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 Table of Contents  
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 46-51

Evaluation of neonatal jaundice based on the severity of hyperbilirubinemia

1 Department of Pediatrics, Neonatal Research Centre, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Midwifery, School of Medical Sciences, Islamic Azad University, Tonekabon Branch, Tonekabon, Iran

Date of Submission25-Jul-2019
Date of Decision08-Sep-2019
Date of Acceptance19-Nov-2019
Date of Web Publication29-Jan-2020

Correspondence Address:
Dr. Maryam Zakerihamidi
Department of Midwifery, School of Medical Sciences, Islamic Azad University, Tonekabon Branch, Tonekabon
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_81_19

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Introduction: Recognition of the characteristics of neonatal jaundice with different levels of severity can help the physician with appropriate treatment and prediction of complications. This study aimed to determine the characteristics of neonatal jaundice in different levels of severity. Materials and Methods: This cross-sectional study was performed on 3005 neonates referring to the Neonatal Intensive Care Unit, Clinic, and Emergency ward in Ghaem Hospital of Mashhad, Iran, from 2009 to 2018. Sampling was carried out through the convenience sampling method. The data collection tool was a researcher-made questionnaire, including laboratory evaluation, as well as assessment of maternal and neonatal characteristics. The newborns were divided into six groups based on the serum bilirubin level and then compared in terms of characteristics, causes, and prognosis according to the severity of jaundice. The data were analyzed using the Student's t-test and Chi-square test. Results: In most cases, the present of jaundice was reported between 2 and 3 days of birth, and the age of neonates' reference was between 6 and 8 days of birth. Causes of neonatal jaundice included unknown reasons (61.25%), increased production of bilirubin (22%), severe weight loss (7%), infections (5.3%), endocrine disorders (2.5%), and other causes (1.7%). In jaundice level lower than 25 mg/dl, about 15% of neonates were reported with complications; however, at the bilirubin level higher than 35 mg/dl, approximately 40% of newborns had complications. Conclusion: The known causes of the jaundice were mostly observed in the increased bilirubin production level higher than 25 mg/dl.

Keywords: Dehydration, hyperbilirubinemia, infection, neonates

How to cite this article:
Boskabadi H, Sezavar M, Zakerihamidi M. Evaluation of neonatal jaundice based on the severity of hyperbilirubinemia. J Clin Neonatol 2020;9:46-51

How to cite this URL:
Boskabadi H, Sezavar M, Zakerihamidi M. Evaluation of neonatal jaundice based on the severity of hyperbilirubinemia. J Clin Neonatol [serial online] 2020 [cited 2020 Jul 14];9:46-51. Available from: http://www.jcnonweb.com/text.asp?2020/9/1/46/277230

  Introduction Top

Neonatal hyperbilirubinemia is observed as the serum total bilirubin level is higher than 5 mg/dl (i.e., 86 μmol/L).[1] Neonatal jaundice is a common problem that is benign in most cases; however, high levels of bilirubin are neurotoxic and can lead to serious damage to the brain.[2] Therefore, the American Academy of Pediatrics recommends that the neonates who are discharged within the first 48 h should have two follow-up visits. The first and the second follow-up visits should be during the 1st–3rd and 3rd–5th days, respectively. If no follow-up is possible, the neonatal discharge is delayed from the 3rd to 4th days until the risk period is passed.[3] Some of the risk factors for neonatal jaundice are prematurity, race, drugs, high altitude, polycythemia, male gender, trisomy 21, cephalohematoma, breastfeeding, weight loss, delayed meconium pass, history of jaundice in family,[4] ABO or RH incompatibility, mode of delivery, and maternal diabetes.[5]

Kernicterus or bilirubin encephalopathy, as a preventable neurological syndrome with undesirable side effects, is caused by unconjugated bilirubin deposition in the cortical nuclei and brain stem.[6] Kernicterus is observed in one-third of the neonates with hemolytic anemia and bilirubin level of 25–30 mg/dL who have not undergone the treatment. Incidence of kernicterus has been reported as 2%–16% in the autopsy of premature neonates with hyperbilirubinemia.[7] Kernicterus has been reported in term newborns from 1 to 30,000 to 1 in 200,000 live births in developed countries.[8]

