INTRODUCTION — Congenital heart disease (CHD) is the most common congenital disorder in newborns [1-3]. Critical CHD, defined as requiring surgery or catheter-based intervention in the first year of life (table 1), accounts for approximately 25 percent of all CHD [4]. Although many newborns with critical CHD are symptomatic and identified soon after birth, others are not diagnosed until after discharge from the birth hospitalization [5-8]. In infants with critical cardiac lesions, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary center with expertise in treating these patients [9-11].
Newborn pulse oximetry screening (POS) for detection of critical CHD will be reviewed here. The presentation of critical CHD and management of specific cardiac conditions are discussed separately. (See "Identifying newborns with critical congenital heart disease" and "Cardiac causes of cyanosis in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)
DEFINITION AND TARGETED LESIONS — The following terms are used in this topic:
●Critical CHD – Critical CHD refers to lesions requiring surgery or catheter-based intervention in the first year of life. This category includes ductal-dependent and cyanotic lesions as well as less severe forms of CHD that are not dependent on the patent ductus arteriosus (PDA) (table 1). Critical CHD accounts for approximately 25 percent of all CHD.
●Targeted lesions – CHD lesions targeted by pulse oximetry screening (POS) include defects that typically: (A) require intervention in the first year of life, and (B) present with hypoxemia some or most of the time [12-14]. These include but are not limited to:
•Hypoplastic left heart syndrome (figure 1) (see "Hypoplastic left heart syndrome: Anatomy, clinical features, and diagnosis")
•Pulmonary atresia with intact ventricular septum (figure 2) (see "Pulmonary atresia with intact ventricular septum (PA/IVS)")
•Pulmonary atresia with ventricular septal defect
•Tetralogy of Fallot (figure 3) (see "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis")
•Total anomalous pulmonary venous connection (figure 4) (see "Total anomalous pulmonary venous connection")
•Transposition of the great arteries (figure 5) (see "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis")
•Tricuspid atresia (figure 6) (see "Tricuspid valve atresia")
•Truncus arteriosus (figure 7) (see "Truncus arteriosus")
•Coarctation of the aorta (figure 8) (see "Clinical manifestations and diagnosis of coarctation of the aorta")
•Double-outlet right ventricle
•Ebstein anomaly (figure 9) (see "Clinical manifestations and diagnosis of Ebstein anomaly")
•Interrupted aortic arch (figure 10)
•Single ventricle
PREVALENCE OF CRITICAL CONGENITAL HEART DISEASE — CHD is the most common congenital disorder in newborns, with a birth prevalence of approximately 1 percent [1-3]. Up to 25 percent of infants with CHD have a "critical" defect. Numerous familial, maternal, and pregnancy-related factors have been reported to be associated with an increased risk of CHD (table 2). In addition, CHD is a common finding in a number of genetic syndromes (table 3). The epidemiology of critical CHD is discussed in detail separately. (See "Identifying newborns with critical congenital heart disease", section on 'Epidemiology'.)
CONSEQUENCES OF LATE DETECTION — Most newborns with critical CHD are diagnosed either prenatally or upon clinical examination during the birth hospitalization. However, up to 30 percent of newborns with critical CHD appear healthy on routine examination, and signs of critical CHD may not be apparent in the first days of life [15,16]. Cyanosis may not be clinically apparent in patients with mild desaturation (>80 percent saturation) or anemia [17]. In newborns with dark skin pigmentation, cyanosis can be especially difficult to appreciate. (See "Identifying newborns with critical congenital heart disease", section on 'Postnatal diagnosis'.)
The timing of presentation varies with the underlying lesion and its dependence upon a patent ductus arteriosus (PDA). In patients with ductal-dependent lesions (table 1), closure of the PDA within the first few days of life can precipitate rapid clinical deterioration with potentially life-threatening consequences (ie, severe metabolic acidosis, seizures, cardiogenic shock, cardiac arrest, or end-organ injury) [18]. Other patients may have lesions that are not dependent on the patency of the PDA (eg, total anomalous pulmonary venous return, truncus arteriosus), yet delayed diagnosis can similarly lead to poor outcomes. For infants with critical CHD who are not diagnosed during the birth hospitalization, the risk of mortality is as high as 30 percent [9,11,19].
