Incidence and risk factors for low serum albumin concentrations in neonates evaluated for jaundice

Abstract

Objective

To examine the incidence and risk factors for low serum albumin concentrations in neonates evaluated for jaundice.

Methods

A retrospective chart review was conducted on inborn neonates who were born at ≥35 weeks gestation and evaluated for jaundice at 3 university hospitals in Thailand from 1 January to 31 December 2023. The neonates’ demographics, neurotoxicity risk factors, serum albumin concentrations, and maternal characteristics were analyzed. The neonates were classified into the hypoalbuminemia (<3.0 g/dL) and normal albumin (≥3.0 g/dL) groups. Univariate and multivariate regression analyses were used to identify the factors associated with hypoalbuminemia.

Results

Among 902 neonates who had jaundice evaluation, 229 (25.4%) had serum albumin <3.0 g/dL. The hypoalbuminemia group had a lower gestational age and Apgar scores, a higher prevalence of male sex, and clinical instability or sepsis compared with the normal albumin group. Neonates in the hypoalbuminemia group were also younger at testing and their mothers were older than those in the normal albumin group. In the univariate analysis, male sex, clinical instability or sepsis, low gestational age, low birth weight, low Apgar scores, and increased maternal age were associated with hypoalbuminemia (p < 0.1). In the multivariate analysis, lower gestational age, male sex, and clinical instability or sepsis remained significant risk factors for hypoalbuminemia (all p < 0.05).

Conclusions

About one-quarter of neonates evaluated for jaundice had serum albumin <3.0 g/dL. Lower gestational age, male sex, and clinical instability or sepsis were significant risk factors, suggesting that targeted albumin screening in these high-risk groups may be warranted.

Keywords

bilirubin neurotoxicity hypoalbuminemia neonatal hyperbilirubinemia neonatal jaundice risk factors

Introduction

Neonatal jaundice is caused by an imbalance between bilirubin production and clearance from pathological and physiological conditions.^1,2 Neonatal jaundice can occur in preterm and term neonates and may cause life-threatening neurotoxic complications, such as acute bilirubin encephalopathy and kernicterus.³ Patients with kernicterus have highly elevated serum bilirubin concentrations, which can lead to persistent neurodevelopmental morbidity and mortality.⁴ To prevent these irreversible consequences, routine physical assessments, close monitoring of serum bilirubin concentrations, and timely treatment with phototherapy or exchange transfusion are crucial for effective management of hyperbilirubinemia.¹

The American Academy Pediatric Guideline in 2022 for the management of hyperbilirubinemia in the newborn aged ≥35 weeks of gestation (AAP Guideline 2022) designated the risk factors for developing significant hyperbilirubinemia and the risk factors for hyperbilirubinemia neurotoxicity. According to this guideline, these risk factors can help pediatricians identify individual causes of jaundice and make treatment decisions. A gestational age <38 weeks, isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency or other hemolytic conditions, sepsis, clinical instability in the previous 24 h, and serum albumin concentrations <3.0 g/dL are defined as risk factors of hyperbilirubinemia neurotoxicity in newborns. The patient’s history, a physical examination, and laboratory results are important for determining the need for treatment of this condition. There are reduced treatment thresholds for patients with a lower gestational age, a younger postnatal age, or at least one risk factor for hyperbilirubinemia neurotoxicity.²

Serum albumin, which is a water-soluble protein, is essential in regulating free plasma bilirubin concentrations. The binding of serum albumin to bilirubin prevents excessive accumulation of free bilirubin in brain tissue, thereby mitigating potential neurotoxic effects.⁵ Serum albumin concentrations are affected by various factors. Previous studies have shown that gestational age and congenital disorders, such as hydrops and gastroschisis, reduce cord albumin concentrations in newborns.⁶ Retrospective studies have demonstrated that serum albumin concentrations in neonates are positively correlated with gestational age and postnatal age, whereas the presence of postnatal clinical disorders is negatively associated with albumin concentrations.^7–9 Additionally, maternal factors, such as age, underlying disease, pregnancy complications, and anthropometry, are associated with fetal growth and nutritional status, which could potentially affect neonatal serum albumin concentrations.^10–13

According to the 2022 AAP guidelines, a serum albumin concentration of less than 3.0 g/dL is considered low and is recognized as a risk factor for bilirubin-induced neurotoxicity. However, routine measurement of serum albumin in all neonates with jaundice is not currently recommended due to limited evidence supporting its clinical benefit. Moreover, data on the incidence and risk factors associated with low serum albumin levels in jaundiced neonates remain scarce.