The first presentations of kernicterus are lethargy, poor feeding, and weakend reflex. Following that, the neonate is weakened and suffers from respiratory distress leading to opisthotonus, bulging fontanelle, abnormal movements in the face and limbs, as well as specific crying.[9] Discharge avoidance of neonates at risk of jaundice, appropriate follow-up after discharge, informing parents of the importance and follow-up of neonatal jaundice, phototherapy, and in resistant cases, rapid blood exchange in neonates can reduce the complications of jaundice. The neonates with bilirubin level >20 mg/dl should be appropriately monitored and treated in terms of sensorineural hearing impairment, developmental status, and eye condition.[10]

Appropriate strategy in the diagnosis, treatment, and follow-up of jaundice has always been one of the major challenges in neonatal medicine. Prevention of jaundice, early diagnosis, as well as proper treatment and prevention of related complications, can reduce the problems of neonatal jaundice. Identifying the characteristics of neonates with jaundice in different levels of severity can help physicians in the process of jaundice, appropriate treatment, and prediction of complications.

Considering the high prevalence of jaundice in Asian countries, such as Iran, associated with serious complications, and since the early referral of neonates with jaundice to hospitals and proper management increase the health of neonates and reduce the associated problems, this study aimed to identify the characteristics of neonates with jaundice in different levels of severity.

  Materials and Methods Top

In this cross-sectional study, out of 25,000 neonates referred to the Neonatal Intensive Care Unit, Clinic, and Emergency Department in Ghaem Hospital of Mashhad, Iran, 3005 newborns with jaundice were selected and enrolled in the study. The neonates with insufficient evaluation (n = 89), no tendency to continue the cooperation (n = 43), no enough data from fetal period or delivery period (n = 63), and those who left the hospital before the complete evaluation (n = 91) were excluded from the present study.

This study was approved by the Ethics Committee of the Research Deputy of Mashhad University of Medical Sciences. In addition, consent form was obtained from the parents of the patients before entering the study. Patients' data were recorded in a questionnaire designed for this purpose. Content validity of the questionnaire was confirmed by five members of the Faculty of Medicine.

In neonatal evaluation, age at referral, age of jaundice, cause of jaundice, complications of jaundice, neonate gender, mode of delivery, and pregnancy problems were recorded, and the complete examination of newborns was performed following that. Then, all the requested tests were conducted to examine the causes of jaundice, including hematocrit, platelet, direct and indirect bilirubin, Coombs test, neonatal and maternal blood groups, glucose-6-phosphate dehydrogenase (G6PD), urine culture, and other tests, if necessary, depending on the doctor's opinion. The neonates were divided into six groups based on the serum bilirubin level, and then the characteristics, causes, and prognosis of these neonates were compared based on the severity of jaundice.

Urine specimens were obtained from the patients with suprapubic aspiration, and if the parents were not satisfied, it was provided with a urine bag under clean conditions, at least two cultures with colony count higher than 100,000. In addition, the presence of leukocyturia or bacteriuria was necessary for the diagnosis of urinary tract infection. The urine specimen was examined in terms of microscopy, leukocyturia, and bacteriuria. Leukocyturia refers to the cases in which more than five leukocytes are observed in the high power field.[11] Diagnosis of sepsis is based on positive blood culture, along with clinical symptoms, and the confirmation of pneumonia is according to radiography with clinical symptoms. Three groups of sepsis, pneumonia, and urinary tract infection in a single group have been introduced as the infectious agents.

The RH incompatibility is diagnosed when the maternal RH is negative, the neonatal RH is positive, and direct Coombs test is reported positive. The ABO incompatibility is diagnosed when the maternal blood group is O, and the neonatal blood group is A or B, and there are at least two of the following conditions:

  1. First-day jaundice
  2. Positive direct Coombs test
  3. Presence of microspherocytosis in the peripheral blood
  4. Positive indirect Coombs test.