In a population-based observational study of 3603 infants with critical CHD born in 1998 to 2007 (prior to institution of routine newborn pulse oximetry screening [POS]) identified through a state Birth Defects Registry, approximately one-quarter of patients were not diagnosed during the birth hospitalization [20]. In this group of late-detected critical CHD (n = 825), 15 deaths were deemed to be potentially preventable (1.8 percent). In addition, adjusted multivariable analysis showed that infants with late-detected critical CHD had a greater number of admissions, more hospitalized days, and higher inpatient costs than those diagnosed prenatally or during the birth hospitalization.
In a simulation model based upon estimates of birth prevalence, prenatal diagnosis rates, late detection rates, and sensitivity of POS, one study estimated that 875 infants with critical CHD will be detected annually in the United States through newborn screening [16]. An additional 880 false-negative screenings are expected.
BENEFITS OF SCREENING
Early detection of critical CHD — The primary benefit of newborn pulse oximetry screening (POS) for critical CHD is timely identification of newborns with critical CHD prior to discharge from the birth hospitalization, thereby minimizing the morbidity and mortality associated with delayed diagnosis.
Universal newborn POS improves detection of critical CHD compared with physical examination alone [10,21]. In one large prospective study, there was a lower rate of missed diagnoses of critical CHD for newborns born in the region that routinely performed POS compared with those born in regions where newborns were not routinely screened (8 versus 28 percent) [10]. In addition, no infant died from a ductal-dependent lesion in the region utilizing routine POS versus five deaths in regions without routine screening.
In a report of one statewide screening program (2011 to 2012) that successfully screened 99 percent of 73,320 eligible newborns born during the study period, 49 newborns had a positive screen and underwent further diagnostic evaluation [22]. Of the 49 newborns with positive screens, 19 had additional signs and symptoms that would have triggered a diagnostic evaluation, whereas 30 underwent evaluation based solely upon the screening result. Of these, three had previously undiagnosed critical CHD.
Further evidence supporting newborn POS comes from studies demonstrating reductions in unplanned CHD hospitalizations and CHD-related mortality among infants born in regions where screening policies have been implemented [23,24]. In one study, implementation of mandatory statewide newborn POS programs was associated with a 33 percent reduction in early infant CHD-related mortality compared with states without mandatory screening (absolute decrease of 3.9 deaths per 100,000 births) [23]. In another study, CHD-related emergency hospitalizations during the first three months after birth were lower in states that had implemented mandatory newborn POS compared with the pre-implementation era and states without mandatory screening (absolute difference of 5.5 fewer hospitalizations per 10,000 live births; adjusted rate ratio [aRR] 0.78, 95% CI 0.64-0.94) [24]. In this study, the impact of POS on reducing hospitalizations differed according to race, with less of an impact among Black infants. This finding highlights the importance of considering healthcare disparities and equity when implementing screening programs.
Detection of other serious conditions — A secondary benefit of newborn POS is that it identifies other serious neonatal conditions associated with hypoxemia. Common noncardiac causes of hypoxemia that are identified through newborn POS include [14,22,25-27] (see "Approach to cyanosis in the newborn", section on 'Causes of central cyanosis'):
●Sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates")
●Pneumonia (see "Neonatal pneumonia")
●Transient tachypnea of the newborn (TTN) (see "Transient tachypnea of the newborn")
●Respiratory distress syndrome (RDS) (see "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis")
●Persistent pulmonary hypertension of the newborn (PPHN) (see "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis")
●Meconium aspiration syndrome (MAS) (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")
●Pneumothorax (see "Pulmonary air leak in the newborn")
Many newborns who screen positive are ultimately found to have one of these conditions. In a study of 253 newborns who had positive screening results, only 22 (9 percent) were ultimately found to have clinically significant CHD [27]. Of the 231 newborns without CHD, 97 percent were diagnosed with serious noncardiac conditions, including pneumonia (33 percent), TTN (26 percent), sepsis (23 percent), PPHN (8 percent), MAS (4 percent), pneumothorax (1 percent), and RDS (1 percent). In the remaining six newborns, the abnormal POS result was attributed to transitional circulation. (See "Overview of neonatal respiratory distress and disorders of transition", section on 'Transition from fetal life'.)