Our neonatology group at the Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Thailand, measured serum albumin concentrations as part of laboratory examinations in all newborns who were evaluated for jaundice at our institutions from 2022 to 2023 to identify the risk of hyperbilirubinemia neurotoxicity. This allowed us to accurately determine the neurotoxicity risks and precisely assign individualized phototherapy treatment thresholds for each neonate, in accordance with the AAP Guideline 2022 recommendations. Using a historical laboratory dataset obtained during that time, this study aimed to identify the incidence and risk factors for low serum albumin concentrations in neonates who were evaluated for jaundice in our centers. The findings may help refine strategies for jaundice assessment in this population.

Methods

A retrospective chart review was performed on neonates who were born in the 3 academic tertiary medical centers of the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand from 1 January to 31 December 2023. The 3 hospital services include Ramathibodi Hospital, Phayathai, Bangkok (RPYT), Somdech Phra Debaratana Medical Center, Phayathai, Bangkok (SDMC), and Chakri Naruebodindra Medical Institute, Bang Phli, Samut Prakan (CNMI). These hospitals’ neonatal services share an integrated multidisciplinary team and neonatal management protocols. Inborn neonates with a gestational age ≥35 weeks who underwent early neonatal evaluation of jaundice were included in this study. During the study period, the jaundice assessment protocol involved the daily screening of all newborns in the hospital during the first week of life, as well as screening of all other newborns with clinical jaundice for transcutaneous bilirubin concentrations, using a transcutaneous bilirubinometer (Dräger Jaundice Meter JM105; Draeger Medical Systems, Inc., Telford, PA, USA). If transcutaneous bilirubin concentrations exceeded or were within 3.0 mg/dL below the phototherapy treatment threshold or if transcutaneous bilirubin concentrations were ≥15 mg/dL, total serum bilirubin concentrations were measured along with other laboratory evaluations. This was performed to assess the risk of neurotoxicity, determine the need for phototherapy or exchange transfusions based on the AAP Guidelines 2022, and identify the cause of jaundice. Standard laboratory evaluations of neonates with jaundice included a complete blood count, a peripheral blood smear, a reticulocyte count, total serum bilirubin measurement, albumin measurement, G6PD screening (fluorescent spot test), blood group (ABO, Rh) identification, and a direct antibody test.

In all centers, the albumin BCP2 assay was used to quantify albumin concentrations in serum or plasma on the Alinity c system (Abbott Laboratories, IL, USA) using the colorimetric method (bromocresol purple). Internal quality control runs were conducted according to the manufacturer’s guidelines, and an external quality assessment was carried out according to ISO 17043:2010 accredited programs.

Preterm infants who were born at <35 weeks’ gestation, those without laboratory evaluation for jaundice, those whose laboratory evaluations were performed after 2 weeks of age, those who were outborn, and those whose maternal prenatal record and delivery record were incomplete were excluded from the study. If multiple serum albumin measurements were performed in the same neonates, the first serum albumin result was used as a reference.

The Faculty of Medicine Ramathibodi Hospital, Mahidol University Ethics Committee approved this study (register no. MURA2024/75). The study was performed in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects and ethical principles of the Declaration of Helsinki. A waiver of individual patient informed consent was granted because of the retrospective nature of the study, and the analysis used anonymous clinical data.

