Narrative review of the epidemiology of neonatal jaundice
Review Article

Narrative review of the epidemiology of neonatal jaundice

Thor Willy Ruud Hansen

Department of Pediatric and Adolescent Medicine, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Correspondence to: Thor Willy Ruud Hansen. Department of Pediatric and Adolescent Medicine, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Langmyrgrenda 45 B, 0861 Oslo, Norway. Email:

Background and Objective: Neonatal jaundice (NJ) is one of the most common causes for medical intervention in the newborn period. While transitory hyperbilirubinemia (HB) is present in almost all newborns, detection of jaundice requires a trained observer and good lighting.

Methods: PubMed and personal archives were searched during the period October-December 2020 for ‘jaundice, neonatal’ in combination with relevant key words, such as ‘measurement’, ‘season’, ‘ethnicity’, ‘geograpy’, ‘birth weight’, ‘genetics OR family’, ‘sex OR gender’, ‘prematurity’, ‘nutrition’, ‘blood group incompatibility’, ‘infection’, ‘labor OR delivery’. ‘Kernicterus’ and ‘bilriubin encephalopathy’ were used as separate key words. Inclusion criteria were: publications dealing with jaundice human neonates and published in any of the Western European languages, publications in other languages or not dealing with humans were excluded.

Key Content and Findings: Thus, jaundice in the newborn has a reported incidence between 60% to more than 90%. Bilirubin, the molecule that causes the color of jaundice, is the end product of disassembly of heme-containing molecules, primarily hemoglobin. Therefore, conditions that increase hemolysis will increase bilirubin production and cause jaundice. Common conditions in the newborn are blood group incompatibilities and congenital hemolytic anemias. A family history of NJ increases the likelihood of jaundice in the present newborn, and is one of several examples of genetic conditions that contribute. Endocrine and metabolic conditions contribute, the most common being maternal diabetes. An increased incidence is seen in infants of Southeast Asian mothers, while African infants have a lower incidence unless they suffer from G-6-PD-deficiency. Drugs taken by the mother during pregnancy may impact on hepatic metabolism of bilirubin in the newborn, often by reducing the incidence of jaundice, and the same may happen with certain drugs given to the newborn. Birth trauma, through extravasation of blood, will increase bilirubin production and jaundice. Preterm infants have immature bilirubin metabolism and a higher incidence of jaundice. Breast-fed infants have an increased incidence of jaundice, which may also last longer.

Conclusions: Extreme NJ, associated with risk of kernicterus spectrum syndrome, has an estimated worldwide incidence of 99/100,000 or more, thus affecting 130,000 or more infants each year and calling for increased vigilance and preparedness for rapid therapeutic intervention.

Keywords: Neonatal jaundice (NJ); neonatal hyperbilirubinemia (HB); bilirubin; epidemiology

Received: 16 January 2021; Accepted: 11 March 2021; Published: 28 May 2021.

doi: 10.21037/pm-21-4


Jaundice in the skin and/or conjunctiva of newborn infants [neonatal jaundice (NJ)] results when unconjugated bilirubin accumulates to a level that makes the yellow color visible to our eyes. Hyperbilirubinemia (HB), on the other hand, denotes a level of total serum bilirubin (TSB) which exceeds the normal range for healthy humans. Because our lab methods are more sensitive than our eyes, HB is usually present before we perceive this as NJ. The lowest TSB level at which NJ can be visually detected in neonates, is around 46–68 µmol/L (2.7–4.0 mg/dL) (1-3), though in older data the range of detectability was as wide as 30–200 µmol/L (4). Infants with TSB levels at the lower end of these ranges may not be perceived as jaundiced by visual examination (3,4). Indeed, in Davidson et al.’s study from 1941 the TSB value above which >50% of infants were perceived to be jaundiced was around 70–85 µmol/L (4–5 mg/dL) (4). Our ability to detect NJ depends on the strength and color of the light we use for examination (5), the pigmentation of the infant’s skin (5), pH and albumin levels in the infant (6), and on the individual who performs the examination, including her/his training and experience (7-9). Thus, it is not surprising that data on the incidence of NJ vary between studies.