HARMS OF SCREENING — The potential benefits of screening must be weighed against the downside of false positives. In a 2018 meta-analysis of 21 studies including >450,000 newborns, the pooled false-positive rate was 0.14 percent (95% CI 0.7-0.22) [28]. Newborns with false-positive screening results undergo additional testing and/or transfer to centers with more advanced pediatric cardiac care. This additional testing has the potential to cause discomfort or harm to the newborn and cause anxiety in the parents. It is important to recognize, however, that in many cases, the evaluation results in identification of other causes of hypoxemia. (See 'Detection of other serious conditions' above.)
In a study evaluating the acceptability of POS to the parents of newborns, parents were mostly satisfied with screening, perceived it as an important test, and would recommend it to others [29]. Mothers given false-positive results were not found to be more anxious after screening than those given true negative results, although they were less satisfied with the test.
APPROACH TO SCREENING
Screening algorithms — In the United States, the 2011 AAP-endorsed guideline is the most commonly used algorithm for newborn POS (algorithm 1A) [30-32]. Alternative algorithms include the New Jersey algorithm [22], the Tennessee algorithm [33], and other modifications to the 2011 AAP algorithm [34].
In 2018, an expert panel was convened to review screening practices in the United States and to identify opportunities to improve screening process [32]. From this meeting, a new algorithm was proposed (algorithm 1B). This modified algorithm has been adopted by many states.
Timing — Screening should be performed after 24 hours of life or as late as possible if early discharge is planned. Screening within the first 24 hours of life is not as specific as later screening, because hypoxemia commonly occurs during the transition from intrauterine to extrauterine life conditions [35-38]. (See "Overview of neonatal respiratory distress and disorders of transition".)
Technique — Screening should be performed by qualified and trained personnel [39]. Oxygen saturation (SpO2) is measured in the right hand (preductal) and either foot (postductal) (algorithm 1A). Screening at both locations can occur simultaneously or in direct sequence. Postductal measurement of SpO2 is important because defects with right-to-left shunting of desaturated blood through the ductus arteriosus will not be detected with only preductal measurement.
The screening should be performed using a motion-tolerant pulse oximeter. Either disposable or reusable probes can be used. Reusable probes reduce the cost of screening but must be appropriately cleaned to minimize the risk of infection. Measurements should not be performed when the newborn is crying or moving, because this reduces the quality of the signal and the accuracy of the test [35,40]. In addition, pulse oximetry testing may fail to detect hypoxemia if there is interference from ambient light, partial probe detachment, electromagnetic interference, poor perfusion at the site of measurement, and/or hemoglobinopathy [41]. (See "Pulse oximetry".)
POSITIVE SCREEN
Criteria for positive screen — Criteria for a positive screen (ie, "failing" the screen) using the 2011 American Academy of Pediatrics (AAP)-endorsed algorithm (algorithm 1A) and the modified 2018 algorithm (algorithm 1B) are generally similar. The main difference between the two algorithms is that for newborns who neither pass nor fail on the initial screen, the modified algorithm requires only one repeat screen; whereas the original 2011 algorithm required two repeat screens.
A positive screen is indicated by any of the following:
●Oxygen saturation (SpO2) measurement <90 percent in either extremity
●SpO2 measurement 90 to 94 percent in both the right hand and a lower extremity on two to three measurements, each separated by one hour
●SpO2 difference ≥4 percent between the upper and lower extremities on two to three measurements, each separated by one hour
A cutoff SpO2 value of <95 percent is used as it provides a sensitivity of around 75 percent and specificity >99 percent [25,28,42]. In a 2018 meta-analysis of 21 studies including >450,000 newborns who were screened using a cutoff SpO2 threshold of <95 or ≤95 percent, the sensitivity for detection of critical CHD was 76.3 percent (95% CI 69.5-82) and specificity was 99.9 percent (95% CI 99.7-99.9) [28].