Data collection and outcome measurement

The neonates’ records were reviewed to collect data on demographics (gestational age, birth weight, size (small for gestational age), sex, route of birth, and Apgar scores), laboratory test results (age at laboratory testing; hours after birth), serum albumin concentrations, the presence of blood group isoimmunization, and G6PD deficiency or other hemolytic conditions), and clinical status (clinical sepsis and/or significant clinical instability in the previous 24 h). Maternal records were reviewed for maternal baseline characteristics (age, pre-pregnancy weight, pregnancy weight gain, body weight at delivery, height, and body mass index (BMI) before pregnancy and at the time of delivery), laboratory test results (blood group), and clinical status during pregnancy (antenatal complications, including diabetes and/or hypertension). The neonates were divided into 2 groups according to the serum albumin concentration. Potential risk factors of hypoalbuminemia were compared between neonates with serum albumin concentrations <3.0 g/dL (hypoalbuminemia group) and those with serum albumin concentrations ≥3.0 g/dL (normal albumin group). The specific terms used in this study were defined as follows. “Hemolytic conditions” included immune and non-immune causes (e.g., ABO and Rh incompatibilities, and red blood cell membrane and enzyme defects), but G6PD deficiency was excluded. “Sepsis” refers to neonates who showed clinical instability, which was suspected or proven to be caused by infection and/or received treatment with intravenous antibiotics. “Significant clinical instability” included neonates who needed respiratory support, such as continuous positive airway pressure, a heated humidified high-flow nasal cannula, and mechanical ventilation, inotropic drugs to maintain blood pressure, altered consciousness, or seizures.

Statistical analysis

Analyses were conducted using complete-case data. Neonates with any missing values for variables included in the analysis were excluded, and no imputation was performed. Univariate analyses were performed to identify significant differences between the groups. The Student’s t-test was used to compare parametric continuous variables, and the results were presented as the mean ± standard deviation. The Mann–Whitney U test was used to compare non-parametric continuous variables. The results were specified accordingly when this test was used, and they are presented as the median (interquartile range). Either Pearson’s chi-square test or Fisher’s exact test was used to compare categorical variables, and the results are presented as the total number (%). A p-value <0.05 was considered statistically significant. To determine the factors associated with serum albumin concentrations <3.0 g/dL in neonates, a univariate Poisson regression analysis was performed to investigate the simple association between each neonate’s baseline characteristics and serum albumin concentrations <3.0 g/dL. Factors demonstrating an association with a p-value <0.1 in the univariate regression were entered into a multivariate Poisson regression model. A p-value <0.05 was considered statistically significant. All statistical analyses were performed using Stata version 18 (StataCorp, College Station, TX, USA).

Results

During the study period, 3334 neonates were born in the 3 hospitals. Of these, 235 preterm infants with a gestational age <35 weeks were excluded from the study. An additional 2197 neonates were further excluded because of no evaluation of jaundice, they underwent an evaluation of jaundice later than 14 days of age, or they had incomplete patient’s data, maternal data, or laboratory results. Consequently, 902 neonates from the 3 hospitals were included in the final analysis. Among these, 229 (25.4%) neonates had serum albumin concentrations <3.0 g/dL and were classified into the hypoalbuminemia group, while 673 (74.6%) had serum albumin concentrations ≥3.0 g/dL and were classified into the normal albumin group (Figure 1).

Figure 1.

Patient flow diagram.

Table 1 shows the clinical features of the neonates and their mothers in the study. Neonates in the hypoalbuminemia group had a lower gestational age, a higher proportion of male sex, a lower birth weight, lower Apgar scores at 1 and 5 min, a higher proportion of clinical instability or sepsis, were younger at the time of testing, and were born to mothers who were older than those of neonates in the normal albumin group (p < 0.05) (Table 1).

Table 1.

Clinical characteristics of infants and their mothers.

