Measurement of serum bilirubin levels is an important indicator for the diagnosis of neonatal hyperbilirubinemia. The use of skin reflexes allows the use of transcutaneous bilirubinometry as an alternative method of assessing the degree of clinical jaundice in the infant room. In addition to laboratory measurements of total bilirubin and direct bilirubin (conjugated bilirubin), the diagnosis of neonatal hyperbilirubinemia requires a thorough clinical examination, including abdominal palpation, a review of the history and laboratory basis of maternal and neonatal blood group incompatibility, antibody titers and Coomb’s test results, and the neonate’s family history, siblings or relatives during childhood. history of jaundice. All mothers should be tested for ABO blood group and Rh blood group before delivery and hospitalization, and if the mother is Rh-negative, the titer of Rh antibodies should be determined to determine the passage of labor and emergency management during and after delivery. Intervention criteria for neonatal jaundice phototherapy and blood exchange should be multiple dynamic curves that vary with gestational age, daytime age, and birth weight, and intervention protocols for neonatal jaundice should be based on medical history, course, physical examination, and weighing the pros and cons.
The superiority of phototherapy does not significantly lower serum bilirubin, but rather converts 10-20% of circulating bilirubin to hydrolyzed isomers that are less likely to cross the blood-brain barrier than the original lipophilic bilirubin IX-α
The recommended intervention criteria for jaundice in preterm infants of different gestational ages/birth weights for phototherapy in preterm infants 35-36w/2000-2500g are
1. serum bilirubin level ≥5mg/dl within 24 hours
2, serum bilirubin level ≥7mg/dl within 24 hours
I. Diagnosis of non-hemolytic hyperbilirubinemia
Measurement of serum bilirubin level is an important indicator for the diagnosis of neonatal hyperbilirubinemia. In the first 4-5 days after birth, most newborns have a peak period of rising serum bilirubin, ranging from 26 μmol/L (1.5 mg/dl) of cord blood bilirubin at birth to 102-205 μmol/(6-12 mg/dl) at 4-5 days after birth. Serum bilirubin levels exceed those of adults even under normal conditions. In adults, bilirubin >34μmol/L (2mg/dl) can be seen as yellow staining of the skin and sclera, and in neonates, due to the abundance of capillaries, bilirubin >86-120μmol/L (5-7mg/dl) before jaundice appears.
Observation and detection of neonatal jaundice should be done daily in nude neonates under appropriate natural light, and jaundice of the skin and sclera can be observed early in most cases. The examiner uses his or her thumb to press on the skin surface of the harder parts of the body, such as the forehead, chest, or thighs, primarily to whiten the skin to help observe the underlying yellow color.
The skin reflex can be used as an alternative method of assessing the degree of clinical jaundice in the infant room using a transcutaneous bilirubin meter. Transcutaneous bilirubinometry correlates well with serum bilirubin levels, and standardized techniques and equipment are available for screening for hyperbilirubinemia. The correlation between transcutaneous bilirubinometry and serum bilirubin is better in Caucasians than in non-Caucasians.
Both clinical observations and transcutaneous bilirubinometry confirm that skin jaundice in term infants progresses downward from the face, with jaundice of the sclera and face observed at bilirubin levels of 6-8 mg/dl, jaundice of the shoulders and trunk at 137-171 μmol/L (8-10 mg/dl), and significant jaundice of the lower extremities at 171-205 μmol/L (10-12 mg/dl) levels. Seeing systemic jaundice estimated serum bilirubin at 205-256 μmol/L (12-15 mg/dl) levels. Although this is only the crudest assessment, used for daily observation of neonatal jaundice, it often allows timely detection and recognition of progressing hyperbilirubinemia. It facilitates early detection, diagnosis and the administration of intervention and follow-up. Abnormal jaundice observed on the first postnatal day requires prompt evaluation and follow-up. Full-term newborns exhibiting mild jaundice at the 3rd-4th postnatal day or at the time of discharge with an average level of bilirubin are generally well and may not be intervened. However, it is necessary to teach parents how to observe neonatal jaundice.
