Factores asociados a ictericia neonatal patológica en un hospital nacional de referencia de Lima, Perú
Factors associated with pathological neonatal jaundice in a national referral hospital of Lima, Perú
DOI:
https://doi.org/10.15446/revfacmed.v73.120372Palabras clave:
Ictericia Neonatal, Deshidratación, Incompatibilidad ABO, Cesárea, Hospitalización (es)Neonatal Jaundice, Dehydration, ABO Incompatibility, Cesarean Section, Hospitalization (en)
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Introducción. La ictericia neonatal por hiperbilirrubinemia no conjugada es una condición común en neonatos prematuros y a término (60-80%). Aunque en la mayoría de los casos es leve y transitoria (fisiológica), su forma grave (ictericia patológica) requiere hospitalización para evitar complicaciones serias como encefalopatía bilirrubínica o kernícterus y las secuelas neurológicas permanentes asociadas.
Objetivo. Determinar los factores asociados a ictericia neonatal patológica en un hospital nacional de referencia del Perú.
Materiales y métodos. Estudio de casos y controles retrospectivo con relación 1:1 realizado en 128 neonatos con ictericia atendidos en un hospital de Lima (Perú) durante 2023. Los casos se definieron como neonatos con ictericia patológica (hospitalización) y los controles, como neonatos con ictericia fisiológica (sin hospitalización). Para identificar los factores asociados a ictericia patológica se realizó un análisis bivariado (prueba de Chi cuadrado) y uno multivariado (regresión logística para analizar asociaciones).
Resultados. Los neonatos nacidos por cesárea tuvieron una menor probabilidad de desarrollar ictericia neonatal patológica (OR: 0.338, p=0.008) en comparación con aquellos nacidos por parto vaginal. Por otra parte, la presencia de deshidratación neonatal y de incompatibilidad ABO se asociaron significativamente con una mayor probabilidad de esta condición (OR: 17.941, p<0.0001 y OR: 2.778, p=0.034). Factores como la edad gestacional, el trauma obstétrico, el sexo, la incompatibilidad Rh y la presencia de infecciones neonatales no se asociaron significativamente con el desarrollo de ictericia patológica.
Conclusiones. La presencia de deshidratación neonatal y la incompatibilidad ABO fueron factores de riesgo de ictericia patológica en neonatos peruanos atendidos por ictericia en un hospital nacional de referencia.
Introduction: Neonatal jaundice due to unconjugated hyperbilirubinemia is a common condition in both preterm and term neonates (60-80%). Although it is mild and transient (physiological) in most cases, its severe form (pathological jaundice) requires hospitalization to prevent serious complications such as bilirubin encephalopathy or kernicterus and associated permanent neurological sequelae.
Objective: To determine the factors associated with pathological jaundice in a national referral hospital in Peru.
Materials and methods: A retrospective case-control study with a 1:1 ratio was conducted in 128 neonates with jaundice treated at a hospital in Lima (Peru) during 2023. Cases were defined as neonates with pathological jaundice (hospitalization) and controls as neonates with physiological jaundice (without hospitalization). To identify the factors associated with pathological jaundice, a bivariate analysis
(Chi-square test), and a multivariate analysis (logistic regression) were performed.
Results: Neonates born by cesarean section had a lower probability of developing pathological neonatal jaundice (OR: 0.338, p=0.008) compared with those born by vaginal delivery. On the other hand, the presence of neonatal dehydration and ABO incompatibility were significantly associated with a higher probability of this condition (OR: 17.941, p<0.0001; OR: 2.778, p=0.034). Factors such as gestational age, obstetric trauma, sex, Rh incompatibility, and neonatal infections were not significantly associated with the development of pathological jaundice.
Conclusions: Neonatal dehydration and ABO incompatibility were risk factors for pathological jaundice in Peruvian neonates treated for jaundice at a national referral hospital. Conversely, cesarean delivery acted as a protective factor.
Original research
Factors associated with pathological neonatal jaundice in a national referral hospital of Lima, Perú
Factores asociados a ictericia neonatal patológica en un hospital nacional de referencia de Lima, Perú
Arianna Jamira Reaño-Velarde1
Yessica Iris Salazar-Quiroz2
Verónica Eliana Rubin-de Celis Massa1
1 Universidad Ricardo Palma - Faculty of Human Medicine - Biomedical Sciences Research Institute - Lima - Perú.
2 Hospital Nacional Sergio E. Bernales - Neonatology Service - Lima - Perú.
Open access
Received: 14/05/2025
Accepted: 25/11/2025
Corresponding author: Arianna Jamira Reaño-Velarde. Instituto de Investigación de Ciencias Biomédicas, Facultad de Medicina Humana, Universidad Ricardo Palma. Lima. Perú. E-mail: arianna.reano@urp.edu.pe.
Keywords: Neonatal Jaundice; Dehydration; ABO Incompatibility; Cesarean Section; Hospitalization (MeSH).
Palabras clave: Ictericia Neonatal; Deshidratación; Icompatibilidad ABO; Cesárea; Hospitalización (DeCS).
How to cite: Reaño-Velarde AJ, Salazar-Quiroz YI. Factors associated with pathological neonatal jaundice in a national referral hospital of Lima, Perú. Rev. Fac. Med. 2025;73:e120372. English. doi: https://doi.org/10.15446/revfacmed.v73.120372.
Cómo citar: Reaño-Velarde AJ, Salazar-Quiroz YI. [Factores asociados a ictericia neonatal patológica en un hospital nacional de referencia de Lima, Perú]. Rev. Fac. Med. 2025;73:e120372. English. doi: https://doi.org/10.15446/revfacmed.v73.120372.
Copyright: ©2025 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, as long as the original author and source are credited.
