Jaundice is a common clinical manifestation in the neonatal period in China, and more than 2/3 of term or late preterm infants develop hyperbilirubinemia early after birth, and bilirubin encephalopathy is not uncommon. One of the main reasons for this is the significant shortening of the average postnatal hospital stay and the lack of systematic follow-up of bilirubin levels after neonatal discharge in China or the lack of awareness of risk factors for hyperbilirubinemia; on the other hand, there is still a problem of excessive clinical intervention for physiological hyperbilirubinemia, and these emerging problems have yet to be addressed by the development of new intervention programs for neonatal jaundice again.
Internationally, a similar situation has occurred in developed countries, and guidelines for the management of neonatal jaundice have been adjusted accordingly in recent years. For bilirubin encephalopathy, a preventable and intervenable disease at an early stage, the goal has been put forward internationally in recent years that it should no longer become a problem in the 21st century, but unfortunately we are still far from this goal.
First, fully understand the seriousness of the current situation of bilirubin encephalopathy in China
Hyperbilirubinemia is one of the common reasons for neonatal visits and hospital admissions. Severe hyperbilirubinemia in early neonatal life can cause bilirubin encephalopathy and nuclear jaundice, leaving sequelae such as hearing loss, cerebral palsy and mental developmental disorders, which bring heavy burden to society and families. In developed countries, with the development of treatment techniques such as phototherapy and blood exchange, this condition has rarely occurred. The incidence of nuclear jaundice reported in Denmark and Canada ranges from 1/43,000 to 1/79,000 live births.
In 2009, Johnson et al. reported results from the Kernicterus Registry in the United States from 1992 to 2004 and found that only 125 confirmed cases were received in this nationwide reporting system over a 13-year period. Although it is not possible to derive an accurate incidence of kernicterus in the United States from this, it provides very valuable epidemiological information.
With our large population, very uneven distribution of medical resources between regions, and the fact that Asians themselves are at high risk for hyperbilirubinemia, the incidence of bilirubin encephalopathy and nuclear jaundice is presumed to be higher than in Western countries, but large sample, demographic-based epidemiological investigations have been lacking. To study the specific incidence of neonatal bilirubin encephalopathy in China, members of the Neonatology Group of the Pediatrics Branch of the Chinese Medical Association conducted a retrospective epidemiologic survey and found that a total of 348 cases of neonatal bilirubin encephalopathy or nuclear jaundice were reported in 28 of 33 hospitals from January to December 2009.
Acute bilirubin encephalopathy in our neonates had the following characteristics: it was more common in term infants (72.4%) and late preterm infants (22.1%); the time of admission (6.9±5.1)d was significantly later than the time of clinical symptoms (5.5±3.7)d; infection and ABO blood group incompatibility hemolysis were important causes; and systematic follow-up was not performed in most of the children.
The above data indicate that bilirubin-induced brain injury is still common in China, and the ability of health care professionals to identify and intervene early on the risk factors of hyperbilirubinemia and the clinical judgment of brain injury still needs to be strengthened. If a corresponding reporting system for bilirubin encephalopathy can be established in China, it will also help in the development of surveillance and related policies.
The identification of risk factors for bilirubin encephalopathy should be emphasized
Bilirubin encephalopathy can be prevented. Early detection of hyperbilirubinemia and timely intervention can largely prevent the occurrence and development of brain damage. While the treatment of infections has evolved considerably in the last 30 years, bilirubin brain injury due to non-infectious factors, especially immune hemolysis, still occurs. The occurrence of bilirubin encephalopathy is associated with free bilirubin levels in the blood, and the extent to which total bilirubin levels can cause brain damage is inconclusive.
A study by Newman et al. followed 140 cases with peak bilirubin >427.5 μmol/L ( 25.0 mg/dl) in the neonatal period, of which 130 had total serum bilirubin levels of 427.5 to 499.3 μmol/L ( 25.0 to 29.2 mg/dl) and 10 cases >513.0 μmol/L ( 30.0 mg/dl), resulting in no None of the cases developed nuclear jaundice, and the differences in the rates of cognitive development, neurological abnormalities and suspected abnormalities were not statistically significant when compared with the control group; this study has been considered an important reference for the management of very severe hyperbilirubinemia [>427.5 μmol/L (25 mg/dl)] in term infants because of its high follow-up rate, large sample size and comprehensive observations.
These results suggest that bilirubin levels between 342.0 and 427.5 μmol/L ( 20-25 mg/dl) are relatively safe if no high-risk factors are present and of short duration. However, a significant number of neonates with serum bilirubin levels <427.5 μmol/L (25 mg/dl) did develop bilirubin encephalopathy in a multicenter survey in China; the reasons for this were mainly the late admission of the children, the long duration of high bilirubin levels and the combination of high-risk factors such as hemolysis and infection. Therefore, we cannot copy the foreign data, and should combine the relevant guidelines with the actual situation in China.
Third, under-treatment or over-treatment of neonatal jaundice should be avoided
In the cases of bilirubin encephalopathy reported by Johnson et al, 72% were discharged within 48 h after birth. At present, there are also more hospitals in China where the age of neonatal discharge from normal birth is advanced from the traditional 4-5 d to 3 d. At this time, the peak of physiological jaundice has not yet been reached, and neonatal discharge with severe hyperbilirubinemia can easily be ignored. Some health care professionals in China still do not pay enough attention to early bilirubin detection and follow-up of newborns.