When there is no RH or ABO incompatibility but positive report of direct Coombs test, it is considered subgroup incompatibility.[6] Three groups of ABO and RH incompatibility, as well as the subgroups, were placed in a larger group as blood incompatibility. Activity of G6PD was evaluated by a semiquantitative and dye fluorescence method, and activity level lower than 30 was considered enzyme deficiency. The neonates with jaundice were divided based on the causes of jaundice with the increased production of bilirubin, including the incompatibilities of blood group, RH, subgroups, G6PD deficiency, cephalohematoma, polycythemia, skin ecchymosis, adrenal bleeding, and brain hemorrhage.

The neonates with weight loss lower than 10% or daily loss lower than 2% with the unknown causes of jaundice were considered jaundice cases with dehydration. The newborns with diabetic and hypothyroidism mothers were categorized as endocrine causes. Other causes include Crigler-Najjar and congenital heart disease. Follow-up of newborns with jaundice in terms of disease development was performed using Denver II Developmental Screening Test in four domains of personal-social, subtle-adaptive movements, language (i.e., speech), and rough movements.

If there is a problem in each of the four above-mentioned domains, it is considered a developmental delay; if there is a problem in just one domain, it is considered mild developmental delay; if there is a problem in two domains, it is considered moderate developmental delay; and if there is a problem in three or four domains, it is considered severe developmental delay.[12] The data were analyzed by SPSS software (version 16, SPSS Inc., Chicago, Ill, USA). Moreover, the data were described using mean, standard deviation, and frequency tables. In addition, the data were analyzed by the Student's t-test and Chi-square test. P < 0.05 was considered statistically significant.

  Results Top

Regarding the frequency of total bilirubin, most neonates in the present study were reported with the bilirubin level of 15.1–20 mg/dL [Figure 1].
Figure 1: Distribution of jaundice frequency regarding the severity of jaundice

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In most cases, the present age of jaundice was reported between 2 and 3 days of birth; however, the age of the neonate referral was between 6 and 8 days of birth [Table 1].
Table 1: Comparison of neonatal characteristics in different levels of jaundice severity

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In this study, the causes of neonatal jaundice included unknown causes (61.25%), increased bilirubin production (22%), severe weight loss (7%), infections (5.3%), endocrine disorders (2.5%), and other causes (1.7%). The most common causes of jaundice in neonates with bilirubin levels <15 were unknown causes (67.5%), increased bilirubin production (19%), and infection (6.8%). The most common causes of jaundice in different levels of bilirubin severity were as follows:

  1. Bilirubin levels within 15.1–20 mg/dL: Unknown causes (65.4%), increased bilirubin production (18.2%), and infection (6.3%)
  2. Bilirubin levels within 20.1–25 mg/dL: Unknown causes (62.2%), increased bilirubin production (22.1%), and dehydration (9.2%)
  3. Bilirubin levels within 25.1–30 mg/dL: Unknown causes (50.8%), increased bilirubin production (24.6%) and dehydration (10.4%)
  4. Bilirubin levels within 30.1–35 mg/dL: Unknown causes (43%), increased bilirubin production (40.9%), and dehydration (5.4%)
  5. Bilirubin levels within 35–38 mg/dL: Increased bilirubin production (64.4%), unknown causes (25.4%), and dehydration (6.8%) [Table 2].

In terms of gender, jaundice was more common in male newborns at all levels of bilirubin >20, except in the bilirubin levels of 5–15. In bilirubin levels of 5–15, 15.1–20, 20.1–25, 25.1–30, and 30.1–35 mg/dL, 27.6%, 24.2%, 23.9%, 27.6%, and 18.6% of mothers were reported with pregnancy problems, respectively. In the present study, the complications of neonatal hyperbilirubinemia included acute kernicterus, abnormal auditory brainstem response (ABR), developmental delay at the age of 3 years old, and abnormal eye status.
Table 2: Comparison of neonatal and maternal variables in different levels of jaundice severity