Abstract
Introduction: Neonatal jaundice due to unconjugated hyperbilirubinemia is a common condition in both preterm and term neonates (60-80%). Although it is mild and transient (physiological) in most cases, its severe form (pathological jaundice) requires hospitalization to prevent serious complications such as bilirubin encephalopathy or kernicterus and associated permanent neurological sequelae.
Objective: To determine the factors associated with pathological jaundice in a national referral hospital in Peru.
Materials and methods: A retrospective case-control study with a 1:1 ratio was conducted in 128 neonates with jaundice treated at a hospital in Lima (Peru) during 2023. Cases were defined as neonates with pathological jaundice (hospitalization) and controls as neonates with physiological jaundice (without hospitalization). To identify the factors associated with pathological jaundice, a bivariate analysis
(Chi-square test), and a multivariate analysis (logistic regression) were performed.
Results: Neonates born by cesarean section had a lower probability of developing pathological neonatal jaundice (OR: 0.338, p=0.008) compared with those born by vaginal delivery. On the other hand, the presence of neonatal dehydration and ABO incompatibility were significantly associated with a higher probability of this condition (OR: 17.941, p<0.0001; OR: 2.778, p=0.034). Factors such as gestational age, obstetric trauma, sex, Rh incompatibility, and neonatal infections were not significantly associated with the development of pathological jaundice.
Conclusions: Neonatal dehydration and ABO incompatibility were risk factors for pathological jaundice in Peruvian neonates treated for jaundice at a national referral hospital. Conversely, cesarean delivery acted as a protective factor.
Resumen
Introducción. La ictericia neonatal por hiperbilirrubinemia no conjugada es una condición común en neonatos prematuros y a término (60-80%). Aunque en la mayoría de los casos es leve y transitoria (fisiológica), su forma grave (ictericia patológica) requiere hospitalización para evitar complicaciones serias como encefalopatía bilirrubínica o kernícterus y las secuelas neurológicas permanentes asociadas.
Objetivo. Determinar los factores asociados a ictericia neonatal patológica en un hospital nacional de referencia del Perú.
Materiales y métodos. Estudio de casos y controles retrospectivo con relación 1:1 realizado en 128 neonatos con ictericia atendidos en un hospital de Lima (Perú) durante 2023. Los casos se definieron como neonatos con ictericia patológica (hospitalización) y los controles, como neonatos con ictericia fisiológica (sin hospitalización). Para identificar los factores asociados a ictericia patológica se realizó un análisis bivariado (prueba de Chi cuadrado) y uno multivariado (regresión logística para analizar asociaciones).
Resultados. Los neonatos nacidos por cesárea tuvieron una menor probabilidad de desarrollar ictericia neonatal patológica (OR: 0.338, p=0.008) en comparación con aquellos nacidos por parto vaginal. Por otra parte, la presencia de deshidratación neonatal y de incompatibilidad ABO se asociaron significativamente con una mayor probabilidad de esta condición (OR: 17.941, p<0.0001 y OR: 2.778, p=0.034). Factores como la edad gestacional, el trauma obstétrico, el sexo, la incompatibilidad Rh y la presencia de infecciones neonatales no se asociaron significativamente con el desarrollo de ictericia patológica.
Conclusiones. La presencia de deshidratación neonatal y la incompatibilidad ABO fueron factores de riesgo de ictericia patológica en neonatos peruanos atendidos por ictericia en un hospital nacional de referencia.
Por el contrario, el parto por cesárea se comportó como un factor protector.
Introduction
Neonatal jaundice is a clinical manifestation of elevated total bilirubin in blood (condition termed neonatal hyperbilirubinemia),1-4 which occurs as a result of bilirubin deposition in the skin of the neonate and is characterized by yellowing of the skin, mucous membranes, and sclerae.1,2
Neonatal jaundice is the most commonly observed medical condition in the first 2 weeks of life and a frequent cause of hospital readmission in this population, occurring in approximately 60% of term neonates and 80% of preterm neonates during the first week of life.1,2 It is usually a mild, harmless, transient, self-limiting condition,1,3 known as physiologic jaundice; however, some neonates may present with pathologic jaundice, a more severe form that requires hospitalization during the first weeks of life.1,3
Neonatal hyperbilirubinemia can be unconjugated (indirect) or conjugated (direct).1 Once neonatal jaundice is confirmed, determining its underlying etiology of neonatal hyperbilirubinemia is critical because, although it is most often caused by unconjugated hyperbilirubinemia (either physiologic or pathologic), in some cases it is secondary to the conjugated form (also called neonatal cholestasis), which is always pathologic and requires prompt assessment and treatment.1 In this regard, it has been reported that conjugated hyperbilirubinemia is much less frequent than the unconjugated form, with an incidence of about 1 case per 2 500 term neonates. In these cases, jaundice is known as cholestatic, with biliary atresia, infections, and parenteral nutrition-induced cholestasis being the most common causes.1
Between 60% and 80% of preterm and term neonates develop clinical jaundice as a result of unconjugated hyperbilirubinemia and, in most cases, it is physiologic.1-3
This jaundice usually appears 24 hours after birth and, as mentioned above, is mild and generally does not require hospitalization,1,3 since it peaks between 48 and 96 hours (total bilirubin level between 5 mg/dL and 6 mg/dL) and resolves at 2 to 3 weeks of life.1,2 In contrast, pathologic jaundice, the most severe form, is much less common and occurs within the first 24 hours of life with a total blood bilirubin level above the 95th percentile on age-specific bilirubin nomograms or increases ≥5 mg/dL/day or >0.2 mg/dL/hour.1,2,4 There are currently two treatment approaches for neonatal unconjugated hyperbilirubinemia, namely phototherapy and exchange transfusion,1,5 with phototherapy being the first-line treatment for pathologic unconjugated hyperbilirubinemia.1
In Peru, the incidence of neonatal jaundice is 39 cases per 1 000 live births and the prevalence of hyperbilirubinemia is similar to that reported in Chile and Bolivia (69.2-76.3%).2,4,5 It has also been reported that 48% of the cases occur in the cities of Lima and Callao.4
Properly differentiating physiological jaundice from pathological jaundice is paramount to ensure proper management, as the severe or pathological form, if not diagnosed and treated promptly, can cause serious complications such as bilirubin-induced neurological dysfunction, acute bilirubin-induced encephalopathy, or kernicterus and associated neurological sequelae, and even jaundice-related death.1-5
Although several risk factors for neonatal jaundice2,4,6 and severe or pathological neonatal jaundice1,4,7,8 related to maternal, perinatal, and neonatal characteristics have been described in the international literature, in Peru the evidence on the subject is scarce and limited to specific populations (preterm or only term neonates)4,9-11 and to gray literature.4,9-14 Therefore, obtaining more scientific and peer-reviewed evidence on the factors associated with pathological neonatal jaundice in the Peruvian population is essential to improve the prognosis of these patients, especially when early detection and timely treatment can prevent serious complications such as neurological damage and permanent disability, delayed growth, encephalopathy, autism, and hearing impairment,4,6 which not only affect the neonate and its family, but, depending on the degree of disability, can represent a high socioeconomic burden for the family and the State, especially in low- and middle-income countries such as Peru.4
In view of the above, the objective of the present study was to determine the factors associated with pathologic neonatal jaundice in a national referral hospital in Peru.