Characteristics Infants characteristics	All infants (n = 902)	Hypoalbuminemia group (n = 229)	Normal albumin group (n = 673)	p-value
Serum albumin, g/dL	3.16 ± 0.28	2.82 ± 0.17	3.280.20	<0.001
Gestational age, week	38.01.3	37.61.4	38.11.3	<0.001
Male gender	440 (48.8)	136 (59.4)	304 (45.2)	<0.001
Birth weight, g	3030457	2959534	3055426	0.010
Hour of life, hour	54.942.3	50.630.6	56.545.6	0.029
Cesarean section	537 (59.5)	147 (64.2)	390 (58.0)	0.096
Apgar scores
at 1 min	8 (8, 9)	8 (8, 9)	8 (8, 9)	<0.001
at 5 min	9 (9, 10)	9 (9, 10)	10 (9, 10)	<0.001
Small for gestational age	103 (11.4)	34 (14.9)	69 (10.3)	0.059
Risk for hemolytic conditions	81 (9.0)	26 (11.4)	55 (8.2)	0.146
Risk for G6PD deficiency	88 (9.8)	20 (8.8)	68 (10.2)	0.542
Risk for sepsis or clinical instability	102 (11.3)	64 (28.0)	38 (5.7)	<0.001
Maternal characteristics
Maternal age, year	32.45.5	33.25.6	32.15.5	0.009
BMI before pregnancy, kg/m²	23.14.8	23.24.9	23.14.8	0.909
BMI at delivery, kg/m²	28.44.8	28.44.9	28.44.7	0.862
Pregnancy weight gain, kg	13.45.3	13.35.3	13.45.2	0.640
Diabetes in pregnancy	192 (21.3)	54 (23.6)	138 (20.5)	0.326
Pregnancy-induced hypertension	61 (6.8)	19 (8.3)	42 (6.3)	0.287

Data are presented as mean ± standard deviation, number of patients (%), or median (interquartile range).

G6PD: glucose-6-phosphate dehydrogenase; BMI: body mass index.

In the univariate regression analysis, a lower gestational age, male sex, a lower birth weight, lower Apgar scores at 1 and 5 min, clinical instability or sepsis, and increased maternal age were associated with an increased risk of hypoalbuminemia (p < 0.1). However, in the multivariate regression model that included the factors mentioned above, only lower gestational age, male sex, and clinical instability or sepsis increased the risk of hypoalbuminemia (p < 0.05), while birth weight, Apgar scores, and maternal age were no longer significant (p > 0.05) (Table 2).

Table 2.

Univariable and multivariable Poisson regression analyses for predictors of serum albumin levels <3.0 g/dL in neonates with jaundice.

Characteristics	Univariable regression		Multivariable regression
Characteristics	IRR (95% CI)	p-value	IRR (95% CI)	p-value
Infants characteristics
Gestational age, week	0.807 (0.734–0.888)	<0.001	0.866 (0.774–0.968)	0.012*
Male gender	1.535 (1.180–2.000)	0.001	1.500 (1.148–1.960)	0.003*
Birth weight, g	1.000 (0.999–1.000)	0.018	1.000 (0.999–1.000)	0.766
Hour of life, hour	0.997 (0.994–1.001)	0.122
Cesarean section	1.218 (0.930–1.596)	0.152
Apgar score
at 1 min	0.847 (0.785–0.914)	<0.001	0.902 (0.797–1.022)	0.104
at 5 min	0.776 (0.693–0.869)	<0.001	0.979 (0.815–1.175)	0.818
Small for gestational age	1.353 (0.940–1.947)	0.104
Risk for hemolytic conditions	1.298 (0.863–1.953)	0.210
Risk for G6PD deficiency	0.884 (0.559–1.399)	0.598
Risk for sepsis or clinical instability	3.042 (2.279–4.060)	<0.001	2.470 (1.812–3.367)	<0.001*
Maternal characteristics
Maternal age, year	1.029 (1.004–1.054)	0.024	1.022 (0.997–1.048)	0.082
BMI before pregnancy, kg/m²	1.001 (0.975–1.028)	0.922
BMI at delivery, kg/m²	0.998 (0.971–1.026)	0.880
Pregnancy weight gain, kg	0.995 (0.971–1.020)	0.686
Diabetes in pregnancy	1.141 (0.841–1.548)	0.397
Pregnancy-induced hypertension	1.246 (0.779–1.993)	0.359

This table presents incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for each clinical characteristic associated with serum albumin levels below 3.0 g/dL. Variables with a p-value <0.10 in univariable analysis (n = 7) were included in the multivariable Poisson regression model. Statistically significant p-values in the multivariable model are indicated with an asterisk (*).

