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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 8
| Issue : 2 | Page : 176-181 |
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Risk factors for early hyperbilirubinemia in neonates: A cross-sectional study
T Rehna1, Suni Ann Thomas2
1 Department of Pediatrics and Neonatology, Al-Azhar Medical College and Super Speciality Hospital, Thodupuzha, Kerala, India
2 Department of Biochemistry, Al-Azhar Medical College and Super Speciality Hospital, Thodupuzha, Kerala, India
| Date of Submission | 18-Mar-2022 |
| Date of Decision | 02-Sep-2022 |
| Date of Acceptance | 03-Sep-2022 |
| Date of Web Publication | 23-Dec-2022 |
Correspondence Address:
T Rehna
Department of Pediatrics and Neonatology, Al-Azhar Medical College and Super Speciality Hospital, Thodupuzha, Kerala
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jcrsm.jcrsm_20_22
Background: Neonatal hyperbilirubinemia is a commonly encountered problem in the early neonatal period. Hence, this study was undertaken in babies with significant hyperbilirubinemia to find out the factors which had caused an early rise of bilirubin (≤48 h) in some neonates compared to those who develop hyperbilirubinemia by 72 h. Factors that can predict early hyperbilirubinemia will help in early intervention.
Methodology: This cross-sectional study was conducted in the neonatal intensive care unit of a tertiary care center from March 2021 to January 2022 among 405 healthy term neonates with significant hyperbilirubinemia. Serum bilirubin values were routinely done at 72 h, and earlier at 48 h if clinical icterus was noted by Kramer's rule and divided into two groups – one with hyperbilirubinemia at 48 h and another with hyperbilirubinemia by 72 h. Statistical analysis was done to find out the factors which could predict early hyperbilirubinemia.
Results: Of the 405 neonates with significant hyperbilirubinemia, 270 (66.6%) had early hyperbilirubinemia and 135 (33.3%) had hyperbilirubinemia by 72 h. There were no statistically significant differences between the two groups with respect to sex, birth weight, mode of delivery, and baby blood group. Forty-two (49.4%) neonates with umbilical cord bilirubin (UCB) <2 mg/dl, 113 (65.6%) with UCB 2–2.5 mg/dl, 75 (72.1%) with UCB 2.5–3 mg/dl, 34 (89.5%) with UCB 3–3.5 mg/dl, and 6 (100%) with UCB >3.5 mg/dl developed early hyperbilirubinemia. Sixty-four (79%) neonates with bilirubin–albumin ratio (BAR) ≥0.79 developed early hyperbilirubinemia compared to 206 (63.6%) neonates with BAR <0.79 who had early hyperbilirubinemia.
Conclusions: The UCB and bilirubin–albumin ratio correlated well with the development of early hyperbilirubinemia. Hence, it was concluded that those babies with a high UCB >2.1 mg/dl and/or high BAR ≥0.79 should be screened early for the development of hyperbilirubinemia.
Keywords: Bilirubin–albumin ratio, cord bilirubin, hyperbilirubinemia, phototherapy, prediction tool
How to cite this article:
Rehna T, Thomas SA. Risk factors for early hyperbilirubinemia in neonates: A cross-sectional study. J Curr Res Sci Med 2022;8:176-81 |
| Introduction | |  |
Hyperbilirubinemia is a common clinical condition encountered in the neonatal period.[1] It affects 60% of term and 80% of preterm neonates during the 1st week of life.[2],[3] Neonatal jaundice is secondary to hyperbilirubinemia resulting from an imbalance between production and excretion.[4] Newborns produce bilirubin at a rate of approximately 6–8 mg/kg/day which is twice more than that in adults.[5] Unconjugated bilirubin is transported in plasma bound to albumin. Albumin has two binding sites which bind up to a maximum of 20 μmol bilirubin/g albumin. One mole of albumin was found to bind 2 mol of bilirubin. The binding of albumin with bilirubin reduces neurotoxicity.[6] The liver converts unconjugated bilirubin to conjugated form which gets excreted in bile.[7] Hyperbilirubinemia is normally benign, but there is a risk of bilirubin-induced neurological dysfunction.[8],[9] Any infant with high serum bilirubin requires treatment either by phototherapy or exchange transfusion to avoid bilirubin-induced neurotoxicity.
