A Systematic Approach in Neonatal Screening

Abstract

In numerous countries, newborns are screened for diseases whose early detection can avoid permanent damage. There tends to be global agreement that the only conditions included in national newborn screening programs are a reliable test and a proven therapy with clear benefits for the child's well-being. Through the National Health Programmes, newborns in Romania are examined for deafness, signs of retinopathy of prematurity and two metabolic disorders (phenylketonuria (PKU) and congenital hypothyroidism).

Expanding the TORCH Panel: Integrating COVID-19 Testing for Comprehensive Prenatal Care

The TORCH panel is a screening test used for diagnosing infections that could potentially affect unborn children. Poor obstetric outcomes such as congenital anomalies, mental retardation, deafness and even abortion and stillbirth can be caused when these infections are not treated [1].

Traditionally, TORCH (Toxoplasmosis, Rubella, Cytomegalovirus, and Herpes) has been the acronym associated with this test. However, with the emergence of the COVID-19 pandemic, healthcare professionals weigh the benefits of including SARS-CoV-2 in the TORCH panel. This article explores the significance of incorporating COVID-19 testing into routine prenatal care.

For CMV, HIV, and HSV infections, transmission occurs throughout pregnancy, during delivery, and after birth through transplacental passage, contact with blood and vaginal secretions, or exposure to breast milk. Infection typically appears at birth, during infancy, or in later years of life [2].

Several studies have been conducted to investigate the potential vertical transmission of SARS-CoV-2. Initial reviews and case studies indicated no conclusive evidence of transplacental transmission or severe morbidity and mortality in pregnant women with COVID-19. However, more recent case reports have provided evidence of vertical transmission and symptomatic disease in newborns [3,4].

One study reported cases from China, where six women with mild COVID-19 gave birth to infants who were immediately isolated. Two of these infants had IgM antibodies to SARS-CoV-2, indicating possible vertical transmission, although subsequent testing showed no viral RNA. Another study identified three neonates born to mothers with COVID-19 who tested positive for SARS-CoV-2 infection, with two infants exhibiting shortness of breath, fever, vomiting, tachycardia, abnormal liver function tests, thrombocytopenia, and pneumothorax. The third was a premature infant (gestational age of 34 weeks), who passed away as a result of multiple organ failure, refractory shock and disseminated intravascular coagulation. A third study detected positive IgM serology in a neonate born to a mother with COVID-19 [3].

While vertical transmission appears possible, other routes of perinatal transmission, such as aerosol or droplet transmission during delivery or transmission through breastfeeding, cannot be ruled out. Breast milk studies have not found evidence of COVID-19, but further research is needed. Lessons from congenital CMV infection suggest that both intrapartum transmission and postnatal acquisition through breastfeeding are possible [2,4].

The studies conducted so far provide mixed findings, and more research is needed to understand the extent and mechanisms of vertical transmission. Until proven otherwise, the transplacental route should be assumed as a mechanism of transmission. Expert guidelines regarding the separation of COVID-19 positive mothers and their newborns vary, with recommendations ranging from room sharing with respiratory hygiene to temporary separation until the mother is asymptomatic and free of infection.

Inconsistencies in expert recommendations highlight the knowledge gaps that exist regarding perinatal transmission of SARS-CoV-2, emphasizing the need for further studies to inform guidelines and protocols in this area.

In conclusion, by incorporating this additional screening, healthcare providers could proactively identify and manage COVID-19 infections, reduce the risk of vertical transmission, and tailor treatment approaches to safeguard the health of both the mother and the developing fetus, but further research on this subject is needed[3] .

Hearing screening

One of the most widespread congenital anomalies is congenital hearing loss. Nearly 60% of hearing loss in children is caused by conditions that may be avoided through preventive measures such as immunization, better maternal and neonatal care, and early screening and treatment of otitis media. As a result, by 2050, it is anticipated that 1 in 4 individuals worldwide will have some degree of hearing loss, and that 1 in 14 (at least 7%) will need hearing care [5].

The aim of neonatal hearing screening is early detection of congenital hearing loss and immediate intervention for better speech and language development. There are two recommended methods for neonatal hearing screening: optoacoustic emission (OAE) and automated auditory brainstem response (AABR) [6].

There are some differences between the two techniques, even though both are sensitive and specific enough to be used in screening. The most significant difference is that the OAE is only examining the cochlear level, where in more than 90% of the cases is the defect, but not the neural pathway, which may be affected in a small proportion of cases. On the other hand, OAE is far less expensive, faster and requires fewer consumables than AABR. Since they don’t require placing electrodes on the skin, they are also less painful. Performance-wise, AABR is more accurate than OAE, especially in the first days after birth [7].