Abbreviations: IRR: incidence rate ratio; CI: confidence interval; G6PD: glucose-6-phosphate dehydrogenase; BMI: body mass index.

Discussion

To the best of our knowledge, this is the first study to assess the incidence and risk factors for low serum albumin concentrations in neonates born at ≥35 weeks’ gestation who were evaluated for jaundice. We found that approximately 25% of the neonates with jaundice in our cohort had serum albumin concentrations <3.0 g/dL, highlighting that this condition is relatively common in neonates with jaundice. Significant risk factors for low serum albumin concentrations included lower gestational age, male sex, and the presence of clinical instability or sepsis. These findings suggest that hypoalbuminemia is more prevalent in neonates with certain perinatal characteristics and clinical conditions.

There is limited research on serum albumin concentrations in newborns, particularly those with jaundice. However, a study from Japan that used cord blood to establish gestational age-dependent reference ranges showed a positive correlation between gestational age and cord albumin concentrations.⁶ This previous study showed that, at 35 weeks’ gestation, the median umbilical cord albumin concentration was approximately 3.0 g/dL. Similarly, a large multicenter, retrospective cohort study of 164,401 neonates born at 23 to 41 weeks’ gestation in neonatal intensive care units identified gestational and postnatal age as positive determinants of serum albumin concentrations, total serum bilirubin concentrations, and the bilirubin-to-albumin ratio.⁷ Notably, up to 50% of neonates born at ≥35 weeks’ gestation had serum albumin concentrations ≤3.0 g/dL in this previous study. Additionally, a recent study from a neonatal intensive care unit in Belgium, which included 5548 serum albumin measurements from 848 neonates (median gestational age of 35 weeks) during the first 28 days of life, reported a median serum albumin concentration of 3.23 g/dL.⁹ This study also proposed a serum albumin prediction model based on several factors, such as gestational age and postnatal age.

These findings suggest that a substantial proportion of newborns born at ≥35 weeks’ gestation may have serum albumin concentrations <3.0 g/dL, which could increase their risk for bilirubin neurotoxicity due to a diminished bilirubin-binding capacity. The incidence of hypoalbuminemia in this study, which is lower than that reported in the studies mentioned above, is still consistent with previous findings.^6,7,9 The differences in incidence rates could be due to variations in the study populations (e.g., differences in ethnicity), clinical conditions of the neonates (e.g., healthy neonates vs those in the neonatal intensive care unit), and the sources or timing of specimen collection (e.g., cord blood vs postnatal serum albumin).

In our study, the incidence of the individual risk of neurotoxicity in neonates with jaundice varied. The incidence of G6PD deficiency in our study was 9.8%, while the overall prevalence of G6PD deficiency in Thai male neonates was reported to range from 3% to 18%.¹⁴ Previous studies from the northeastern region of Thailand reported a higher prevalence of G6PD deficiency (23.7%) in male neonates with jaundice in Khon Kaen Province than in those (15.7%) in Chaiyaphum Province.^15,16 A study performed from 2006 to 2007 in our institution, Ramathibodi Hospital, Phayathai, Bangkok, which is located in the central region of Thailand, reported a lower incidence (8.7%) of G6PD deficiency in full-term neonates with jaundice.¹⁷ This finding is consistent with our current study. These differences in the reported incidence of G6PD are likely attributable to variations in the studied populations and geographic location.

In our study, hemolytic conditions, such as isoimmune hemolytic disease and red blood cell membrane defects, were found in 9.0% of newborns with jaundice. Previous studies in Thailand reported a higher incidence of ABO incompatibility in neonates with jaundice, with percentages of 14.8% and 14.3%, according to Wongnate et al. and Prachukthum et al., respectively.^16,17 However, data on the prevalence of red blood cell membrane defects in newborns with jaundice are scarce.