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  Discussion Top

In the present study, half of the neonates who were referred due to jaundice had bilirubin levels >20 mg/dl that confirms the late referral of the parents. Based on the results of this study, in most cases, the incidence age of jaundice was between 2 and 3 days after birth; however, the age of the neonate referral was between 6 and 8 days after birth. The parents referred to a physician about 4 days after they noticed jaundice. In one study, neonates with ABO incompatibility on days 3–8 after birth, newborns with Rh incompatibility on days 1–7 after birth, neonates with G6PD deficiency on days 1–10 after birth, and newborns with blood subgroups incompatibility on days 2–7 after birth referred to the hospital.[6]

According to the results of a study, jaundice presented in G6PD-deficient neonates with 3 days of age who were referred at 7 days of age. Moreover, although the incidence age of blood incompatibility in newborns was the first 3 days, they referred about 2 days afterward. Therefore, the referral of these newborns in the most common time of occurrence and reception of appropriate and timely treatment can help reduce serious complications, such as kernicterus, and increase their health.[13]

Therefore, the late referral of parents despite noticing jaundice suggests that parents do not know the importance of jaundice and maybe jaundice is not taken seriously by medical personnel. As a result, given the importance of jaundice and its preventable complications, training mothers since pregnancy period about the symptoms of jaundice, timely referring of neonates with jaundice, and informing physicians and medical team are very helpful in the reduction of the serious complications of jaundice such as jaundice.

Cause of jaundice was unknown in two-thirds of the neonates in the present study, and the most common cause of jaundice (22%) was the increased levels of bilirubin production, including blood group incompatibilities, RH, G6PD deficiency, cephalohematoma, polycythemia, skin ecchymosis, adrenal hemorrhage, and brain hemorrhage. Hemolytic causes play a greater role in increasing the severity of jaundice so that about 19% of neonates with bilirubin level <15 had hemolytic jaundice. However, 64% of neonates with bilirubin level >35 had hemolytic jaundices. In addition, the level of hematocrit decreased with increasing bilirubin levels.[6]

According to the literature, the known causes of jaundice was identified in 27.9%, known causes of the jaundice included blood groups incompatibility (40%), infection (19%), deficiency of glucose 6-phosphate dehydrogenase (12%), endocrine disorders (8%), hypernatremic dehydration (7%), polycythemia (6%), congenital heart disease (4%), occult bleeding (3%) and Crigler-Najjar syndrome (2%).[13] In a study conducted by Najib et al., the causes of severe hyperbilirubinemia included ABO and RH incompatibility, G6PD deficiency, sepsis, and unknown causes.[14]

The second known cause was severe dehydration (7%), of which about 80% had jaundice <25 mg/dl and 40% <20 mg/dl. Healthy neonates who are hospitalized due to hyperbilirubinemia may be suffering from dehydration and prerenal azotemia, which is neglected, leading to kidney failure or hypernatremia and neurological outcomes. Therefore, it is recommended to measure the levels of urea, creatinine, and electrolytes of blood in hyperbilirubinemia neonates with significant weight loss.[15] In another study, hypernatremia was associated with severe hyperbilirubinemia (i.e., bilirubin >25 mg/dl) in 20% of neonates that increased the probability of long-term neurological outcomes; because hypernatremia and hyperbilirubinemia worsen the cycle of dehydration, jaundice, and hypernatremia, leading to brain damage.[16]

The third known cause of jaundice is infection that accounts for about 5% of the causes of jaundice (i.e., urinary tract infection, sepsis, and pneumonia). Most infectious cases had bilirubin levels <20 mg/dl (i.e., 60% of cases), and the risk of infection as a cause of jaundice has decreased with the increased severity of jaundice. Based on the evidence, infections have been the second most common cause of jaundice with the highest incidence after the 1st week of life. Urinary tract infection (13%) and sepsis (5.6%) are the known causes of jaundice, and the most common cause of jaundice after 13 days was urinary tract infection (15.5%).[13]

Endocrine disorders (in neonates of diabetic and hypothyroid mothers) in 50% of cases have bilirubin levels <20 mg/dl. Newborns of diabetic mothers have several problems, including prematurity and its complications, hypoglycemia, macrosomia, and jaundice.[17] There are various causes for the occurrence of jaundice in the neonates of diabetic mothers, including prematurity, polycythemia, macrosomia, and poor control of maternal glucose, increased concentration of free fatty acids following hypoglycemia, and ineffective hematopoiesis.[18]