The characteristics of the screening test will depend on which algorithm is being used [43]. The New Jersey algorithm, which considers SpO2 <95 percent in either extremity on three measurements to be a positive screen, has a higher sensitivity but lower specificity than the 2011 AAP algorithm. The Tennessee algorithm, which initially tests only the lower extremity and considers an initial SpO2 of at least 97 percent to be a negative screen, has lower resource utilization than the AAP algorithm but may have lower sensitivity. The 2018 modified algorithm is expected to perform similar to the New Jersey algorithm, with potentially a slightly higher false-positive rate.
As the SpO2 threshold is decreased, the sensitivity of pulse oximetry to detect critical CHD decreases and the specificity increases [35,44]. In a study that evaluated different criteria for an abnormal pulse oximetry test, lowering the SpO2 threshold from <95 to <90 percent resulted in greater specificity (88 versus 100 percent, respectively) but lower sensitivity (75 versus 53 percent, respectively) [44]. Hence, using a lower SpO2 threshold decreases the number of false positives and thus may avoid unnecessary transfers, echocardiograms, and pediatric cardiology consultations. However, this comes at the cost of potentially missing some newborns with critical CHD.
In a multicenter prospective study of 122,738 newborn newborns born between 2011 and 2012, the sensitivity of detecting critical CHD was greatest using the combination of pulse oximetry plus clinical assessment (93 percent) compared with either pulse oximetry alone (84 percent) or clinical assessment alone (77 percent) [21].
Assessment of newborns with positive screens — A neonate with hypoxemia should be not discharged from the hospital without excluding potentially life-threatening conditions. Newborns with positive screening results should undergo evaluation to identify the cause of hypoxemia. (See "Approach to cyanosis in the newborn", section on 'Evaluation'.)
If a noncardiac cause of the hypoxemia cannot be identified, then evaluation of critical CHD as the cause should include high-quality echocardiography, with interpretation by a clinician with expertise in the diagnosis of CHD. Patients should have access to these diagnostic services at the birth center, via telemedicine, or via short-distance transport. Each birthing institution should establish a protocol to ensure a timely evaluation for newborns with a positive screening test. However, evaluation of the baby with low SpO2 using other means (eg, chest radiograph, blood work) should not be delayed while awaiting an echocardiogram. (See "Identifying newborns with critical congenital heart disease", section on 'Diagnostic approach'.)
Common noncardiac causes of hypoxemia that are identified through newborn POS include [14,22,25-27] (see "Approach to cyanosis in the newborn", section on 'Causes of central cyanosis'):
●Sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates")
●Pneumonia (see "Neonatal pneumonia")
●Transient tachypnea of the newborn (TTN) (see "Transient tachypnea of the newborn")
●Respiratory distress syndrome (RDS) (see "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis")
●Persistent pulmonary hypertension of the newborn (PPHN) (see "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis")
●Meconium aspiration syndrome (MAS) (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")
●Pneumothorax (see "Pulmonary air leak in the newborn")
In newborns in whom an alternative cause (other than critical CHD) is identified and treated, an echocardiogram may not be needed if the hypoxemia resolves. (See "Overview of neonatal respiratory distress and disorders of transition".)
If critical CHD is identified on echocardiography, urgent consultation with a pediatric cardiologist and/or transfer to a medical facility with pediatric cardiology expertise is warranted. Newborns with ductal-dependent lesions are at increased risk for death and significant morbidity unless interventions are initiated to maintain patency of the ductus arteriosus, ensure adequate mixing of deoxygenated and oxygenated blood, and/or relieve obstructed blood flow. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Initial management'.)
NEGATIVE SCREEN — Newborns with negative screening results (ie, those who "pass" the test) who are clinically well without signs concerning possible CHD (eg, cardiac murmur, weak femoral pulses) do not require additional evaluation. However, it is important to recognize that infants with a negative screen may still have critical CHD because hypoxemia may not be present all of the time in some CHD lesions.