Sepsis or clinical instability was observed in 11.3% of neonates with jaundice in our study. Although data on the incidence of sepsis or clinical instability in neonates with jaundice in Thailand are limited, Wongnate et al. reported a much lower incidence of neonatal sepsis (2.1%) as a cause of jaundice than in our study.¹⁶ In contrast, a study from China showed that infections were the cause of early neonatal jaundice in 16.1% of term infants.¹⁸ In the same Chinese cohort, they also reported that 9.7% of the term infants had G6PD deficiency, 3.5% had ABO isoimmunization, and 22.3% were classified as having a mixed etiology. This suggest that there may be greater number of neonates with each of the etiologies listed above. While the incidence of ABO isoimmunization in this Chinese study¹⁸ was lower than that in our study, the incidence of infection was slightly higher, and the prevalence of G6PD deficiency was comparable.

Our study identified several risk factors for hypoalbuminemia, including lower gestational age, male sex, and the presence of sepsis or clinical instability. According to our multivariable regression analysis, each additional week of gestational age was associated with a 12% lower incidence of hypoalbuminemia (adjusted IRR = 0.88, 95% CI: 0.80–0.97). Male infants had a 53% higher incidence compared with females (adjusted IRR = 1.53, 95% CI: 1.23–1.91), and those with clinical instability or sepsis had more than double the incidence (adjusted IRR = 2.47, 95% CI: 1.81–3.37).

The association between gestational age and hypoalbuminemia is consistent with previous studies, which suggests that serum albumin concentrations tend to increase with advancing gestational age.^6–9 Interestingly, our finding that male sex is a risk factor for low serum albumin concentration is novel and not yet well understood. Watchko et al. found a higher proportion of male neonates with serum albumin concentrations <2.5 g/dL than those with serum albumin concentrations ≥2.5 g/dL, suggesting a potential sex-based vulnerability.⁷ Hormonal or genetic variables influencing albumin metabolism and increased male vulnerability to prenatal stress and inflammation, which limit albumin production, might all be contributing causes. However, in a study by Ikuta, there was no significant difference in the correlation between gestational age and umbilical cord albumin concentrations between sexes.⁶ Therefore, further studies are required to validate our findings and to determine the mechanisms underlying these sex differences in hypoalbuminemia and their effects on neonatal outcomes.

In this study, we included the risk of sepsis and clinical instability together as a risk factor for hypoalbuminemia because we found that many neonates had both clinical sepsis and clinical instability (e.g., patients who were suspected or proven to have infection were likely to have unstable vital signs, receive respiratory support, or receive mechanical ventilation).

The finding of sepsis or clinical instability as a risk factor for hypoalbuminemia in our study may be explained by physiological and clinical factors. Sepsis and clinical instability are causes and consequences of hypoalbuminemia.¹⁹ Critical illness in newborns may have a physiological effect on albumin production and its distribution throughout the body. Critical conditions, such as infection, severe malnutrition, liver disease, and chronic kidney disease, lead to a decrease in albumin synthesis and an increase in albumin degradation. Inflammatory processes promote vascular permeability, which leads to albumin leakage and loss.⁵ On the other hand, hypoalbuminemia can exacerbate infection by directly suppressing the immune system and may contribute to organ failure and increased mortality.¹⁹ Multiple studies have also linked low serum albumin concentrations with neonatal morbidity and associated hypoalbuminemia with conditions, such as respiratory distress syndrome,²⁰ acute kidney injury,²¹ necrotizing enterocolitis,²² neonatal infections,¹⁸ and even mortality.^7,18,23 A recent study by Vander et al. aimed at developing a multivariable prediction model for serum albumin concentrations in neonates also showed that sepsis and mechanical ventilation were significant non-maturational covariates, further reflecting the lower serum albumin concentrations observed in critically ill neonates.⁹ Therefore, our observation that the presence of sepsis and clinical instability was associated with hypoalbuminemia is consistent with the body of evidence in the literature.