Since early discharge from the hospital has become a norm nowadays, it carries the risk of missed hyperbilirubinemia which may be deleterious to the baby. Hence, the American Academy of Pediatrics in 2004 recommended that newborns discharged within 48 h should be followed up after 2–3 days for any development of significant jaundice.[10] Many studies have proved that umbilical cord bilirubin (UCB) values >2.5 mg/dl can predict hyperbilirubinemia.[11],[12],[13],[14],[15] Other parameters such as umbilical cord albumin levels <2.8 mg/dl[16],[17] and bilirubin–albumin ratio (BAR) are also good predictors of hyperbilirubinemia.[14],[15],[18],[19]
Hyperbilirubinemia is commonly observed usually by Day 3 of life in term babies.[20] Routine screening of serum bilirubin of neonates is done at 72 h of life to detect hyperbilirubinemia. Many babies may develop hyperbilirubinemia before Day 3. Such babies may have very high bilirubin values if screened at 72 h warranting a longer duration of phototherapy or invasive interventions like exchange transfusions. The factors that can predict the early development of hyperbilirubinemia can help in the early screening of neonates, thereby helping in early institution of therapy and an early discharge than those detected by the routine screening of jaundice at 72 h. Hence, this study was undertaken in babies with significant hyperbilirubinemia to find out the factors which had caused an early rise of bilirubin (≤48 h) in some neonates compared to those who develop hyperbilirubinemia by 72 h.
| Materials and Methods | | |
This cross-sectional study was conducted in the neonatal intensive care unit of a tertiary care center from March 2021 to January 2022. After obtaining institute ethical committee clearance (AAMC/IEC/2021/07) and written informed consent from the guardian, 424 babies who had hyperbilirubinemia requiring treatment according to age-specific nomograms were selected for the study. Due to a lack of parental consent in eight neonates and incomplete laboratory records in 11 neonates, a total of 19 babies were not included in the study. Thus, a total of 405 babies with hyperbilirubinemia were included in the study.
Inclusion criteria
All neonates with significant hyperbilirubinemia who are born term (gestational age ≥36 completed weeks) of either gender born through normal vaginal delivery or cesarean section with a birth weight of ≥2 kg and APGAR score ≥7 at the first minute of birth were included in the study.
Exclusion criteria
Preterm babies, neonates with Rh and/or ABO incompatibility, neonates born by instrumental delivery, neonates who were asphyxiated at birth and had a low APGAR of <7 at the first minute of life, neonates born to mothers with gestational diabetes or pregnancy-induced hypertension, and neonates with a significant illness such as sepsis, respiratory distress, shock, and those with major congenital anomalies were excluded from the study.
Four hundred and five neonates who had significant hyperbilirubinemia were included in the study. Babies were routinely screened for serum bilirubin values at 48 h and 72 h, and earlier if clinical icterus was noted by Kramer's rule according to the institute protocol. They were divided into two groups – one group who developed hyperbilirubinemia early at 48 h of life and another group who had developed hyperbilirubinemia by 72 h of life. The babies who had hyperbilirubinemia were treated with either phototherapy or exchange transfusion. The criteria for phototherapy and exchange transfusion were based on the Indian Academy of Pediatrics and National Neonatal Forum (IAP–NNF) guidelines which recommend phototherapy for serum bilirubin >13 mg/dl on Day 2 or ≥17 mg/dl on Day 3 for term babies and exchange transfusion if the serum bilirubin is ≥25 mg/dl.[21]
Statistical analysis
The data of all neonates including their demographic profile, sex, birth weight, mode of delivery, mother and baby blood group, umbilical cord blood bilirubin, umbilical cord blood albumin, BAR, serum bilirubin levels, duration, and type of treatment instituted either phototherapy or exchange transfusion were entered into a pro forma and later entered into an Excel sheet. Data were analyzed using the Statistical Package for the SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc. The baseline characteristics of neonates who required phototherapy at 48 h of life or before were then compared with those who required phototherapy after 48 h. Qualitative data were expressed as numbers and percentages and quantitative data were expressed as mean ± standard deviation. Analysis of correlation was done with Pearson's correlation and Chi-square test. A P ≤ 0.05 was considered statistically significant.
