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Extra catch with neonatal screening for CCHDs

Apart from critical congenital heart defects, other significant pathology can be detected and treated at an early stage. Universal screening guidelines applying to all countries are difficult to establish

Ilona C Narayen MD
Arjan B te Pas MD PhD
Department of Neonatology
Nico A Blom MD PhD
Pediatric Cardiology, Leiden University Medical Center, Leiden, the Netherlands
Pulse oximetry screening for critical congenital heart defects (CCHD) has been studied widely and was proven to be safe, accurate, acceptable for parents, and cost effective.1–3 As a result, the screening method is implemented increasingly in countries worldwide. Among the false positive screenings many other significant pathologies are detected as secondary targets. 
The pulse oximetry technique
The assessment of oxygen saturation with pulse oximetry is based on the difference in absorption of red and infrared light of oxygenated and deoxygenated haemoglobin. A light emitter shines red and infrared light through the tissue of application, and on the opposite side of the tissue there is a photodetector receiving the through light transmitted red and infrared signals. Oxygenated haemoglobin absorbs more light in the infrared wavelength band, while deoxygenated haemoglobin absorbs more light in the red wavelength band. The ratio of absorbance of infrared and red light is used to calculate the oxygen saturation. Pulse oximetry has been used for continuous monitoring of oxygen saturations in newborns since the 1980s.4 It is currently the standard of care for sick or at risk infants at neonatal intensive care units (NICUs). The first studies with the use of pulse oximetry as a screening method for congenital heart defects in neonates were published in 2002 and these were followed by many studies in different settings.5,6
Pulse oximetry screening for critical congenital heart defects
CCHD leads to death within 28 days of life if no medical intervention is performed.2 Early recognition of the defects can lead to improved survival and less morbidity. Ideally, all CCHDs would be detected during pregnancy, so the delivery can be planned in a centre with specialised paediatric cardiologic care. However, antenatal ultrasound scans detect approximately 50% of all CCHDs.7,8 After birth, symptoms of CCHD can be missed, since the human eye can not detect cyanosis unless oxygen saturations drop below 80%.9 In addition, in more than 50% of CCHDs a murmur is absent. With the addition of pulse oximetry screening, more than 95% of CCHDs can be detected at an early stage, increasing the chances of survival without severe neurocognitive and/or motor impairment.10
Secondary catch with pulse oximetry screening
In most protocols pulse oximetry screening is positive if the oxygen saturation is below 90% at the pre- or post-ductal measurement, or if there is a repeat measurement with both readings below 95% or a difference of more than 3% between the two readings. All cases of true and persistent hypoxaemia should be further investigated and different causes should be taken into account. Indeed, the screening is set up primarily to detect CCHD, but also other significant pathology in neonates should be considered. Previous studies report up to 78% of significant non CCHD pathology found with positive screenings.8,11 Although this pathology is a secondary target of the screening, the label ‘false positive’ underestimates the value of the detection of these cases. Examples of significant pathology leading to hypoxaemia in neonates are persistent pulmonary hypertension of the newborn (PPHN), infection, sepsis, pneumonia and non-critical congenital heart defects. 
Persistent pulmonary hypertension of the newborn (PPHN)
In children with PPHN the pulmonary vascular resistance fails to decrease adequately after birth, leading to hypoxaemia due to intracardial and ductal right to left shunting.12,13 The incidence of PPHN is one to two per 1000 live births in the developed world and PPHN leads to death in approximately 10% of the cases.14 PPHN is associated with neurodevelopmental impairment. Neonates with PPHN usually present with cyanosis on the first day of life and the gold standard for diagnosis is echocardiography.13 Treatment of PPHN consists of improving the oxygenation and increasing the systemic blood pressure. Early treatment and close monitoring can prevent deterioration and the need of more intensive treatment, such as high frequency oscillation ventilation, inhaled nitric oxide and/or extracorporeal membrane oxygenation (ECMO).12,13
Wet lung
Wet lung, or transient tachypnoea of the newborn, is characterised by pulmonary oedema, caused by delayed clearance of alveolar liquid after birth.15 The incidence is one to two percent of the newborns. Neonates with wet lung often present with cyanosis and respiratory distress. Although wet lung is usually benign and self-limiting, it sometimes can lead to PPHN. Early detection with pulse oximetry and adequate monitoring is therefore important. Initial treatment consists of providing adequate oxygenation, and if needed, continuous positive airway pressure.15
Early onset sepsis (during the first seven days of life) has a mortality rate of 3% in term infants and occurs in one to two per 1000 live newborns.16 Sepsis is still responsible for 5% of the perinatal mortality.17 Hypoxaemia can be an early sign of infection or sepsis, and pulse oximetry screening can lead to early detection. Full-blown disease, including shock and organ failure can be prevented when it is treated at an early stage. This reduces the risk of adverse outcome considerably.
Non-critical congenital heart defects
Non-critical congenital heart defects, such as septal defects, can also be detected at an early stage with pulse oximetry screening. Early diagnosis enables early detection and treatment of heart failure and surgery can be planned at an early stage. 
