatal metabolic screening was introduced in Romania in 2010, being performed in the first 24-72 hours of life. The two conditions found in this metabolic screening are PKU and ChT because they can cause severe neurological damage and developmental disorders if not detected and treated in time.
Symptomatology of PKU ranges from mild to severe. Classic PKU is The most severe form of this metabolic disorder. Infants with classic PKU appear normal until a few months of age. Without treatment, these children develop permanent intellectual disabilities. Neurological manifestations ranging from seizures to psychiatric disorders are also common. Untreated people may have a musty or musty odor as a side effect of excess phenylalanine in the body.
Less severe forms of this condition, sometimes called variant PKU and non-PKU hyperphenylalaninemia, have a lower risk of brain damage.
The signs and symptoms of congenital hypothyroidism result from thyroid hormone deficiency. Affected children may show no signs of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and may be constipated. If left untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals screen newborns for congenital hypothyroidism. If treatment is started within the first two weeks after birth, infants usually develop normally.
In 2022, cystic fibrosis (CF) was also included in the panel of metabolic diseases for which screening is carried out in maternity hospitals.
Cystic fibrosis or mucoviscidosis is a genetic disease with systemic manifestations that mainly affect the lung and pancreas. The disease is present from birth and usually manifests itself in the first years of life, but there are also rare cases where it is discovered later, even in adulthood.
Patients with cystic fibrosis produce mucus of increased consistency in the bronchi and in the digestive tract (pancreas, liver). The plugs formed by the thick mucus clog the bronchi, producing their dilations (bronchiectasis) which can easily become infected with different microbes. Thick secretions can block the pancreatic and bile ducts, with secondary damage to the pancreas and liver, possibly causing growth failure, diabetes mellitus, or liver cirrhosis.
Screening for congenital hearing loss was introduced nationally in 2016. It is performed in the maternity ward before discharge. Basic screening consists of checking for transient evoked auto emissions (TEOAEs), and preterm and term neonates requiring prolonged admission and treatment in the neonatal intensive care unit require auditory brainstem response (ABR) testing.
Congenital hypoacusis is one of the most common congenital anomalies with a frequency of 2-3/1000 in newborns. Failure to detect hearing loss in the first months or even the first years of life will dramatically interfere with the child's ability to learn to speak. Only a hearing child can learn to speak normally. The longer congenital hearing loss goes undiagnosed, the harder it will be for the child to recover from the deficit in language development. Early detection of congenital hearing loss can be corrected with hearing aids and special audiological aid.
Until the introduction of hearing screening for newborns, in Romania, the age at which hearing loss was detected varied between 3 and 4 years; at 3 years old it is already too late to ensure optimal speech development. Magnetic resonance techniques have proven the existence of the phenomenon of "auditory deprivation", that is, the decrease in the volume of the cerebral white matter by decreasing the myelination of the auditory pathways, a phenomenon that has irremediable effects on the possibilities of auditory-verbal rehabilitation; it is known that the period of time during which the hypoacoustic patient was deprived of hearing decisively influences his auditory-verbal performances even after the prosthetic "remediation" of the hearing deficit. Severe, permanent hearing loss, if not detected early, will influence and cause serious repercussions on speech development, language acquisition and cognitive development, having a negative effect on the quality of emotional and social life. International scientific research in this field clearly demonstrates that the level of language development is significantly better in the case of children diagnosed as hearing impaired up to the age of 6 months and who are treated with hearing protection or, where appropriate, a cochlear implant immediately after diagnosis compared to children. in which the diagnosis of hearing loss is established after 6 months. It is known that 90% of hearing-impaired children at the age of 5 have permanent hearing loss from the neonatal period. (22)
Screening for retinopathy of prematurity was initiated in 2002 in several maternity hospitals in Bucharest, later expanding to maternity hospitals in the province after 2004. It is routinely performed in premature infants with VG ≤ 34 weeks and Gn ≤ 2000 g. They are also included in the screening and premature with VG > 34 weeks and Gn > 2000 g with perinatal risk factors (hypoxia at birth, respiratory distress syndrome of the newborn for which they received oxygen therapy with FiO2 > 40%, mechanical ventilation, intraventricular hemorrhage, hyperbilirubinemia, jaundice prolonged, neonatal sepsis, anemia, necrotizing enterocolitis, neonatal shock for which he received dopamine treatment).
The first examination is done 28 days after birth but not before 31 postconceptional weeks. The following examinations for RP are similarly done at intervals of 7 – 14 days or even more often, depending on the stage of RP, the area where the lesions are located and the presence of the plus factor.
Data from the literature show that, in economically developed countries, the proportion of childhood blindness is 600 to 10 million people, of which 60 cases are caused by retinopathy of prematurity, in contrast to developing countries, where the proportion of blindness to child reaches 1,800 per 10 million people, of which 450 cases are caused by retinopathy of prematurity . (23)
The incidence of retinopathy of prematurity (ROP) is inversely proportional to birth weight (BW) and gestational age (GA) and, in addition, with the technological development and modernization of neonatal intensive care units, the rates of survival of preterm infants with gestational age ≤28 weeks and, as a result, the incidence of ROP has also increased. (24,25)
Screening for congenital hip dislocation has not yet been introduced as a national program, but it is recommended at the discharge of newborns in most maternity hospitals in Romania. Hip ultrasound according to the Graf method provides an efficient evaluation method for the coxofemoral joint, allowing the early detection of developmental dysplasia and the follow-up of the applied treatment. The most used technique is the static technique developed by Prof. Reinhard Graf. It is performed approximately 3-4 weeks after birth.