In addition to the need for laboratory determination of total and direct bilirubin (conjugated bilirubin), a thorough clinical investigation of hyperbilirubinemia should be made, including abdominal palpation, review of the history and laboratory basis of blood group incompatibility between mother and newborn, antibody titers and Coomb’s test results, as well as the family history of the newborn, siblings or relatives with a history of jaundice during childhood.
II. Diagnosis of neonatal hemolytic disease
1. Hemolysis of Rh blood group incompatibility
Rh homozygous immune hemolysis is one of the causes of severe hyperbilirubinemia and a common cause of nuclear jaundice in full-term infants. Sixteen percent of North American women are Rh-negative, and most are D antigen negative. Rh hemolysis is relatively uncommon in this country. In the delivery of the first Rh-positive newborn due to placental hemorrhage, the mother had an abortion of the Rh-positive fetus when the Rh-negative mother received a small transfusion of Rh-positive fetal cells. When these Rh-positive cells entered the circulation of the Rh-negative mother, the mother’s immune system developed antibodies to the foreign Rh-positive red blood cell antigens. The latter exposure to Rh-positive fetal cells increases the mother’s IgG titer against her fetal antibodies in any subsequent pregnancy with an Rh-positive fetus, or in the same pregnancy with fetal cells passing through the placenta, and the mother’s anti-Rh-positive IgG antibodies then pass through the placenta to the fetus, destroying the Rh-positive fetal erythrocytes. Due to the increase in maternal antibodies, fetal red blood cells are destroyed and lysed inside and outside the blood vessels once they become antigenic and are recognized by circulating antibodies. The second pregnancy results in further hemolysis and intrauterine hyperbilirubinemia. In severe cases, the intrauterine anemia is so severe that it causes heart failure with high cardiac output and generalized edema, and the edematous fetus can be visualized by ultrasound.
The passage of pregnancy in Rh-negative mothers can be monitored by measuring antibody titers to Rh. Hepatosplenomegaly and peripheral edema can be detected by ultrasound monitoring, and the presence of bilirubin in the amniotic fluid can be detected by transabdominal amniocentesis. An increase in bilirubin in the amniotic fluid, especially when combined with ultrasound confirmation of hepatosplenomegaly or edema, suggests a critical prognosis and requires ultrasound-guided transabdominal wall transfusion of red blood cells, and if the fetus is near term the pregnancy should be terminated as soon as possible.
2.Hemolysis of ABO blood group incompatibility
ABO hemolysis is more common than Rh hemolysis, but it passes well. In almost all cases, the mother’s blood type is O and the newborn’s blood type is A or B. The mother’s anti-A or anti-B IgG is passively delivered to the infant in late pregnancy or at delivery. With recognition and rejection of the antigen-antibody complex by the spleen, early fetal hemolysis occurs rapidly. This is because the fetus has only nearly 7,500-8,000 A or B antigen attachment sites per 100 red blood cells (compared to 15,000-20,000 in adults). Antibodies do not adhere easily to fetal cells and are not completely destroyed. The low number of antigen-antibody attachment sites on fetal cells can result in a weakly positive or even negative direct Coomb test. Although 25% of pregnant women have an underlying ABO blood group incompatibility, only a minority (10-15%) of newborns have a positive Coomb test. In the absence of a positive antibody result, the diagnosis of neonatal hemolysis cannot be confirmed. Because not all ABO blood group incompatibilities result in neonatal hemolysis, a positive result of direct or indirect Coombs test or antibody release test is necessary to establish the diagnosis.
In conclusion, all mothers should be tested for ABO blood group and Rh blood group before delivery and hospitalization, and if the mother is Rh negative, the titer of Rh antibodies should also be determined to determine the passage of labor and emergency management during and after delivery. If the mother’s blood type is O or Rh negative, the newborn should be checked for ABO blood type and Rh blood type; those with incompatible blood types should be screened for antibodies, except for the direct anti-human globulin test (Coombs), a positive free antibody test in the serum indicates that antibodies are already present in the newborn, which does not necessarily sensitize and cannot be used as a basis for diagnosis, while the antibody release test confirms that the newborn’s red blood cells have been The diagnosis is established.