Pulse oximetry screening around the globe
The authors of a large systematic review and meta analysis in the Lancet concluded that pulse oximetry screening meets the criteria for universal screening.1 In 2011 the American Academy of Pediatrics endorsed the recommendation by the US Secretary of Health and Human Services to add pulse oximetry screening for CCHD to the uniform screening panel.18 Currently, legislation of CCHD screening is enacted in 44 of 50 states in the US, whereas the screening is regulatory added to the Newborn Screening Panel in four states. (
Scandinavia has the highest implementation rate in Europe, with the highest rate in Finland.19 The implementation rate is also high in the United Arabic Emirates.20 Furthermore, pilot studies with pulse oximetry screening for CCHD are performed in many countries including the UK, Germany, Italy, Spain, Australia, China and the Netherlands. Although there is awareness for the screening in individual countries in Central and South America and in Africa, there are still concerns on availability and accessibility of proper treatment for CCHD.20
Although many large and important studies were performed in Europe, it remains difficult to develop universal European guidelines. In contrast to the US, there is a large variability in perinatal healthcare among different countries in Europe. For example, the rate of home births and duration of hospitalisation after delivery show large differences, with the highest rate of home births and early discharge after delivery in hospital in the Netherlands.21,22 It is important to share experiences from pilots among the different countries, so each country can produce a guideline that is adapted to their national perinatal healthcare system. A group of international experts have formed a scientific board on CCHD screening in order to share knowledge and enhance implementation of the screening among the European countries.23
The endorsed protocol in the US performs screening 24–48 hours after birth, since the false positive rate was higher when the screening was performed in less than 24 hours of life.1,24 However, infants with CCHD had presented with symptoms prior to the screening, with circulatory collapse in up to 9% of the infants when screening was performed after 24 hours.25 Other studies showed a higher sensitivity with screening before 24 hours after birth.2,26 The benefit of detecting CCHD and other significant pathology at an earlier stage should be balanced against the disadvantage of having more false positive screenings. Since hospitalisation after delivery and home birth rates vary between countries, an optimal screening time for specific settings should be defined.
Pulse oximetry screening in different care settings
There is broad experience in CCHD screening in a hospital setting, in both large and smaller regional hospitals. This setting has been studied widely and the proof of concept has been demonstrated. The extra value of pulse oximetry screening at NICUs has been studied, but only in small trials.27,28 Screening at NICUs is feasible, but can lead to a higher false positive rate and there remains a debate on the timing and eligibility of the screening at NICUs.27,28
Australia, Wisconsin and the Netherlands have experience in pulse oximetry screening out of hospital.22,29,30 Especially in the Netherlands, where 30% of all births are supervised by community midwives, an adapted protocol for pulse oximetry screening at home was needed.22 An adjusted protocol has been developed and was proven feasible in the Dutch perinatal care system. Accuracy and cost effectiveness are currently being tested in a large implementation trial. 
In remote settings there has been little experience with pulse oximetry screening so far. A possible solution for echocardiography is telemedicine. However, there are also regions were proper treatment for CCHD is not available. An advantage of screening in this setting could be the possibility of transporting to specialised centres, detection of treatable secondary targets, or the possibility for parents to prepare for deterioration of their infant and giving the infant comfort.
Studies performed at moderate and high altitude showed a higher false positive rate for pulse oximetry screening with the usual cut-off values as compared to studies at sea level.31,32 This can be explained by a delay in decrease of pulmonary vascular resistance at altitude. Optimal cut-off values remain to be developed for settings at moderate or high altitude.
The devices of Masimo (Irvine, California) and Medtronic (Dublin, Ireland) are most frequently used in the performed accuracy studies. However, all new generation pulse oximeters that are cleared for use in newborns, are usable in low perfusions state, report functional oxygen saturation, and are motion tolerant can be used for pulse oximetry screening.33
Although the diagnostic gap is decreased, not all CCHDs can be detected with the addition of pulse oximetry screening to the regular screening pathways. Defects with aorta obstruction are most commonly missed; these are the coarctation of the aorta and the interrupted aortic arch. Unfortunately, these defects are also difficult to detect with an antenatal ultrasound. When both pre- and post-ductal pulse oximetry measurements are performed, there is a higher chance of detecting heart defects with left outflow tract obstruction.1,2
Pulse oximetry screening for CCHDs has been proven to be accurate, acceptable and cost effective. As an important advantage, significant other pathology can be detected in an early setting. Both the detection of CCHDs and other pathology including infection, sepsis, and PPHN have the ability to make perinatal healthcare safer, especially in countries with home births or early discharge after delivery in hospital. Pulse oximetry screening is being implemented increasingly around the world, but due to differences in logistics and duration of hospitalisation it remains difficult to produce universal guidelines that fit in the perinatal care systems of all countries. The available knowledge and experience should be shared in order to enable implementation in more settings.
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