Internationally, the Bhutani curve is commonly used to assess the risk of hyperbilirubinemia, and some experts in China have also developed relevant bilirubin assessment curves. Referring to these curves, combined with the presence of high-risk factors for comprehensive assessment and intervention, it is entirely possible to avoid the occurrence of bilirubin encephalopathy.
In terms of clinical intervention, the application of anti-D serum in Europe and the United States for the prevention of Rh incompatibility hemolysis has significantly reduced the number of cases of neonatal blood exchange; while in China, although the incidence of Rh incompatibility hemolysis is low, conditions are not yet available for universal prevention, so blood exchange therapy is still needed. For children with other hemolysis or severe hyperbilirubinemia, there are still problems in China such as excessive or untimely blood exchange due to incomplete judgment. Phototherapy is generally considered to be safe.
There is more evidence-based medical evidence regarding phototherapy intervention strategies for term infants, but most guidelines for preterm infants are still based on expert consensus due to the lack of randomized controlled clinical data; in recent years, there are also more clinical studies on prophylactic phototherapy for jaundice below the threshold of phototherapy in very low birth weight infants, which basically confirm the effects of prophylactic phototherapy on reducing the incidence of cerebral palsy, reducing the chance of blood exchange and improving However, it was also found that prophylactic phototherapy increased mortality in very low birth weight infants with a birth weight of 500-750 g. The mechanism is not clear.
Although the above studies did not directly observe the relationship between bilirubin and brain injury, they provide a strong basis for the development of intervention guidelines, the reduction of potential toxicity of hyperbilirubinemia, and the evaluation of the safety of the treatment itself.
It is necessary to adjust the guidelines or intervention programs for the management of neonatal hyperbilirubinemia to new conditions
It should be emphasized that the definition of hyperbilirubinemia is a dynamic process, which is related to the birth gestational age, daily age and the presence of high-risk factors in newborns. Therefore, the management of hyperbilirubinemia should not be defined by one value alone, but should be based on the line graph of bilirubin dynamics and combined with relevant risk factors for timely and correct intervention.
The new expert consensus on the diagnosis and management of jaundice published in this issue has standardized the difference between determining whether neonatal hyperbilirubinemia is abnormal and whether intervention is needed, so that it can be applied in practice. Clarification is provided on when to start phototherapy, when to discontinue phototherapy, and when to perform follow-up to avoid unnecessary interventions. The risk of developing severe hyperbilirubinemia or brain damage is objectively assessed in combination with new techniques.
With regard to breastfeeding and jaundice, care should be taken to distinguish between the management of early breastfeeding due to inadequate breastfeeding and late breast milk jaundice, emphasizing that breastfeeding should not be easily stopped for this type of jaundice. In terms of health promotion, systematic follow-up in the community after obstetric discharge should be emphasized, and screening and monitoring by transcutaneous bilirubin meter should be performed when appropriate.
V. Introduction of new technologies for assessment and prediction of hyperbilirubinemia risk
Neonatal jaundice is a relatively traditional clinical problem, most of the etiological diagnosis is well established, and phototherapy is a therapeutic intervention with proven efficacy. The identification of risk factors for jaundice is of great importance for clinical management and prevention of bilirubin encephalopathy. In recent years some new diagnostic tools have been applied in the clinic, which are represented by.
(1) End-expiratory carbon monoxide (ETCO) test: its principle is based on hemolysis in human body, after the destruction of red blood cells, heme is oxidized to bilirubin Ⅸa catalyzed by heme oxygenase (HO), and then reduced to bilirubin Ⅸa by bilirubin reductase, and at the same time, CO is produced. the degree of hemolysis and the rate of bilirubin production can be assessed by measuring the ETCO growth rate, and this technique is useful for This technique is of great value in the diagnosis of neonatal immune hemolysis, especially when the Coombs test is false positive or false negative.
(2) Clinical detection of free bilirubin: increased free bilirubin is directly related to the occurrence of encephalopathy, but it has long been difficult to promote clinically because of the cumbersome detection technique; in recent years, the technique of measuring free bilirubin by micro blood bedside has been developed, making it possible to assess the risk of encephalopathy by free bilirubin measurement.
(3) Uridine diphosphate glucuronosyltransferase (UGT) gene polymorphism determination: it is of special significance for the assessment of high-risk factors for jaundice and the diagnosis of jaundice of unknown etiology.
(4) Magnetic resonance imaging techniques and brainstem evoked potential testing: provide important tools for the confirmation of morphological and electrophysiological evidence of bilirubin brain injury.
Neonatal bilirubin encephalopathy is preventable; it is the responsibility of neonatologists to make it less of a problem that threatens the life and quality of life of newborns in the 21st century, for which national epidemiological data on bilirubin encephalopathy are still needed first to assess its current incidence and the effectiveness of intervention strategies.
At present, experts are conducting a multicenter study to obtain a large sample of information on postnatal bilirubin levels in normal newborns in China, which will certainly provide an important reference for clinical management of neonatal jaundice; domestic units are also conducting research on new technologies related to hyperbilirubinemia, such as ETCO and serum free bilirubin determination, which will enable the prevention and treatment of bilirubin brain injury in China to reach a world advanced level. Ultimately reduce and avoid the occurrence of bilirubin brain injury.