In addition to serum bilirubin, hematocrit, erythrocyte pressure, reticulocyte count, and red blood cell morphology should also be examined if high bilirubin is suspected to be the cause of neonatal hemolysis. For cases with high suspicion of Rh hemolysis, hematocrit, erythropoietic pressure and bilirubin measurements of cord blood specimens were done immediately after birth. In cases of suspected ABO hemolysis, it is not necessary to do the examination of cord blood because ABO hemolysis rarely causes significant jaundice and anemia at birth.
III. Prediction of hyperbilirubinemia
The age at which jaundice first appears and the subsequent rate of increase in serum bilirubin can be used clinically to predict the likely clinical course and degree of hyperbilirubinemia and whether there is a delay in remission of bilirubin later. For example, the maximum rate of bilirubin rise in a normal neonate with non-hemolytic hyperbilirubinemia is 85 μmol/L.d (5 mg/dl.d), or 3.24 μmol/L.h (0.2 mg/dl.h). Jaundice visible to the naked eye on the first day after birth or a bilirubin level ≥ 171 μmol/L (10 mg/dl) within the first 48 hours after birth, with an increase in bilirubin above the normal range, may have some underlying pathology. Assessment of the rate of bilirubin increase allows estimating the likely level of bilirubin in the next 12-24 hours. In most cases, if jaundice is observed to be significant in the newborn during the first 24 hours, serum indirect bilirubin levels ≥ 103 μmol/L (6 mg/dl) are measured and the rate of increase of bilirubin is 3.24 μmol/L.h (0.2 mg/dl.h), the measurement should be repeated every 8 hours until the bilirubin level stabilizes or until the intervention criteria are met to give treatment. During this time, if the jaundice is not definitely physiological, further laboratory tests and analysis of the underlying etiology can be done clinically based on the initial bilirubin level and its increase.
End-tidal CO (end-tidal CO corrected for ambient COETCOc) is a good indicator to monitor endogenous CO production. CO is released from hemoglobin produced by senescent erythrocytes and hemoglobin proteins during the conversion of hemoglobin to bilirubin by hemoglobin oxidase, and an equivalent number of grams of CO is produced for each gram of metabolized ferrous hemoglobin. in clinical practice, monitoring endogenous CO production in neonates with severe hyperbilirubinemia can be a more intuitive predictor of serum bilirubin production.
In addition, hyperbilirubinemia can also occur in the neonatal period due to various causes of obstructive liver disease. Diagnosis requires the measurement of total and direct bilirubin. A direct bilirubin higher than 17.1-26 μmol/L (1.0-1.5 mg/dl), especially in the first days or weeks of life, with a persistent increase in direct bilirubin, should be suspected and requires a differential diagnosis. In principle, all neonatal bilirubin determinations should include both total and direct bilirubin. Rapid microhematology can only measure total bilirubin, which is suitable for follow-up, and direct bilirubin should also be measured if available.
IV. Management of hyperbilirubinemia
(A) Management of neonatal hemolysis
Neonatal hemolysis can be used as a model for the management of severe neonatal hyperbilirubinemia.
1.Before birth, the mother should be screened for blood type before delivery, and the pediatrician should be notified before delivery in cases where the mother is Rh-negative.
2, At birth, cord blood samples should be sent for determination of serum bilirubin, hematocrit, erythrocyte pressure product and reticulocytes as soon as possible. Hemolytic individuals are characterized by the presence of a large number of nucleated red blood cells. The fetuses known as myeloid erythropoietic fetuses. The presence of these nucleated red blood cells responds to the extremely active bone marrow and increased extramedullary hematopoiesis trying to make the fetal red blood cells grow at the same rate as the red blood cells destroyed by antibodies.