The reference interval for normal TSB values in adults is defined based on a range of test results that encompass 95% of a healthy population, and is ~5–25 µmol/L (0.3–1.45 g/dL) (10). Therefore, in adults HB strictly speaking is any TSB value above this range. It is less clear how we should define HB in newborn infants, as most newborn infants have maximum TSB values that (I) exceed the normal adult range, (II) increase significantly during the first hours and days of life, and (III) in some cases may continue to be elevated for weeks and even months after birth (11). Bhutani et al. proposed the following definitions for severity of HB: ‘significant’: ≥291 µmol/L (≥17 mg/dL); ‘severe’: ≥342 µmol/L (≥20 mg/dL); ‘extreme’: ≥427 µmol/L (≥25 mg/dL); and ‘hazardous’: ≥513 µmol/L (≥30 mg/dL) (12). Maisels defined ‘severe’ in the same way as Bhutani et al., but subsumed the ‘hazardous’ category from the latter under the label ‘extreme’ (13). Maisels also suggested that HB in neonates be defined as TSB levels that exceed the 95th percentile for the infant’s age in hours for a given population (13). However, data on the 95th percentile for TSB relative to postnatal age in hours do not appear to be available for most populations, making the application of this proposal challenging. While reviewing the literature for the present paper, it became apparent that the terms NJ vs. neonatal HB have been used interchangeably (1,4,7,8,14-30) and variably (31-45). Herein I will use the term NJ to denote jaundice in the newborn identified by visual identification. I will use the term HB for any elevation of bilirubin values beyond the normal range for adults, whether identified by TSB or transcutaneous measurement (TcB), recognizing that neither TSB nor TcB measurements are precise, and that concurrent measurements using both methods often yield discrepant results (46). I will use the terms ‘severe’ HB, ‘extreme’, and ‘hazardous’ HB as defined by Bhutani et al. (12), recently also used by Olusanya et al. (47). Other definitions have also been used (32,48,49).


PubMed and the author’s personal archives were searched during the period October-December 2020 with the following search terms: jaundice, neonatal; jaundice, neonatal and epidemiology; jaundice, neonatal and lab methods; jaundice, neonatal and measurement; jaundice, neonatal and season; jaundice, neonatal and ethnicity; jaundice, neonatal and geography; jaundice, neonatal and birth weight; jaundice, neonatal and [genetics or family]; jaundice, neonatal and maternal age; jaundice, neonatal and maternal illness; jaundice, neonatal and prematurity; jaundice, neonatal and birth weight; jaundice, neonatal and [sex or gender]; jaundice, neonatal and nutrition; jaundice, neonatal and blood group incompatibility; jaundice, neonatal and infection; jaundice, neonatal and [labor or delivery]; kernicterus; bilirubin encephalopathy, only studies in human infants and published in western European languages were included, while non-human studies and in vitro studies published in other languages were excluded. This is a single author review, and publications were selected if the abstract showed that themes relevant to the overarching theme of this review were discussed therein, and also if the publication provided historical background for the development of our understanding of the epidemiology of neonatal jaundice. For this reason, strict modern criteria for population size or study design were not applied.

The incidence of NJ vs. neonatal HB

Early in the 20th century Hirsch studied the relationship between clinical jaundice and serum bilirubin, the latter quantitated by an early version of the diazo reaction (50). She observed 100 infants daily during the first 5 days of life, and found that 80 of them had some degree of NJ during this period. She further noted that there was a relationship between her serum bilirubin measurements and the presence of NJ, however this claim does not seem to be based on any mathematical or statistical calculations (50).

Davidson and collaborators examined 99 infants daily for NJ during the first days of life under daylight conditions, using a tongue depressor to squeeze blood from the skin of the forehead and chin, and from the mucous membrane of the lower jaw (4). NJ was recorded as present on a least 1 occasion in 63 infants, i.e., 64%. In 16 of these infants (~25%) jaundice was noted to be present on the first day of life, corresponding to a mean TSB of ≥85 µmol/L (≥5 mg/dL). The duration of NJ depended on its intensity. Thus in 89% of infants with ‘moderate’ NJ duration was <1 week, while in 75% of infants with ‘marked’ NJ duration was >1 week, and all infants with ‘severe’ NJ remained jaundiced for >1 week. Davidson et al. also refer to an apparently separate group of 120 infants for whom a total of 1,215 concomitant TSB values and clinical observations were available (4). These data make it clear that there is no fixed relationship between TSB and the absence respectively presence of NJ. Although NJ was not observed when TSB was ≤17 µmol/L (≤1 mg/dL), ‘moderate jaundice’ was noted in a handful of the 240 observations with TSB values between 17–34 µmol/L (1–2 mg/dL), increasing to about 50% of the observations with TSB values between 68–85 µmol/L (4–5 mg/dL) with a few additional observations categorized as ‘marked jaundice’. With TSB values ≥205 µmol/L (≥12 mg/dL) about 80% of observations were in the ‘marked jaundice’ category, and the remainder were ‘moderate jaundice’ except for a single observation where NJ was not noted (4).

The US Collaborative Perinatal Project included data from 54,795 live births at 12 US centers from 1959-65 (38). TSB levels were obtained from 28,807 infants at 48 h of age, of these ~20% had TSB levels ≤52 µmol/L (≤3 mg/dL), while ~33% had TSB levels between 53–103 µmol/L (3.1–6 mg/dL). If we apply Kramer’s data (1) and assume that the lower limit of our ability to visually detect jaundice in an infant is ~70 µmol/L (4 mg/dL), interpolating this assumption with the Perinatal Project data suggests that ~70% of these infants were jaundiced, while ~30% were not jaundiced at 48 h of age.