Materials and methods
Study design and type
Unpaired, retrospective case-control study.
Study population and sample
The study population consisted of all neonates (0-28 days) with jaundice treated at the Neonatology Department of the Hospital Nacional Sergio E. Bernales (Lima, Peru) between January 1 and December 31, 2023 (N=165).
Sample size was calculated in the OpenEpi software, taking as a reference the study by Huambo et al.,15 which evaluated the association between preterm birth and pathologic neonatal jaundice. The calculation took into account an expected Odds Ratio (OR) of 5.526, a confidence level of 95%, a statistical power of 80%, a reported proportion of exposure in controls of 5.7%, and a case-control ratio of 1:1, obtaining a minimum sample size of 128 neonates (64 cases and 64 controls).
Cases were defined as neonates with pathologic jaundice and controls as neonates with physiologic jaundice. Both cases and controls were selected by consecutive sampling using the service database. Neonates referred to another hospital center, with congenital malformations, or with incomplete medical records were excluded.
Pathological jaundice was defined as neonatal jaundice requiring hospitalization when at least one of the following criteria was met: onset within the first 24 hours of life, increased bilirubin levels ≥5 mg/dL/day, or accelerated increase as measured by nomogram per hour of life; it should be noted that the requirement for phototherapy was not considered as an operational criterion in this definition. Physiologic jaundice was defined as neonatal jaundice that did not require hospitalization.
Procedures and variables
Once selected, the neonates’ medical records were reviewed to collect information on the following variables:
- Dependent variable: pathological neonatal jaundice.
- Independent variables: maternal age (<18 years, 18-35 years, >35 years), parity (primiparous or multiparous), type of delivery (vaginal or cesarean), obstetric trauma, sex, gestational age (preterm or term), neonatal dehydration, ABO incompatibility, Rh incompatibility, and neonatal infection.
Statistical analysis
Data were entered into and organized in a data collection form created in Microsoft Excel 2019 and then exported to XLSTAT software (version 2025) for statistical analysis. They are described using absolute frequencies and percentages since all variables were categorical.
To evaluate the association between the independent variables and the dependent variable (presence of pathological neonatal jaundice), bivariate analyses were performed first (Yates’ Chi-square test and calculation of crude ORs with their respective 95% confidence intervals [95%CI]), followed by a multivariate analysis using a logistic regression model in which variables that were statistically significant in the bivariate analysis were included. A significance level of p<0.05 was considered.
Ethical considerations
The study followed the ethical principles for biomedical research involving human subjects established in the Declaration of Helsinki.16 It was also approved by the Ethics Committee of the Hospital Nacional Sergio E. Bernales (minutes No. 0165-2024 of
December 20, 2024) and the Research Ethics Committee of the Universidad Ricardo Palma (minutes No. PG 3292024 of December 29, 2024). Patient confidentiality and anonymity were guaranteed at all times.
Results
Male sex was slightly more frequent (55.47%), with a higher proportion in controls than in cases (57.81% vs. 53.12%), and only 17 neonates (13.29%) had a preterm delivery, with a higher frequency in the pathological jaundice group (7.84% vs. 18.75%). Regarding delivery characteristics, the most frequent maternal age range was 18-35 years (82.03%; 82.81% vs. 81.25%) with 66.41% of babies born by vaginal delivery, with a higher proportion in cases (54.68% vs. 78.12%). Finally, 25.78%, 22.66%, and 24.22% of the neonates presented neonatal dehydration, ABO incompatibility, and infections, respectively, with these conditions being more common in cases (4.69% vs. 46.87%, 14.06% vs. 31.25%, and 18.75% vs. 29.68%). The characteristics of the neonates are described in Table 1.
Table 1. Characteristics of neonates with jaundice treated at the neonatology service of a Peruvian hospital in 2023 (n=128). Univariate analysis.