Children all over the world struggle with hearing loss and neurological abnormalities as a consequence of congenital cytomegalovirus (cCMV) infection. Even though just a few percent of infants with cCMV will show symptoms at birth, these children are most at risk for long-term effects. The majority of newborns with cCMV are asymptomatic, but 10-15% are likely to develop hearing loss. The virus must be detected within the first three weeks of life in saliva or urine, although saliva PCR is the preferred approach due to its simplicity and high sensitivity. The standard care for newborns with symptomatic cCMV is antiviral therapy with valganciclovir for 6 months. According to a consensus among experts, mildly symptomatic cCMV disease refers to one or two isolated, temporary symptoms (e.g., isolated petechiae or mild hepatomegaly). On the other hand, mildly to severely symptomatic cCMV infection includes several manifestations: thrombocytopenia, petechiae, hepatomegaly, splenomegaly and hepatitis. Moderate to severe symptomatic CMV can be characterized as the involvement of the central nervous system (e.g., microcephaly, seizures and/or radiographic abnormalities of the central nervous system) with or without additional clinical signs of cCMV [8].

A cohort study investigated the prognostic value of neonatal cranial ultrasound (cUS) and cranial magnetic resonance imagining (cMRI) for symptomatic and asymptomatic CMV-infected patients to predict long-term hearing outcomes. In children with a CMV infection, hearing loss is correlated with neuroimaging evidence of neonatal central nervous system involvement. In 22.2% of cUS abnormalities were revealed to be linked to CMV infection, whereas 26.9% of cMRI showed abnormalities. It’s not possible to predict the first signs of delayed-onset hearing loss based on imaging abnormalities [9].

Screening of inborn errors of metabolism

Inborn errors of metabolism cover up a large group of rare diseases caused by an inherited deficiency or absence of proteins that have certain roles such as enzymatic, carrier, receptor, or structural.

The screening of inborn metabolic diseases (IMD) has a major role in early diagnosis and aims to start the treatment before the onset of symptoms [10]. In a study from the German network that spanned over 11 years it was shown that implementation of a successful program of secondary prevention provides a correct diagnosis in more than 90% of asymptomatic cases [11].

Clinical examination can sometimes be of tremendous help in asking for the right markers of inborn error metabolism disorders. The presence of vesicular or bullous lesions has been linked to complex phospholipids and fatty acid synthesis/remodeling defects as well as peroxisomal disorders. Dilated cardiomyopathy with secondary heart failure in neonates is rare but it is connected to mitochondrial disorders and Pompe’s disease [12].

Another factor to take into consideration is the moment of diagnosis of the metabolic disease. A study from the US showed that blood collection before 24 hours of life can be associated with false positive results for inborn metabolic disorders such as phenylketonuria, methylmalonic acidemia and carnitine transport defect. The quantification of amino acids and acylcarnitines in dried blood spots allows the simultaneous detection of more than 30 metabolic disorders, including those associated with amino acid, organic acid, and fatty acid metabolism [13].

Primary carnitine deficiency is a rare metabolic disease that is characterized by low plasmatic concentrations of carnitine in the muscle (muscle carnitine deficiency affecting proximal limbs and neck) or systemic carnitine deficiency which presents as an autosomal recessive disease caused by the function of a carnitine transporter from the plasma to the cytosol. With the help of neonatal screening, diagnosed newborns can be treated with a high dosage of carnitine, improving the development of cardiomyopathy and myopathy [14].

Skeletal muscles are also affected by spinal muscular atrophy, a rare disorder that affects 1 in 11000 people and it can be diagnosed in asymptomatic newborns with genetic defects on the SMN1 gene. If it is discovered early, newborns can receive proper treatment that helps replace the missing protein that the SMN1 gene normally makes. Screening and this kind of treatment is extremely useful in slowing the process of the disease and preventing of worsening symptoms [15].

Maple syrup urine disease (MSUD) is an autosomal recessive disorder and occurs in approximately 1 in 200,000 live births. It is caused by a deficiency of the branched chain alpha keto acid dehydrogenase complex that increases certain amino acids in the blood and urine. According to the UK guidelines for metabolic screening, It is likely that patients with the classic condition will be detected (vomiting or difficulty feeding associated with lethargy) but may not detect individuals with intermediate or intermittent forms that have a spectrum of clinical and biochemical severity [16].

As part of the small molecule disorders, nonketotic hyperglycinemia is a rare neurometabolic disease caused by the accumulation of glycine in all tissues, mostly in the central nervous system due to the breakdown of glycine to carbon dioxide and ammonia [17]. The severe form presents with epileptic encephalopathy while other symptoms include lethargy, coma, myoclonic jerks and seizures resulting in a profound developmental delay in all these patients [18]. On the other hand, even though the attenuated form may mimic the severe form in the neonatal period, it usually presents itself with delayed neuro-motor achievements later in life and does not have congenital brain malformations associated [19].

As a take home message, inborn errors of metabolism are rare and with the help of newborn bloodspot screening there is early diagnosis and accessibility to preventive treatment because the diseases with which they are associated often have a significant impact on the growth and long-term health of the affected children [20].