The strengths of our study include a well-defined population and systematic data collection from 3 medical centers affiliated with university hospitals, which allowed for the identification of risk factors with high relevance in the clinical setting. Our findings not only confirm previously reported direct associations between lower gestational age or clinical instability/sepsis and low serum albumin level, but also extend prior evidence by identifying male sex as one of the risk factors. This suggests that a subset of neonates with jaundice are at increased risk of hypoalbuminemia, which in turn heightens the risk of bilirubin-induced neurotoxicity. As serum albumin measurement is not routinely performed in all neonates, targeted screening of infants with identified risk factors, such as prematurity, male sex, or the presence of sepsis or clinical instability, may be warranted. Early identification of hypoalbuminemia in these high-risk groups could facilitate individualized adjustment of phototherapy thresholds in accordance with the 2022 AAP guideline, thereby optimizing neurotoxicity prevention while minimizing unnecessary testing in lower-risk infants.

However, this study has limitations. First, it was conducted in tertiary care university hospitals in central Thailand, which may limit the generalizability of the findings to other settings, particularly Western countries, with different healthcare infrastructures, perinatal care protocols, patient demographics, and genetic backgrounds that may affect albumin metabolism and bilirubin handling (e.g., prevalence of G6PD deficiency). Second, its retrospective design may be subject to inherent biases such as incomplete documentation, insufficient sample size justification, and unmeasured confounding variables. Third, serum albumin concentrations were assessed at a single time point, precluding analysis of longitudinal changes or trends. Finally, the degree of hyperbilirubinemia or the treatment received associated with serum albumin was not reported, as it may be influenced by various factors and may not consistently reflect the underlying severity. This limits the interpretability of hypoalbuminemia as bilirubin-albumin binding and treatment thresholds are essential aspects of neonatal jaundice management.

Future research should prioritize multicenter, longitudinal studies to validate these findings across diverse populations and healthcare settings. Further investigation into the pathophysiology of hypoalbuminemia in neonates is essential to better understand its clinical significance. In addition, exploring the interplay between serum albumin levels, bilirubin concentrations, treatment decisions, and neonatal outcomes may help refine strategies for the evaluation and management of neonatal jaundice.

Conclusions

Approximately 1 in 4 infants evaluated for jaundice had serum albumin concentrations <3.0 g/dL, and lower gestational age, male sex, and clinical instability or sepsis were significant risk factors. Targeted screening of infants with these identified risk factors could help refine strategies for the evaluation and management of neonatal jaundice.

Footnotes

Acknowledgments

We would like to express our sincere gratitude to Prof. Pornpen Srisawasdi and Ms Sirirat Promnuch from the Department of Pathology at Ramathibodi Hospital for their assistance in providing laboratory data for patients at Somdech Phra Deparatana Medical Center and Ramathibodi Hospital. We also extend our thanks to Prof. Sinitdhorn Rujirabanjerd and Mr Atthapong Sararat from the Laboratory Department at Chakri Naruebodindra Medical Institute for their support in supplying laboratory data from patients at this institute. We are especially grateful to Ms Nattacha Chumsunthorn for her assistance with the statistical analysis. We are grateful to Prof. Pracha Nuntnarumit for supporting our project and providing helpful feedback.

ORCID iDs

Napat Rojsirikulchai

Buranee Swatesutipun

Rachaporn Rattanamalee

Chayatat Ruangkit

Ethical considerations

Consent to participate

A waiver of individual patient informed consent was granted because of the retrospective nature of the study, and the analysis used anonymous clinical data.

Author contributions

Napat Rojsirikulchai: Conceptualization, Data curation, Investigation, Writing – original draft. Suchanun Keesukphan: Data curation, Investigation. Kanuengnit Emrat and Prathana Kongurai: Data curation, Resources. Buranee Swatesutipun and Rachaporn Rattanamalee: Validation, Supervision. Sasivimon Soonsawad: Visualization, Writing – review and editing. Chayatat Ruangkit: Conceptualization, Methodology, Project administration, Validation, Formal analysis, Visualization, Writing – review and editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.*

References

Maisels

. Neonatal jaundice. Pediatr Rev 2006; 27(12): 443–454.