3, after birth newborns with edema, severe anemia and heart failure require emergency treatment with red blood cell replacement transfusions, diuresis, anti-heart failure and ventilatory support. In a few severe cases, normal at birth but accompanied by progressive anemia and hyperbilirubinemia after birth, the hematocrit can drop >1g/dl.d to severe anemia in untreated cases. Serum bilirubin increases from 86-171 μmol/L (5-10 mg/dl) in cord blood to very high unconjugated bilirubin levels at a rate of >17.1 μmol/L.h (1 mg/dl.h). Correct hematocrit as soon as possible with concentrated red blood cells. If hematocrit is ≤10 g/dl at birth, transfusion may be 25-50 ml/kg of concentrated red blood cells, estimated to correct hematocrit of 11-13 g/dl in newborns, with attention to the rate of transfusion. In addition, if the cord blood bilirubin > 86μmol/L (5mg/dl), or the postnatal bilirubin growth rate ≥ 17.1μmol/L.h (1mg/dl.h), exchange the blood with double the amount of whole blood as soon as possible.
4, ABO blood group incompatibility at birth rarely has severe jaundice or anemia. However, in the first few days after birth if the rate of bilirubin increases too rapidly, such as the rate of increase > 17.1μmol/L.h (1mg/dl.h), or there is significant anemia (hematocrit <10g/dl), as well as the serum bilirubin level reaches 256-342μmol/L (15-20mg/dl) within 24 hours after birth, indirect bilirubin has exceeded 256μmol /L (15 mg/dl) and should also be prepared for blood exchange before exceeding 20 mg/dl. Typically, early serum bilirubin increases rapidly to 256-342 μmol/L (15-20 mg/dl) or slightly higher, followed by stabilization at 256-342 μmol/L (15-20 mg/dl) the day after. In these cases, blood can be cross-matched in preparation for blood exchange, but unless there is hemolytic anemia or serum bilirubin exceeds 20 mg/dl, blood exchange is not required.
As a general rule, any newborn with an unconjugated bilirubin level of 342-428 μmol/L for any reason that does not respond to phototherapy should be considered for blood exchange. Persistent hyperbilirubinemia in this range is potentially neurologically damaging to the neonate. There are occasional cases of kernicterus at this level of jaundice due to the marked alteration in brainstem conduction time, which causes changes in the neonate’s feeding behavior and response to the outside world. This is quickly followed by a rebound back to 274-291 μmol/L (16-17 mg/dl). If the cause of the high bilirubin is not resolved, or if bilirubin cannot be ruled out, serum bilirubin levels can increase again to the pre-transfusion level within a few hours, which would necessitate a second blood exchange.
5. Choice of blood type. Rh blood type is used for Rh blood type incompatibility with the mother and ABO blood type with the newborn. In Rh (anti-D) hemolytic disease without Rh-negative blood, Rh-positive blood without anti-D (IgG) is also available. Phototherapy and other adjuvant therapy should be actively used before blood exchange.
In case of ABO blood group incompatibility, it is better to use AB plasma and O red blood cell mixture, or O blood or blood of the same type as the newborn.
6. According to the bilirubin growth rate after blood exchange, bilirubin monitoring should be performed every 4 hours, not less than 8-12 hours. In the early stage after blood exchange, the degree of reduction of serum bilirubin is close to 50% of that before blood exchange. However, extravascular bilirubin soon equilibrates with plasma and causes a short-lived bilirubin rebound, increasing plasma bilirubin levels by another 30%. For example, the initial bilirubin level was 342 μmol/L (20 mg/dl), which decreased to 171 μmol/L (10 mg/dl) after blood exchange and rebounded to 222 μmol/L (13 mg/dl) within 1 hour. This growth rate allows assessment of bilirubin levels 12-24 hours after blood exchange. If bilirubin is measured 2-3 times consecutively with a sustained growth rate >8.6 μmol/L.h (0.5 mg/dl.h) for more than 10-12 hours, the blood should be retransfused before bilirubin reaches 342 μmol/L (20 mg/dl). A second blood exchange is also required if there is progressive anemia after birth and the hematocrit decreases to <10 g/dl. After the first postnatal day, with a serum bilirubin growth rate <8.5 μmol/L.h (0.5 mg/dl.h) and a stable hematocrit, the newborn should be closely observed and monitored for bilirubin, and if the unconjugated bilirubin level reaches or exceeds 342 μmol/L (20 mg/dl), a blood exchange should be prepared.