It is estimated that universal newborn POS may miss as many cases of critical CHD as it detects [16]. POS cannot "rule out" the presence of critical CHD [45]. In addition, POS will not detect noncritical CHD lesions that are nonetheless clinically significant (eg, aortic stenosis, large atrial or ventricular defects) [26]. If there is clinical suspicion for CHD, additional evaluation should be pursued even in the setting of a normal pulse oximetry result. (See "Identifying newborns with critical congenital heart disease" and "Suspected heart disease in infants and children: Criteria for referral".)
SPECIAL SETTINGS
High altitude — False-positive rates are higher in centers at high altitude [46,47]. The pulse oximetry screening (POS) guidelines recommended by the American Academy of Pediatrics (AAP) are feasible up to an elevation of 2643 feet (806 meters) without any needed adjustments [48,49]. Criteria have not been validated for newborns cared for at centers at higher altitudes [50]. A modified protocol has been proposed for testing at moderate altitude [51].
Out-of-hospital delivery — For newborns delivered out-of-hospital (ie, home births and birth centers), critical CHD screening using pulse oximetry can be performed using portable pulse oximetry probes [52-57]. Care providers in these situations should have protocols in place to manage the newborn who fails screening in accordance with published guidelines. (See "Birth centers" and "Planned home birth", section on 'Special issues'.)
Neonatal intensive care unit — There are no clear guidelines for performing screening in the neonatal intensive care unit (NICU) setting, yet these newborns are similarly at risk for undetected critical CHD. Most neonates admitted to NICUs have pulse oximetry performed as part of their routine care; however, protocols used in newborn nurseries to identify critical CHD may not be appropriate for the NICU [58,59]. A modified protocol has been proposed for use in the NICU [60].
Premature infants may have a higher false-positive rate due to having lower saturations at baseline as compared with term newborns. False negatives may also occur in this population because pulse oximetry may overestimate the arterial oxygen saturation (SpO2; as compared with direct measurement via co-oximetry) [59]. In addition, POS may be delayed because many neonates in the NICU setting require supplemental oxygen during the initial days of life [61]. Unless mandated by state law, the child who has had a postnatal echocardiogram may not separately need pulse oximetry testing to be performed. Further work in this area is needed.
COST-EFFECTIVENESS — The cost of a universal critical CHD screening program includes the direct costs of pulse oximetry (equipment, training of personnel, staff time required for screening) and the costs of further evaluation and possible transfer of patients who fail the initial screening oximetry test [31]. The cost and quality of follow-up vary depending on the accessibility and cost of pediatric cardiac subspecialty care and the need for transfer. In the United States, the additional cost for pulse oximetry universal screening has been estimated to be around $5 to $6 per newborn [62,63].
Critical CHD screening may result in reducing the costs associated with delayed diagnosis of critical CHD. As mentioned above, in a population-based observational study of 3603 infants with critical CHD, there was a greater number of admissions, more hospitalized days, and higher inpatient costs among infants with late-detected CHD (n = 825) compared with those who were diagnosed prenatally or during the birth hospitalization. The authors suggest that screening may lead to decreased costs, but further prospective studies are needed to confirm this.
In studies of the cost-effectiveness of newborn POS, the incremental cost of pulse oximetry plus clinical examination compared with examination alone have been estimated to be $20,000 to $35,000 per timely diagnosis [63,64]. The cost per life-year gained is estimated to be approximately $12,000 to $40,000 [63,65]. The greatest variation in costs between centers is in the use of equipment, with the use of reusable probes leading to considerable cost savings as compared with disposable probes [66].
IMPLEMENTATION — Universal newborn screening for critical CHD is endorsed by the American Academy of Pediatrics (AAP), American Heart Association (AHA), and American College of Cardiology (ACC) [30,31]. Screening was added to the United States Recommended Uniform Screening Panel in 2011. Since then, all 50 states and the District of Columbia have implemented policies mandating that critical CHD screening be performed or offered [67]. However, not all states have data systems in place for tracking screening results and outcomes. Screening programs are also in place in some European countries and other parts of the world [68-71].
In 2012, an expert panel developed the following consensus recommendations for implementation of newborn POS [72]:
●Selection of screening equipment, which should be approved for hospital use in neonates by the US Food and Drug Administration (FDA), should also be tolerant of motion, use a neonatal sensor, and not require a fixation method. Of note, the FDA has not tested the performance of oximeters in critical CHD screening protocols.