|
Physiological jaundice (no hospitalization required) (n=64) |
Pathological jaundice (hospitalization required) (n=64) |
Total |
||
|
Maternal age |
<18 years old |
0 (0.00%) |
2 (3.12%) |
2 (1.56%) |
|
18-35 years old |
53 (82.81%) |
52 (81.25%) |
105 (82.03%) |
|
|
>35 years old |
11 (17.19%) |
10 (15.62%) |
21 (16.4%) |
|
|
Parity |
Multiparous |
35 (54.68%) |
31 (48.43%) |
66 (51.56%) |
|
Primiparous |
29 (45.31%) |
33 (51.56%) |
62 (48.44%) |
|
|
Type of delivery |
Vaginal |
35 (54.68%) |
50 (78.12%) |
85 (66.41%) |
|
Cesarean section |
29 (45.31%) |
14 (21.87%) |
43 (33.59%) |
|
|
Obstetric trauma |
No |
60 (93.75%) |
55 (85.93%) |
115 (89.85%) |
|
Yes |
4 (6.25%) |
9 (14.06%) |
13 (10.16%) |
|
|
Sex |
Female |
27 (42.18%) |
30 (46.87%) |
57 (44.53%) |
|
Male |
37 (57.81%) |
34 (53.12%) |
71 (55.47%) |
|
|
Gestational age |
Preterm |
5 (7.81%) |
12 (18.75%) |
17 (13.29%) |
|
Full term |
59 (92.18%) |
52 (81.25%) |
111 (86.72%) |
|
|
Neonatal dehydration |
No |
61 (95.31%) |
34 (53.12%) |
95 (74.22%) |
|
Yes |
3 (4.69%) |
30 (46.87%) |
33 (25.78%) |
|
|
ABO incompatibility |
No |
55 (85.93%) |
44 (68.75%) |
99 (77.35%) |
|
Yes |
9 (14.06%) |
20 (31.25%) |
29 (22.66%) |
|
|
Rh incompatibility |
No |
63 (98.43%) |
63 (98.43%) |
126 (98.44%) |
|
Yes |
1 (1.56%) |
1 (1.56%) |
2 (1.56%) |
|
|
Neonatal infections |
No |
52 (81.25%) |
45 (70.31%) |
97 (75.79%) |
|
Yes |
12 (18.75%) |
19 (29.68%) |
31 (24.22%) |
|
According to the bivariate analysis (Table 2), type of delivery, neonatal dehydration, and ABO incompatibility were significantly associated with the presence of pathological jaundice. Neonates born by cesarean section were 66.2% less likely to develop pathologic jaundice compared to those born by vaginal delivery (OR: 0.33, 95%CI: 0.15-0.72; p=0.008), while patients with neonatal dehydration and those with ABO incompatibility were 17.94 times and 2.78 times more likely to develop pathological jaundice than those without these conditions (OR: 17.94, 95%CI: 5.50-58.50; p<0.0001, and OR: 2.77, 95%CI: 1.17-6.59; p=0.03). No significant associations were found for the other variables.
Table 2. Association between the variables considered and the risk of developing pathological neonatal jaundice in the neonatology service of a Peruvian hospital.
|
Variable |
Categories |
p-value |
Crude OR |
95%CI |
|
|
Lower |
Upper |
||||
|
Maternal age |
<18 years old |
- |
- |
- |
- |
|
18-35 years old |
0.87 |
1.07 |
0.42 |
2.75 |
|
|
>35 years old |
- |
Ref. |
- |
- |
|
|
Parity |
Multiparous |
- |
Ref. |
- |
- |
|
Primiparous |
0.59 |
1.28 |
0.64 |
2.55 |
|
|
Type of delivery |
Vaginal |
- |
Ref. |
- |
- |
|
Cesarean section |
0.008 |
0.33 |
0.15 |
0.72 |
|
|
Obstetric trauma |
No |
- |
Ref. |
- |
- |
|
Yes |
0.24 |
2.45 |
0.75 |
7.98 |
|
|
Sex |
Female |
- |
Ref. |
- |
- |
|
Male |
0.72 |
0.82 |
0.41 |
1.65 |
|
|
Gestational age |
Preterm |
- |
Ref. |
- |
- |
|
Full term |
0.11 |
0.36 |
0.12 |
1.07 |
|
|
Neonatal dehydration |
No |
- |
Ref. |
- |
- |
|
Yes |
<0.0001 |
17.94 |
5.50 |
58.50 |
|
|
ABO incompatibility |
No |
- |
Ref. |
- |
- |
|
Yes |
0.03 |
2.77 |
1.17 |
6.59 |
|
|
Rh incompatibility |
No (0) |
- |
Ref. |
- |
- |
|
Yes (1) |
1 |
1 |
0.10 |
9.87 |
|
|
Neonatal infections |
No (0) |
- |
Ref. |
- |
- |
|
Yes (1) |
0.21 |
1.83 |
0.81 |
4.12 |
|
Finally, the three variables continued to show a statistically significant association in the multivariate analysis: neonates born by cesarean section were 67.5% less likely to develop pathological jaundice (aOR: 0.32, 95%CI: 0.12-0.83), while the probability of presenting this condition was 20.2 and 2.9 times higher in those with neonatal dehydration
(aOR: 20.16, 95%CI: 5.47-74.28) and ABO incompatibility (aOR: 2.93, 95%CI: 1.08-7.89), respectively (Table 3).
Table 3. Factors associated with pathologic jaundice in the neonatology service of a Peruvian hospital. Multivariate analysis.
|
Categories |
p-value |
Crude OR |
95%CI |
||
|
Lower |
Upper |
||||
|
Type of delivery |
Vaginal |
- |
Ref. |
- |
- |
|
Cesarean section |
0.01 |
0.32 |
0.12 |
0.83 |
|
|
Neonatal dehydration |
No |
- |
Ref. |
- |
- |
|
Yes |
<0.0001 |
20.16 |
5.47 |
74.28 |
|
|
ABO incompatibility |
No |
- |
Ref. |
- |
- |
|
Yes |
0.03 |
2.93 |
1.08 |
7.89 |
|
Discussion
Association between maternal characteristics and the development of pathologic neonatal jaundice
The present study aimed to determine the factors associated with the development of pathologic neonatal jaundice in a hospital in Lima. In this regard, none of the maternal characteristics analyzed (maternal age and parity) were significantly associated with the development of this type of neonatal jaundice, which is in line with what has been reported in similar literature. For example, Bulbul et al.,7 in a research conducted in 1 335 neonates ≥35 weeks of gestation (137 with a bilirubin level ≥25 mg/dL [severe hyperbilirubinemia] and 1 198 with a bilirubin level <25 mg/dL) who required phototherapy in a hospital in Istanbul (Türkiye), reported no significant association between parity and occurrence of severe hyperbilirubinemia. Similarly, in the study by Bizuneh et al.,17 conducted in
447 newborns admitted to the neonatal intensive care units of 6 hospitals in the Amhara region of Ethiopia (149 with pathologic neonatal jaundice and 298 healthy), parity was also not significantly associated with pathologic jaundice.