7. The immunosuppressive effect of intravenous gammaglobulin (IVIG) is used to prevent neonatal hemolysis, either in the mother or the fetus, or in the onset neonate. High-dose IVIG can directly inhibit the proliferation of B lymphocytes and also promote the function of T suppressor cells (Ts) and indirectly inhibit B lymphocytes, thus suppressing antibody production. High-dose IVIG competes for Fc receptors on the surface of placental trophoblast cells, preventing maternal antibodies from entering the fetus via the placenta. It also binds to the Fc receptor on fetal monocyte-macrophages to play a closed role and prevent the destruction of fetal erythrocytes. For severely sensitized pregnant women IVIG 400mg/(kg.d) for 4-5 days as a course of treatment, repeated every 2-3 weeks until delivery. For fetal IVIG, IVIG is injected directly into the fetus (200-480mg/kg) by fetal umbilical vein puncture through the amniotic cavity under ultrasound guidance, which can stop hemolysis without intrauterine blood exchange. IVIG in neonates can reduce the need for blood exchange, and in the early stages of severe hemolytic disease, the dosage is 1000 mg/(kg.d) administered intravenously over 4-6 hours or 400 mg/(kg.d) for 3 days. IVIG does not reduce pre-existing bilirubin levels and should be administered simultaneously with phototherapy.
Fortunately, extensive screening for Rh hemolysis and the use of anti-Rh immunoglobulin have reduced the incidence of neonatal Rh hemolysis in late pregnancy and after delivery. Continuous screening and immunotherapy are necessary to maintain the success of treatment.
(ii) Phototherapy
Phototherapy is the most commonly used treatment for hyperbilirubinemia. The mechanism of phototherapy was once thought to be the degradation of bilirubin and the excretion of the degradation products into small molecules. Phototherapy has now been found to form structural isomers of induced and unconjugated bilirubin structures. The formation of these bilirubin isomers is more readily hydrolyzed than the original compound and less likely to enter the central nervous system. They pass through the liver and are excreted via bile and urine more rapidly than the original form of unconjugated bilirubin. The ideal spectrum is 400-500 nm (the highest absorption wavelength of serum bilirubin is 460-465 nm).
Current studies of phototransformation and excretion processes point to a limited excretion of the photoisomer through the neonatal liver, and in addition, in vitro tests have found that the transformed isomer can be reversed in the dark, and once the isomer of bilirubin reaches the gallbladder and intestine, as it is no longer exposed to phototherapy, it can be reconverted to its original form of unconjugated bilirubin via the hepatic-intestinal circulation. In contrast, bilirubin in plasma is stable and in equilibrium with its photo-oxidation products. During the complex conversion process, the rate of bilirubin production, reabsorption and excretion is balanced, as shown by the slow response of phototherapy to the reduction of serum bilirubin.
The superiority of phototherapy does not significantly reduce serum bilirubin, but rather converts 10-20% of circulating bilirubin into hydrolyzed isomers that are less likely to cross the blood-brain barrier than the original lipophilic bilirubin IX-α. Early use of phototherapy in high-risk neonates, followed by photoconversion of circulating bilirubin, may lead to a reduction in the occurrence of karyorrhexis with low bilirubin levels in these neonates. Photoconversion of bilirubin may be protective against bilirubin encephalopathy, but the mechanism of this protection has not been demonstrated.
Intervention criteria for phototherapy and blood conversion for neonatal jaundice should be multiple dynamic curves that vary with gestational age, daytime age, and birth weight, and intervention protocols for neonatal jaundice should be based on history, course, physical examination, and trade-offs. Because of racial and geographical differences in neonatal jaundice, there is no simple and uniform standard for managing neonatal hyperbilirubinemia worldwide. The Neonatology Group of the Pediatrics Branch of the Chinese Medical Association adopted a recommended intervention program for neonatal jaundice suitable for our national situation at the National Conference on Neonatal Jaundice in Guangzhou in 2000 (see Tables 1 and 2 or Figure 1.) and made the following statement.