●Establishment of reporting standards for each birth facility and state public health monitoring. This includes patient demographic information, results of oximetry screening, type of protocol and oximeter used, and the requirements for reporting by birth facilities to public health programs.
●Training of health care providers and education of families. Development of educational material for both staff and families.
●Ongoing assessment of the outcome of screening, particularly in the context of other screening efforts (eg, fetal ultrasound), noncardiac conditions, quality of the equipment, cost of screening including educational efforts, and reimbursement.
Implementation of critical CHD screening varies by state and county. Clinicians should refer to the guidelines of their local public health agency to determine the appropriate algorithm and protocols for their practice area.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital heart disease in infants and children".)
SUMMARY AND RECOMMENDATIONS
●Importance – Congenital heart disease (CHD) is the most common congenital disorder in newborns. Critical CHD, defined as requiring surgery or catheter-based intervention in the first year of life (table 1), accounts for approximately 25 percent of all CHD. In infants with critical cardiac lesions, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary center with expertise in treating these patients. (See 'Prevalence of critical congenital heart disease' above and 'Consequences of late detection' above.)
●Rationale for screening – The goal of critical CHD screening in newborns is to reduce mortality and morbidity associated with delayed diagnosis by identifying newborns with critical CHD in a timely manner. There is evidence that universal newborn pulse oximetry screening (POS) improves the identification of patients with critical CHD compared with physical examination alone and may lead to decreased infant morbidity and mortality from critical CHD. (See 'Benefits of screening' above.)
●Targeted lesions – CHD lesions targeted by POS include defects that typically (A) require intervention in the first year of life, and (B) present with hypoxemia some or most of the time. (See 'Definition and targeted lesions' above.)
●Approach to screening – For all newborns, we suggest routine POS to detect critical CHD screening (Grade 2C). (See 'Approach to screening' above.)
•Screening is performed at >24 hours after birth or as late as possible if early discharge is planned. Oxygen saturation (SpO2) should be measured in the right hand (preductal) and either foot (postductal) (algorithm 1A-B). (See 'Timing' above and 'Technique' above.)
•Criteria for a positive screen using the 2011 algorithm (algorithm 1A) and the modified 2018 algorithm (algorithm 1B) are generally similar. The main difference between the two algorithms is that for newborns who neither pass nor fail on the initial screen, the modified algorithm requires only one repeat screen, whereas the original 2011 algorithm required two repeat screens. A positive screen is indicated by any of the following (see 'Criteria for positive screen' above):
-SpO2 <90 percent in either extremity
-SpO2 90 to 94 percent in both the right hand and a lower extremity on two to three measurements, each separated by one hour
-SpO2 difference ≥4 percent between the upper and lower extremities on two to three measurements, each separated by one hour
•The screening procedure may require modification in certain settings, such as high altitude, out-of-hospital births (ie, home births and birth centers), and infants admitted to neonatal intensive care units (NICUs). (See 'Special settings' above.)
●Evaluation of newborns with positive screening results – Newborns with positive screening results should undergo evaluation to identify the cause of hypoxemia. If critical CHD is identified on echocardiography, urgent consultation with a pediatric cardiologist and/or transfer to a medical facility with pediatric cardiology expertise is warranted. (See 'Assessment of newborns with positive screens' above and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Initial management'.)
●Negative screen – Newborns with a negative screen may still have critical CHD because hypoxemia may not be present all of the time in some CHD lesions. If there is clinical suspicion for critical CHD, additional evaluation should be pursued even in the setting of a normal pulse oximetry result. (See 'Negative screen' above and "Identifying newborns with critical congenital heart disease".)
●Implementation – In the United States, all states require that newborn POS for critical CHD be offered. Screening programs are also in place in some European countries and other parts of the world. Clinicians should refer to the guidelines of their practice area to determine the appropriate algorithm and protocols to use. (See 'Implementation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Carolyn A Altman, MD, who contributed to an earlier version of this topic review.
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