Regarding maternal age, Jiang et al.,8 in a study conducted in Pingyang (China) on 1 309 newborns, also found no significant association between this variable and the development of pathological jaundice. On this point, it should be noted that, both in our study and in the study by Jiang et al.,8 most of the mothers were between 18 and 35 or 34 years of age (82.03% and 84.49%), which may have influenced the lack of statistical significance in this association.
Risk factors during labor
Regarding the type of delivery, neonates born by cesarean section had a lower probability of developing pathologic neonatal jaundice (aOR: 0.325, 95%CI: 0.13-0.83; p=0.019). This is consistent with the findings of Bizuneh et al.17 who, when evaluating the duration of labor during vaginal deliveries, found that prolonged vaginal delivery, compared to a normal vaginal delivery and excluding cesarean sections, increases the probability of developing this type of jaundice by almost 2.5 times (aOR: 2.45; 95%CI: 1.34-4.47). Along the same lines, Cui et al.,18 in a study conducted in Jilin (China) in 3 258 neonates (372 with hyperbilirubinemia), also reported that cesarean section was a protective factor against neonatal hyperbilirubinemia (OR: 0.71; 95%CI: 0.54-0.92; OR: 0.71; 95%CI: 0.54-0.92; p=0.01). From a pathophysiological standpoint, this protective effect of cesarean section could be related to the potential for trauma during delivery, which subjects the newborn to physical stress and increases the likelihood of hemorrhage and hemolysis, resulting in neonatal jaundice.19
Nevertheless, it is worth bearing in mind that obstetric trauma in our study was not significantly associated with the development of pathologic neonatal jaundice. This differs from the results reported by Chávez-Rosero et al.20 in a study carried out in Cajamarca (Peru) in 116 neonates with jaundice who required phototherapy, in whom the presence of cephalohematomas (1.7%) was significantly associated with this type of jaundice. This difference may be explained by variations in obstetric practices and quality of care during childbirth between institutions.
In any case, it is worth mentioning that Chávez-Rosero et al.20 evaluated jaundice in general and considered the need for phototherapy as an outcome, without differentiating between physiological and pathological forms. However, considering that only about
10% of newborns with jaundice require phototherapy and that this treatment is usually used in cases of pathologic or severe jaundice,1 it is reasonable to infer that the majority of patients included in this analysis had pathologic forms of the condition.
Risk factors after delivery
One notable finding is the strong association between neonatal dehydration and the development of pathological jaundice (aOR: 20.16, 95%CI: 5.47-74.29; p<0.0001). The magnitude of the effect suggests that neonates with clinical signs of dehydration are at markedly increased risk of developing significant hyperbilirubinemia. However, the width of the confidence interval reflects some imprecision of the estimate, possibly attributable to the small size of the exposed group, individual clinical variations, or differences in the degree of dehydration at the time of evaluation.
These results are consistent with those reported by Bulbul et al.,7 who found in their cohort that pathologic weight loss (i.e., when >12% or clinical or biochemical evidence of dehydration) was significantly more frequent in neonates with severe hyperbilirubinemia (OR: 3.6, 95%CI: 2.26-5.84; p<0.001). Although their study did not use a case-control design, the direction and consistency of the effect support our finding, reinforcing that volume depletion and insufficient breast milk intake are critical pathophysiologic factors that amplify bilirubin accumulation.
Similarly, Akdeniz et al.,21 in a study conducted in Türkiye in 85 term newborns with hypernatremic dehydration found that jaundice was one of the most frequent reasons for admission (22.3%). Although that study does not report an OR or an RR for that association, it does show that the coexistence of significant dehydration and jaundice is highly frequent in neonates with intake disorders. Furthermore, Akdenis et al.21 point out that weight loss and hypernatremia are mainly caused by insufficient intake of breast milk,
especially in primiparous mothers or mothers with difficulties in breastfeeding technique. In this regard, it has been reported that dehydration due to inadequate breastfeeding may contribute to the development of clinically relevant hyperbilirubinemia.11,13,14
ABO incompatibility was also significantly associated with increased likelihood of pathologic neonatal jaundice (aOR: 2.93, 95%CI: 1.09-7.98; p=0.03), a finding that has been reported in similar studies.6,7,15,17 For example, in a recent systematic review and
meta-analysis including 14 studies, Lin et al.6 found that maternal-fetal ABO incompatibility behaved as a risk factor for neonatal hyperbilirubinemia (OR =1.64, 95%CI: 1.42-1.89, Z=6.75, p<0.00001; 5 studies). It is worth mentioning that the consistency of the results between studies from different epidemiological contexts supports the robustness of this factor as a clinical determinant of neonatal jaundice.
Finally, the variables Rh incompatibility, neonatal infection, gestational age, and sex did not exhibit significant associations in our final model. This is in agreement with the findings of Bulbul et al.,7 but partially contradicts the findings of Bizuneh et al.,17 who found that neonatal sepsis and male sex were determinants of pathological neonatal jaundice (aOR: 2.49 [95%CI: 1.22-5.11; p=0.005] and aOR: 3.54 [95%CI: 1.99-6.29; p<0.001]), highlighting that these factors may vary depending on the clinical context,
the population analyzed, and the operational criteria used.
Limitations and strengths
This study has several strengths, namely, a multivariate analysis that allowed us to control for confounding variables and obtain more precise associations, as well as a comparison of the findings reported in national and international studies, reinforcing their external validity and relevance.