In one study, the neonate of diabetic neonates (4%) and hypothyroidism (4.2%) were the causes of jaundice that jaundice occurred at 3 days of age in neonates of diabetic mother and had referred at 8 days of age, while jaundice occurred at 4 days of age in neonates of hypothyroidism mothers and had referred at 13 days of age.[13]

In macrosomic neonates of diabetic mothers, bilirubin levels increase due to hemoglobin F, polycythemia, or ineffective hematopoiesis.[19] Results of a study carried out by Keren showed that gestational diabetes mellitus has various and dangerous side effects on the neonate, the most common of which is neonatal jaundice (17.3%).[20] Karamizadeh demonstrated that the most common clinical finding in congenital hypothyroidism is prolonged icter.[21] Cause of jaundice in hypothyroidism is not exactly clear; however, it is probably due to the decreased activity of the enzyme of uridyl glucuronyl transferase, which may be lower than normal for weeks or months.[6]

In terms of gender, most of the neonates were male at all bilirubin levels higher than 20 mg/dl, except for the bilirubin level of 5–15 mg/dl. In a study carried out by Saber et al., about 53% of the neonates were male.[22] In other studies also male gender was a risk factor for neonatal jaundice.[5],[23] No cause for a higher prevalence of jaundice in boys has been mentioned in the review of the literature.

Complications of jaundice increased with increasing the levels of total bilirubin. Mechanism of neurological damage caused by bilirubin is not completely known, and several pathways, such as bilirubin-induced lipid peroxidation, nerve inflammation, as well as sustained energy failure, seem to be involved. Unconjugated bilirubin has direct effects on plasma membranes, mitochondria, or endoplasmic reticulum, leading to defects in mitochondrial energy and levels of elevated intracellular calcium. These mechanisms, either directly or indirectly, cause apoptosis and cell necrosis. If the exposure to unconjugated bilirubin lasts for a long time, it causes irreversible neurological damage.[24] Immaturity of brain cells, especially in preterm neonates, increases neuronal damage even at lower levels of bilirubin.[25]

In the bilirubin level >35 mg/dl, 60% of neonates had abnormal ABR. According to the evidence, it is suggested that hearing neural pathways are the most sensitive system to bilirubin toxicity associated with hearing loss.[26] Results of one study revealed that bilirubin level had a predictive power of about 82% for the prognosis of sensory-neural hearing disorders.

Hearing disorders in neonates with severe jaundice is about 10–50 times higher in comparison to the newborns with other disorders, and this disorder is associated with the severity, cause, and treatment method of hyperbilirubinemia. Therefore, the screening of neonates with jaundice using ABR helps to early diagnose hearing impairment caused by hyperbilirubinemia, conduct appropriate treatment, and ultimately promote children health.[27] Limitation of the present study was not considering the referral time of neonates. Therefore, it is recommended to carry out future studies with larger sample sizes and subjects' matching in terms of the referral time to the hospital.

  Conclusion Top

In the present study, the parents of the neonates had referred about 3–4 days after noticing their neonates' jaundice that might be the cause of severe jaundice in their newborns. The most common known causes of jaundice were increased bilirubin production (22%), severe weight loss (7%), infections (5.3%), and endocrine causes (1.7%). Hemolytic causes played a greater role in increasing the severity of jaundice so that 64% of neonates with bilirubin levels >35 mg/dl had hemolytic causes.

Severity of neonatal jaundice was mild to moderate with infectious causes, dehydration, endocrine disorders. However, increased bilirubin production was determined as the most known cause of jaundice in cases with bilirubin levels >25 mg/dl. Rate of jaundice complications increased with the increase in total bilirubin levels; therefore, 15% of the neonates had complication in bilirubin levels <25 mg/dl. Nevertheless, about 40% of the newborns had complications in bilirubin levels >35 mg/dl.

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  References Top

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  [Figure 1]

  [Table 1], [Table 2]


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