| Results | | |
This cross-sectional study was conducted on 405 neonates who had significant hyperbilirubinemia requiring treatment such as phototherapy or exchange transfusion. Two hundred and one (49.6%) were boys and 204 (50.4%) were girls. About 297 (73.3%) were born by normal vaginal delivery and 108 (26.7%) were born by cesarean section. The majority (81.7%) had a birth weight of 2.5–3 kg. The most common blood group was O + seen in 190 (46.9%) neonates. The least common blood group was AB-which was seen only in 2 (0.5%) neonates. The mean birth weight of the babies was 3.01 ± 0.37 kg, the mean cord bilirubin was 2.43 ± 0.48 mg/dl, mean cord albumin was 3.6 ± 0.35, and the mean BAR was 0.68 ± 0.15.
Among the 405 babies with significant hyperbilirubinemia, 270 (66.7%) babies developed early hyperbilirubinemia, whereas 135 (33.3%) developed hyperbilirubinemia subsequently by 72 h. The treatment instituted was phototherapy as per the IAP–NNF guidelines.[21] None had bilirubin in the exchange transfusion range. There were no statistically significant differences between the two groups regarding sex, birth weight, mode of delivery, and baby blood group as shown in [Table 1].
Among the total study population, 42 (49.4%) with UCB <2 mg/dl, 113 (65.6%) with UCB 2–2.5 mg/dl, 75 (72.1%) with UCB 2.5–3 mg/dl, 34 (89.5%) with UCB 3–3.5 mg/dl, and 6 (100%) with UCB >3.5 mg/dl developed early hyperbilirubinemia. There was a highly statistically significant difference between the two groups with a P < 0.001 as depicted in [Table 2]. | Table 2: Cross-tabulation between cord bilirubin levels and phototherapy
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Among the two babies who had umbilical cord albumin (UCA) <2.5 mg/dl, all (100%) developed early hyperbilirubinemia at 48 h of life compared to 43 (51.5%) neonates who developed early hyperbilirubinemia in the category with cord albumin <2.5–3 mg/dl. There was a statistically significant difference between the two groups with a P value of as depicted in [Table 3].
Among the total study population, 324 (81%) had BAR <0.79, and 81 (20%) had BAR ≥0.79. Sixty-four (79%) neonates with BAR ≥0.79 developed hyperbilirubinemia at 48 h of life compared to 206 (63.6%) neonates with BAR <0.79 who had early hyperbilirubinemia. There was a statistically significant difference between the two groups with a P = 0.008 as depicted in [Table 4]. | Table 4: Cross-tabulation between bilirubin-albumin ratio and phototherapy
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The cutoff UCB, albumin, and BAR which could predict an early rise of bilirubin in neonates were 2.1 mg/dl, 2.5 mg/dl, and 0.79, respectively. Areas under the receiver operating characteristic (ROC) curve for cord bilirubin, albumin, and BAR were 0.649, 0.633, and 0.581, respectively, as shown in [Figure 1], [Figure 2], [Figure 3], respectively. | Figure 1: ROC curve of umbilical cord bilirubin, ROC: Receiver operating characteristic
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 | Figure 2: ROC curve of umbilical cord albumin, ROC: Receiver operating characteristic
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 | Figure 3: ROC curve of bilirubin–albumin ratio, ROC: Receiver operating characteristic
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| Discussion | | |
In this cross-sectional study of 405 babies who had significant hyperbilirubinemia requiring treatment, 81.1% of neonates had birth weights between 2.5 kg and 3.5 kg. The mean birth weight of the study population was 3.01 kg which is the average birth weight of the Indian population.[22] The majority (72.6%) were delivered by spontaneous vaginal delivery, whereas 27.4% were delivered by cesarean section. The percentage of cesarean section is in concordance with the study done by Bhatia et al.