However, it also has several limitations. First, its retrospective design based on clinical records implies a potential information bias because it is not possible to ensure the quality of data recording by the treating physicians. Second, its single-center nature
(a single hospital in the city of Lima) restricts the generalizability of the findings. Third, the low frequency of some maternal and neonatal subgroups (e.g., adolescent mothers or mothers older than 35 years) may limit the statistical power to detect significant associations. Fourth, other possible confounding factors, such as type of neonatal feeding (exclusive, mixed, or artificial breastfeeding), birth weight, and time to discharge (24, 48, or 72 hours), which could influence the occurrence of jaundice and, therefore, the results obtained, were not included. Fifth, the definition of outcome (i.e., pathologic neonatal jaundice) based on the requirement for hospitalization and not specifically phototherapy introduces methodological differences with other studies, although epidemiologic rationale was considered to support comparability with those studies.
Regarding this last limitation, it should be noted that even though our study evaluated jaundice requiring hospitalization and not specifically jaundice requiring phototherapy, this approach is still comparable, since, as mentioned above, only about 10% of newborns with jaundice eventually require phototherapy, which is the first-line management in pathologic or severe forms.1 In this sense, it is reasonable to assume that neonates requiring phototherapy represent a clinical subset comparable to cases with pathologic neonatal jaundice requiring hospitalization, such as the neonates included in our study, and for that reason we include studies performed in patients requiring phototherapy in the discussion of our findings.
Conclusions
The presence of neonatal dehydration and ABO incompatibility were associated with an increased risk of pathologic jaundice in Peruvian neonates treated for jaundice in a national referral hospital. On the contrary, cesarean delivery behaved as a protective factor.
Conflicts of interest
None stated by the authors.
Funding
None stated by the authors.
Acknowledgments
None stated by the authors.
References
1.Ansong-Assoku B, Adnan M, Daley SF, Ankola PA. Neonatal Jaundice. 2024 Feb 12. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Dec 17]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK532930/. PMID: 30422525.
2.Taipe-Paucar A, Toaquiza-Alvarado A, Merchán-Coronel G. Ictericia Neonatal a Nivel de América Latina. FACSalud UNEMI. 2022;6(10):76-84. doi: 10.29076/issn.2602-8360vol6iss10.2022pp76-84p.
3.World Health Organization (WHO). WHO recommendations on maternal and newborn care for a positive postnatal experience [Internet]. Geneva: WHO; 2022 [cited 2024 May 13]. Available from:
https://www.who.int/publications-detail-redirect/9789240045989.
4.Tapia-Monsalve LA. Prevalencia y factores asociados a ictericia neonatal patológica en recién nacidos pretérmino tardíos del Hospital Nacional Cayetano Heredia en julio-diciembre del 2019 [Thesis] [Internet]. Lima: Facultad de Medicina, Universidad Peruana Cayetano Heredia; 2019 [cited 2025 Mar 4]. Available from: https://repositorio.upch.edu.pe/handle/20.500.12866/7100.
5.Perú. Ministerio de Salud, Hospital Nacional Arzobispo Loayza. Guía de Práctica Clínica para el Diagnóstico y Tratamiento de Ictericia Neonatal no conjugada [Internet]. Lima: Hospital Nacional Arzobispo Loayza; 2023 [cited 2025 Dec 17]. Available from: https://cdn.www.gob.pe/uploads/document/file/4121138/041-2023-HNAL-DG.pdf.pdf.
6.Lin Q, Zhu D, Chen C, Feng Y, Shen F, Wu Z. Risk factors for neonatal hyperbilirubinemia: a systematic review and meta-analysis. Transl Pediatr. 2022;11(6):1001-9. doi: 10.21037/tp-22-229. PMID: 35800274; PMCID: PMC9253931.
7.Bulbul A, Cayonu N, Sanli ME, Uslu S. Evaluation of risk factors for development of severe hyperbilirubinemia in term and near term infants in Turkey. Pak J Med Sci. 2014;30(5):1113-8. doi: 10.12669/pjms.305.5080. PMID: 25225537; PMCID: PMC4163243.
8.Jiang N, Qian L, Lin G, Zhang Y, Hong S, Sun B, et al. Maternal blood parameters and risk of neonatal pathological jaundice: a retrospective study. Sci Rep. 2023;13(1):2627. doi: 10.1038/s41598-023-28254-3. PMID: 36788268; PMCID: PMC9929053.
9.Torres-Marin R. Factores asociados a ictericia patológica en neonatos a término-Hospital “El Carmen”, 2019 [Thesis] [Internet]. Huancayo: Facultad de Medicina, Universidad Peruana los Andes; 2020 [cited 2025 2025 Dec 17]. Available from: https://repositorio.upla.edu.pe/bitstream/handle/20.500.12848/1438/TORRES%20MARIN%20RODERIK.pdf?sequence=1&isAllowed=y.
10.Balbin-García YT, Taipe-Gonzales N. Factores neonatales asociados a ictericia patológica en recién nacidos a término en un hospital de Huancayo, 2021 [Thesis] [Internet]. Huancayo: Facultad de Ciencias de la Salud, Universidad Peruana los Andes; 2023 [cited 2025 2025 Dec 17]. Available from:
https://repositorio.upla.edu.pe/bitstream/handle/20.500.12848/6124/T037_76349000-47801165_T.pdf?sequence=1&isAllowed=y.
11.Zarate-Luque DV. Factores neonatales asociados a ictericia en el recién nacido a término en el Hospital Nacional PNP Luis N. Sáenz: periodo enero 2012 - diciembre 2012 [Specialization Thesis] [Internet].
Lima: Facultad de Medicina Humana, Universidad Nacional Mayor de San Marcos; 2013 2023 [cited 2025 2025 Dec 17]. Available from: https://cybertesis.unmsm.edu.pe/backend/api/core/bitstreams/b5554fef-1df8-4d6a-963a-5c93dfe17118/content.