Kemper

Newman

Slaughter

, et al. Clinical practice guideline revision: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2022; 150(3): 2022058859.

Singla

Sharma

, et al. Evaluation of risk factors for exchange range hyperbilirubinemia and neurotoxicity in neonates from hilly terrain of India. Int J Appl Basic Med Res 2017; 7(4): 228–232.

Shapiro

. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med 2010; 15(3): 157–163.

Chen

Hammo

Barry

, et al. Overview of albumin physiology and its role in pediatric diseases. Curr Gastroenterol Rep 2021; 23(8): 11.

Ikuta

Iwatani

Okutani

, et al. Gestational age-dependent reference ranges for albumin levels in cord serum. Neonatology 2022; 119(3): 327–333.

Watchko

Spitzer

Clark

. Prevalence of hypoalbuminemia and elevated bilirubin/albumin ratios in a large cohort of infants in the neonatal intensive care unit. J Pediatr 2017; 188: 280–286.e4.

Lee

Youn

Lim

, et al. Serum albumin concentrations and clinical disorders by gestational ages in preterm babies. Korean J Pediatr 2005; 48(2): 148–153.

Vander Elst

Laenen

Deberdt

, et al. Human serum albumin: prediction model and reference values for preterm and term neonates. Pediatr Res. 2024; 11.

10.

Wang

Yang

Shang

, et al. Changing trends of birth weight with maternal age: a cross-sectional study in Xi'an city of northwestern China. BMC Pregnancy Childbirth 2020; 20(1): 744.

11.

Desta

Damte

Hailu

. Maternal factors associated with low birth weight in public hospitals of Mekelle city, Ethiopia: a case-control study. Ital J Pediatr 2020; 46(1): 124.

12.

Liu

Wang

, et al. Maternal body mass index and risk of neonatal adverse outcomes in China: a systematic review and meta-analysis. BMC Pregnancy Childbirth 2019; 19(1): 105.

13.

Manal

Hanaa

. Influence of maternal anthropometric measurements and serum biochemical nutritional indicators on fetal growth. J Med Sci 2007; 7(8): 1330–1334.

14.

Tanphaichitr

. Glucose-6-phosphate dehydrogenase deficiency in Thailand; its significance in the newborn. Southeast Asian J Trop Med Publ Health 1999; 30(Suppl 2): 75–78.

15.

Paopongsawan

Kiatchoosakun

Jirapradittha

, et al. Prevalence of Glucose-6-Phosphate dehydrogenase deficiency in Male newborn infants and its relationship with neonatal jaundice in Thailand. Am J Perinatol 2024; 41(S 01): e1631–e1638.

16.

Wongnate

. Incidence and causes of neonatal jaundice in neonates at PhuKieochalermprakiat hospital, Chaiyaphum province. Chai Med J 2021; 41(1): 85–93.

17.

Prachukthum

Nunnarumit

Pienvichit

, et al. Genetic polymorphisms in Thai neonates with hyperbilirubinemia. Acta Paediatr 2009; 98(7): 1106–1110.

18.

Yang

Liu

Tian

, et al. Relationship between serum albumin levels and infections in newborn late preterm infants. Med Sci Monit 2016; 22: 92–98.

19.

Wiedermann

. Hypoalbuminemia as surrogate and culprit of infections. Int J Mol Sci 2021; 22(9): 4496.

20.

Ying

You

Luo

, et al. Maternal-neonatal serum albumin level and neonatal respiratory distress syndrome in late-preterm infants. Front Pediatr 2021; 9: 666934.

21.

Nada

Askenazi

Kupferman

, et al. Low albumin levels are independently associated with neonatal acute kidney injury: a report from AWAKEN study group. Pediatr Nephrol 2022; 37(7): 1675–1686.

22.

Atkinson

Tuggle

Tunell

. Hypoalbuminemia May predispose infants to necrotizing enterocolitis. J Pediatr Surg 1989; 24(7): 674–676.

23.

Torer

Hanta

Yapakci

, et al. Association of serum albumin level and mortality in premature infants. J Clin Lab Anal 2016; 30(6): 867–872.