Congenital dysplasia of the hip can be diagnosed from birth, the first 6 weeks of the child's life being decisive for the further development of the hip. Left untreated, this condition will progress to hip subluxation or dislocation after the child begins to walk. The incidence of the disease is around 1:1,000 births, with a significantly higher frequency in girls compared to boys, respectively 8:1. (26)
Neonatal screening – possibilities to expand the current package
To define the requirements that must be met to include additional diseases in screening programs, the World Health Organization published the Wilson and Jungner criteria for screening in Principles and Practice of Screening for Diseases in 1968. These criteria aimed to ensure that these programs fulfill the main objective: maximum benefit with minimum cost. A screening test is cost-effective when it reduces expenses or when the cost of the test, lifetime treatment, and follow-up are offset by the health benefits to the patient. (27)
Certain conditions can be added to the national neonatal screening, they are intensively studied while new therapeutic possibilities have created the premises of a story with a happy ending.
Screening for spinal muscular atrophy (SMA)
SMA is a rare and devastating disease.
SMA affects about 1 in 10,000 people. Most cases of SMA occur when a segment of a gene called SMN 1 is missing, causing the gene to be unable to make proteins. SMN1 is primarily responsible for the production of the survival motor neuron (SMN) protein, which is required to maintain normal motor neuron function. Lacking enough SMN protein, progressive loss of controlled muscle movement will appear due to motor neuron degeneration. There are different levels of SMA severity. Usually, the earlier the onset of the disease, the more severe the symptoms. SMA can affect the infant's ability to swallow, breathe, sit, and walk. (28)
New disease-modifying treatments have recently been approved, and early treatment has been linked to a better outcome. Due to these discoveries, some newborn screening programs were implemented in some countries. Tamara Dangouloff et al. conducted a survey and contacted experts from 152 countries, collecting 87 responses. The results were published in 2021. They identified 9 screening programs that also contain SMA testing. They have so far detected 288 newborns with SMA out of 3,674,277 newborns tested. Many respondents highlighted the lack of cost-benefit data as a major obstacle to the implementation of tests for SMA in neonatal screening programs. For the next four years, the data predicts 24% coverage of newborns in countries where a disease-modifying drug is available and 8.5% coverage in countries without a disease-modifying drug. The annual proportion of newborns to be tested is expected to increase steadily. Experts have expressed a strong need for the implementation of tests for early detection of SMA in neonatal screening programs as a means of increasing the care of patients with SMA. (29)
Screening for congenital heart malformations
Critical congenital heart disease (CCHD) is a group of heart defects that cause severe, life-threatening symptoms and require intervention in the first days or first year of life. CCHD is one of the leading causes of death in infants under one year of age. The CDC reports that 7,200 babies are born with the condition each year in the United States.
CCHD is often treatable if caught early. It can include heart rhythm abnormalities as well as a wide range of structural heart problems.
CCHD is defined as any cardiac injury from which newborns die or require surgery or cardiac catheterization within the first 28 days of life to prevent death or severe organ damage. (30,31) Early detection of congenital heart diseases before acute cardiovascular collapse improves cardiopulmonary outcomes. However, most newborns are asymptomatic at birth. Newborn screening for CCHD can help identify cases to allow prompt diagnosis and treatment and prevent disability or fatal outcomes. In the absence of newborn screening for CCHD, the combination of antenatal ultrasonography and simple clinical examination of the newborn results in up to 30% of cases of CCHD being referred home before diagnosis, with mortality rates of up to 50%. (32,33)
PO is a simple, non-invasive and painless tool that measures oxygen saturation and therefore could detect CCHD with channel-dependent systemic or pulmonary blood flow that usually presents with hypoxemia. Seven severe lesions were identified as primary targets for screening by PO; these are hypoplastic left heart syndrome, truncus arteriosus, pulmonary atresia, tetralogy of Fallot, total abnormal pulmonary venous return, transposition of the great arteries and tricuspid atresia. (34)
Discussions
Currently, the variability of the content of screening programs in the European Union is very high, as there are programs that include up to 30 disorders and others that include only 2. In addition, different conditions or diseases vary not only between different European countries but also within different regions of a given country. There is therefore an urgent need to create a consensus on which diseases should be included in the 48 European countries. (35) For the Middle East and North Africa, comprising 21 countries, there is no consensus on the package of diseases included in the screening program, and SMBN by MS/MS (mass spectrometry) is selective or limited, while for congenital hypothyroidism there is high coverage.(36) The 20 countries in Latin America and the 24 countries in the Asia Pacific area do not have a uniform screening package and, except for 1 or 2 countries, all screen for congenital hypothyroidism. Currently, developed countries around the world have adopted the SMBN program. (37,38)
The expansion of screening programs in Romania could have a positive financial impact on the health system, managing to detect conditions in time that could improve the infant mortality rate and decrease the number of hospitalizations generated by these conditions.
Along with the introduction of a new range of neonatal screenings at the national level, it is also necessary to develop a network that can effectively treat the discovered conditions, both surgically (the addition of neonatal cardiovascular surgery centers) and medicinally (the treatment of AMS and CF).
Conclusion
Newborn screening for various conditions has brought about a considerable decrease in the rate of infant morbidity and mortality. The costs for carrying out national screening programs have proven to be considerably lower than those for late treatment of the conditions included in the screening. The medical implications of some pathologies with increased incidence in the neonatal age are constantly evaluated and cost estimates are made for introduction into national screening programs. The creation of common databases at the national level, accessible to all doctors, could encourage and improve the reporting of cases that fall within the diagnostic criteria of the diseases included in the national neonatal screening programs. There is a need to expand the current package of diseases included in the screening programs to achieve a national improvement in the quality of life for newborns at risk and to achieve a better use of financial resources within the Romanian health system.
References