12.Cabrera-Villanueva KM. Factores perinatales asociados a la presencia de ictericia patológica neonatal Hospital Vitarte 2014 [Specialization Thesis] [Internet]. Lima: Facultad de Medicina humana, Universidad San Martin de Porres; 2014. Available from: https://repositorio.usmp.edu.pe/bitstream/handle/20.500.12727/1221/Cabrera_km.pdf?sequence=1&isAllowed=y.
13.Huaraca-Hualla J. Factores asociados a la ictericia neonatal patológica en el servicio de Neonatología del Hospital Regional del Cusco - 2023 [Thesis] [Internet]. Cusco: Facultad de Ciencias de la Salud, Universidad Tecnológica de los Andes; 2024 [cited 2025 Dec 17]. Available from: https://repositorio.utea.edu.pe/server/api/core/bitstreams/f45d318a-7938-41ea-ba6c-c5b5dab62f76/content.
14.Vera-Borja DR. Factores asociados conocidos a ictericia neonatal patológica [Specialization Thesis] [Internet]. Lima: Facultad de Medicina Humana, Universidad de San Martín de Porres; 2014 [cited 2025 Dec 17]. Available from: https://repositorio.usmp.edu.pe/bitstream/handle/20.500.12727/2267/vera_dr.pdf?sequence=1.
15.Huambo-Panduro MC, Ramirez-Ortega AP, Roldan-Arbieto L, Vela-Ruiz JM. Factores asociados a ictericia con requerimiento de fototerapia: Estudio de tipo casos y controles en un hospital de Perú. Rev. Fac. Med. Hum. 2024;24(1):85-91. doi: 10.25176/rfmh.v24i1.6340.
16.World Medical Association. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human participants. JAMA. 2025;333(1):71-74. doi: 10.1001/jama.2024.21972. PMID: 39425955.
17.Bizuneh AD, Alemnew B, Getie A, Wondmieneh A, Gedefaw G. Determinants of neonatal jaundice among neonates admitted to five referral hospitals in Amhara region, Northern Ethiopia: an unmatched case-control study. BMJ Paediatr Open. 2020;4(1):e000830. doi: 10.1136/bmjpo-2020-000830.
PMID: 33024837; PMCID: PMC7511639.
18.Cui Z, Shen W, Sun X, Li Y, Liu Y, Sun Z. Developing and evaluating a predictive model for neonatal hyperbilirubinemia based on UGT1A1 gene polymorphism and clinical risk factors. Front Pediatr. 2024;12:1345602. doi: 10.3389/fped.2024.1345602. PMID: 38487473; PMCID: PMC10937529.
19.Ayalew T, Molla A, Kefale B, Alene TD, Abebe GK, Ngusie HS, et al. Factors associated with neonatal
jaundice among neonates admitted at referral hospitals in northeast Ethiopia: a facility-based unmatched case-control study. BMC Pregnancy Childbirth. 2024;24(1):150. doi: 10.1186/s12884-024-06352-y. PMID: 38383399; PMCID: PMC10880319.
20.Chávez-Rosero VF. Factores de riesgo asociados a ictericia neonatal tributaria de fototerapia en el Hospital Regional Docente de Cajamarca, enero - diciembre del 2022 [Thesis] [Internet]. Cajamarca: Facultad de Medicina, Universidad Nacional de Cajamarca; 2023 [cited 2025 Dec 26]. Available from: https://repositorio.unc.edu.pe/bitstream/handle/20.500.14074/5707/T016_71739675_T.pdf?sequence=1&isAllowed=y.
21.Akdeniz O, Çelik M, Samancı S. Evaluation of term newborn patients with hypernatremic dehydration. Turk Arch Pediatr. 2021;56(4):344-9. doi: 10.5152/TurkArchPediatr.2021.20153. PMID: 35005729;
PMCID: PMC8655962.
Referencias
1. Ansong-Assoku B, Adnan M, Daley SF, Ankola PA. Neonatal Jaundice. 2024 Feb 12. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Dec 17]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK532930/. PMID: 30422525.
2. Taipe-Paucar A, Toaquiza-Alvarado A, Merchán-Coronel G. Ictericia Neonatal a Nivel de América Latina. FACSalud UNEMI. 2022;6(10):76-84. doi: 10.29076/issn.2602-8360vol6iss10.2022pp76-84p.
3. World Health Organization (WHO). WHO recommendations on maternal and newborn care for a positive postnatal experience [Internet]. Geneva: WHO; 2022 [cited 2024 May 13]. Available from:
https://www.who.int/publications-detail-redirect/9789240045989.
4. Tapia-Monsalve LA. Prevalencia y factores asociados a ictericia neonatal patológica en recién nacidos pretérmino tardíos del Hospital Nacional Cayetano Heredia en julio-diciembre del 2019 [Thesis] [Internet]. Lima: Facultad de Medicina, Universidad Peruana Cayetano Heredia; 2019 [cited 2025 Mar 4]. Available from: https://repositorio.upch.edu.pe/handle/20.500.12866/7100.
5. Perú. Ministerio de Salud, Hospital Nacional Arzobispo Loayza. Guía de Práctica Clínica para el Diagnóstico y Tratamiento de Ictericia Neonatal no conjugada [Internet]. Lima: Hospital Nacional Arzobispo Loayza; 2023 [cited 2025 Dec 17]. Available from: https://cdn.www.gob.pe/uploads/document/file/4121138/041-2023-HNAL-DG.pdf.pdf.
6. Lin Q, Zhu D, Chen C, Feng Y, Shen F, Wu Z. Risk factors for neonatal hyperbilirubinemia: a systematic review and meta-analysis. Transl Pediatr. 2022;11(6):1001-9. doi: 10.21037/tp-22-229. PMID: 35800274; PMCID: PMC9253931.