[23] No statistically significant difference was found between the two groups concerning gender, birth weight, mode of delivery, and baby blood group. Among the study population of 405 neonates, 270 (66.7%) developed hyperbilirubinemia early (≤48 h) than 270 (33.7%) neonates who developed hyperbilirubinemia subsequently. None required exchange transfusion. About 42 (49.4%) neonates with cord bilirubin <2 mg/dl, 113 (65.7%) neonates with cord bilirubin 2.5–3 mg/dl, 75 (72.1%) neonates with cord bilirubin 3–3.5 mg/dl, and 6 (100%) neonates with cord bilirubin >3.5 mg/dl developed early hyperbilirubinemia. It was observed that even though the absolute numbers were less, 100% of neonates with cord bilirubin >3.5 mg/dl had significant early hyperbilirubinemia. It was found that as the cord bilirubin level increased, the percentage of babies who underwent phototherapy also increased. There was a highly statistically significant correlation between UCB and early hyperbilirubinemia confirming the finding that UCB can predict early hyperbilirubinemia. Awasthi and Rehman found that bilirubin at 18–24 h can be used as a prediction tool for neonatal hyperbilirubinemia.[24] ROC curve analysis found that the cutoff bilirubin was 2.1 mg/dl for early hyperbilirubinemia. This is in concordance with the cutoff of 2.1 mg/dl found by Zeitoun et al. and Knudsen[25],[26] Menon et al. also found that cord bilirubin level above 2.05 predicts the need for treatment of jaundice.[27] Studies by Taksande et al., Ghamsari et al., and Sun et al. found out cutoff cord bilirubin was 2 mg/dl.[28],[29],[30]
A huge majority (99.8%) had cord albumin >2.5 mg/dl. There was only one neonate with cord albumin <2.5 mg/dl, and that baby developed early hyperbilirubinemia. It was not possible to infer that a cord albumin <2.5 mg/dl was a factor for early hyperbilirubinemia as the absolute number was very less. It was proposed to have a study including more neonates with cord albumin <2.5 mg/dl to find a correlation between cord albumin and early hyperbilirubinemia. Gupta et al. and Chan et al. also found out that cord albumin <2.8 mg/dl was a prediction tool for hyperbilirubinemia.[16],[17]
Seventy-nine percent of babies with BAR ≥0.79 developed hyperbilirubinemia early as compared to 63.6% among those who had a BAR <0.79. It was also found that the neonates with high cord BAR. BAR ≥0.79 had a higher risk of development of early hyperbilirubinemia than those with a BAR <0.79. There was a highly statistically significant correlation with a P < 0.05. ROC curve analysis found a cutoff of 0.79. This is in concordance with previous studies were done by Sharma et al., and Khairy et al. found the cutoffs as 0.719 and 0.78, respectively.[31],[32] Studies by Rehna et al. and. EL Mashad et al. found the cutoffs as 0.59 and 0.6, respectively.[14],[33]
The UCB, albumin, and BAR helped in the detection of early hyperbilirubinemia and institution of therapy. The strengths of our study were the large sample size of 405 babies with significant hyperbilirubinemia, uniform estimation of parameters, and protocol-based approach to the treatment, thereby avoiding any bias. Limitations of our study were a lack of inclusion of high-risk babies and a relatively less number of babies with cord albumin <2.5 mg/dl. Another limitation is that the study presents data from a single center that is different compared to the whole Indian population.
| Conclusions | | |
This study demonstrated that parameters such as UCB, albumin, and BAR could predict the early development of early hyperbilirubinemia warranting an early screening in those neonates, thereby helping in the early institution of therapy and avoiding the use of invasive treatment modalities for the same.
Acknowledgments
The authors would like to acknowledge the help received from Mrs. Neethu, our statistician in the help received during the analysis of the study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
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