7. Bulbul A, Cayonu N, Sanli ME, Uslu S. Evaluation of risk factors for development of severe hyperbilirubinemia in term and near term infants in Turkey. Pak J Med Sci. 2014;30(5):1113-8. doi: 10.12669/pjms.305.5080. PMID: 25225537; PMCID: PMC4163243.
8. Jiang N, Qian L, Lin G, Zhang Y, Hong S, Sun B, et al. Maternal blood parameters and risk of neonatal pathological jaundice: a retrospective study. Sci Rep. 2023;13(1):2627. doi: 10.1038/s41598-023-28254-3. PMID: 36788268; PMCID: PMC9929053.
9. Torres-Marin R. Factores asociados a ictericia patológica en neonatos a término-Hospital “El Carmen”, 2019 [Thesis] [Internet]. Huancayo: Facultad de Medicina, Universidad Peruana los Andes; 2020 [cited 2025 2025 Dec 17]. Available from: https://repositorio.upla.edu.pe/bitstream/handle/20.500.12848/1438/TORRES%20MARIN%20RODERIK.pdf?sequence=1&isAllowed=y.
10. Balbin-García YT, Taipe-Gonzales N. Factores neonatales asociados a ictericia patológica en recién nacidos a término en un hospital de Huancayo, 2021 [Thesis] [Internet]. Huancayo: Facultad de Ciencias de la Salud, Universidad Peruana los Andes; 2023 [cited 2025 2025 Dec 17]. Available from:
11. Zarate-Luque DV. Factores neonatales asociados a ictericia en el recién nacido a término en el Hospital Nacional PNP Luis N. Sáenz: periodo enero 2012 - diciembre 2012 [Specialization Thesis] [Internet].
Lima: Facultad de Medicina Humana, Universidad Nacional Mayor de San Marcos; 2013 2023 [cited 2025 2025 Dec 17]. Available from: https://cybertesis.unmsm.edu.pe/backend/api/core/bitstreams/b5554fef-1df8-4d6a-963a-5c93dfe17118/content.
12. Cabrera-Villanueva KM. Factores perinatales asociados a la presencia de ictericia patológica neonatal Hospital Vitarte 2014 [Specialization Thesis] [Internet]. Lima: Facultad de Medicina humana, Universidad San Martin de Porres; 2014. Available from: https://repositorio.usmp.edu.pe/bitstream/handle/20.500.12727/1221/Cabrera_km.pdf?sequence=1&isAllowed=y.
13. Huaraca-Hualla J. Factores asociados a la ictericia neonatal patológica en el servicio de Neonatología del Hospital Regional del Cusco - 2023 [Thesis] [Internet]. Cusco: Facultad de Ciencias de la Salud, Universidad Tecnológica de los Andes; 2024 [cited 2025 Dec 17]. Available from: https://repositorio.utea.edu.pe/server/api/core/bitstreams/f45d318a-7938-41ea-ba6c-c5b5dab62f76/content.
14. Vera-Borja DR. Factores asociados conocidos a ictericia neonatal patológica [Specialization Thesis] [Internet]. Lima: Facultad de Medicina Humana, Universidad de San Martín de Porres; 2014 [cited 2025 Dec 17]. Available from: https://repositorio.usmp.edu.pe/bitstream/handle/20.500.12727/2267/vera_dr.pdf?sequence=1.
15. Huambo-Panduro MC, Ramirez-Ortega AP, Roldan-Arbieto L, Vela-Ruiz JM. Factores asociados a ictericia con requerimiento de fototerapia: Estudio de tipo casos y controles en un hospital de Perú. Rev. Fac. Med. Hum. 2024;24(1):85-91. doi: 10.25176/rfmh.v24i1.6340.
16. World Medical Association. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human participants. JAMA. 2025;333(1):71-74. doi: 10.1001/jama.2024.21972. PMID: 39425955.
17. Bizuneh AD, Alemnew B, Getie A, Wondmieneh A, Gedefaw G. Determinants of neonatal jaundice among neonates admitted to five referral hospitals in Amhara region, Northern Ethiopia: an unmatched case-control study. BMJ Paediatr Open. 2020;4(1):e000830. doi: 10.1136/bmjpo-2020-000830.
PMID: 33024837; PMCID: PMC7511639.
18. Cui Z, Shen W, Sun X, Li Y, Liu Y, Sun Z. Developing and evaluating a predictive model for neonatal hyperbilirubinemia based on UGT1A1 gene polymorphism and clinical risk factors. Front Pediatr. 2024;12:1345602. doi: 10.3389/fped.2024.1345602. PMID: 38487473; PMCID: PMC10937529.
19. Ayalew T, Molla A, Kefale B, Alene TD, Abebe GK, Ngusie HS, et al. Factors associated with neonatal
jaundice among neonates admitted at referral hospitals in northeast Ethiopia: a facility-based unmatched case-control study. BMC Pregnancy Childbirth. 2024;24(1):150. doi: 10.1186/s12884-024-06352-y. PMID: 38383399; PMCID: PMC10880319.
20. Chávez-Rosero VF. Factores de riesgo asociados a ictericia neonatal tributaria de fototerapia en el Hospital Regional Docente de Cajamarca, enero - diciembre del 2022 [Thesis] [Internet]. Cajamarca: Facultad de Medicina, Universidad Nacional de Cajamarca; 2023 [cited 2025 Dec 26]. Available from: https://repositorio.unc.edu.pe/bitstream/handle/20.500.14074/5707/T016_71739675_T.pdf?sequence=1&isAllowed=y.
21. Akdeniz O, Çelik M, Samancı S. Evaluation of term newborn patients with hypernatremic dehydration. Turk Arch Pediatr. 2021;56(4):344-9. doi: 10.5152/TurkArchPediatr.2021.20153. PMID: 35005729;
PMCID: PMC8655962.
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