Osborn et al. followed 866 newborn infants with twice-daily clinical examination for jaundice, having first excluded 100 infants for prematurity, SGA, or illness requiring admission to their NICU (18). 80% of their cohort was Hispanic and 20% were Caucasian or African-American. Of these, 82% went on to develop clinical jaundice.

Maisels and Gifford measured TSB in 2,416 consecutive infants admitted to their well-baby nursery (20), and their data allow for an approximate comparison with the normal range for adults. In their total population 93% of the infants had a maximum TSB level that exceeded the normal adult range—among the breast-fed infants 94.2% exceeded this range and among the bottle-fed 91.5%. If we again assume that jaundice was detectable in infants with TSB ≥70 µmol/L (≥4.0 mg/dL) we can estimate that 72% of all infants were jaundiced (77% of the breast-fed vs. 66% of the bottle-fed) (20). These data appear very similar to those from the Collaborative Perinatal Project, as described above (38), in spite of the much higher rate of breastfeeding.

Corchia et al. followed 431 full-term Sardinian neonates with birth weight ≥2,500 G for 4 days with clinical assessment for NJ and then twice daily TSB tests for those found to be jaundiced (51). Of these, 71.9% were jaundiced and 28.1% were not jaundiced. However, because they were looking for factors contributing to increased risk for NJ, they excluded infants already known to have increased risk. These included infants who were G-6-PD-deficient, those who were not blood group compatible with their mothers, and infants who were preterm or low birthweight. Among infants with NJ, 47 (15.2%) had TSB values <137 µmol/L (<8.0 mg/dL). As the 121 non-jaundiced infants did not have TSB tests, we cannot know how many of them may have had HB. Also, it is reasonable to assume that the percentage of infants with NJ in the total birth population was higher than reported, given the exclusion of infants with known risk for NJ/HB (51).

Szabo et al. followed 140 healthy full-term neonates up to 6 days of life and compared data from clinical assessment of NJ according to Kramer’s zones (assessed independently by a nurse and a pediatrician in daylight or ‘warm white’ fluorescent light), TSB measurement(s), and TcB measured by two different meters (Minolta Airshields JM-102 and BiliCheck respectively) (5). Some data can only be estimated from their figures, but apparently only 3/140 infants were judged clinically to be non-jaundiced, all 3 were hyperbilirubinemic as defined herein, although with TSB values ≤85 µmol/L (≤5.0 mg/dL). However, among the 16 infants judged to be jaundiced at Kramer’s zone 1, one appears not to have been hyperbilirubinemic, and an additional five had TSB values ≤100 µmol/L (≤6.0 mg/dL) (5). No mention was made of feeding mode in this study.

Keren et al. examined 812 term and near-term infants with clinical assessment (by nurses) using the Kramer homunculus grading on, or close to, day 3 of life, as well as daily TcB measurements until discharge, supplemented with TSB if the TcB values exceeded preset values (52). Eighty-three percent of the infants were judged to be jaundiced, while 17% were not jaundiced. Bilirubin values for the non-jaundiced infants ranged from 0–215 µmol/L [0–12.5 mg/dL (mean =5)], the range was similar for both black and non-black infants. Also, it should be noted from this study that assessment of jaundice extent correlated poorly with TSB level in late preterm infants (35–38 weeks’ GA).

Maisels et al. followed 1,044 predominantly breastfed infants of ≥35 weeks GA for a full month with TcB measurements and clinical assessment. TcB values measured on the chest peaked at 3 days of life, at which time 94% of the measurements were ≥85 µmol/L (≥5 mg/dL) (39). Kramer zone scores were obtained on many infants during the month of follow-up but were not reported relative to day-of-life. However, it is noteworthy that for a Kramer zone score of 0, i.e., absence of jaundice, TcB values ranged from 0 to ~265 µmol/L (0–15.5 mg/dL), with a median of ~47 µmol/L (2.7 mg/dL). Bhutani et al. performed visual assessment of NJ at discharge from the nursery as well as TcB/TSB, and reported that 84% of the infants were clinically jaundiced (37). However, the Kramer scale data were not reported in detail, nor was the relationship with the TcB/TSB data.

The above 10 studies of NJ cover a full century and vary both as far as the methods employed for TSB (or TcB) analyses, the lighting conditions and techniques used to examine the infants for jaundice, and the feeding modes. Nevertheless, the following conclusions seem permissible:

  • >90% of all newborn infants at some point(s) during the first days of life have HB as defined by TSB values that exceed the normal range for adults.
  • The majority of newborn infants are judged to have NJ at some point during their first days of life, but the reported data for occurrence vary from 60% to nearly 100%, and are often not comparable because methods and criteria vary between studies.
  • HB is often present even in infants who clinically do not appear jaundiced.
  • HB >205 µmol/L (>12 mg/dL) is rarely going to be missed by clinical assessment of NJ, but with few exceptions most studies show that our ability to judge the actual level of TSB by visual examination is limited.

Jaundice of the eyes may first have been described in 1,847 by Hervieux who autopsied 45 infants who had died while still jaundiced (53). Forty-four of these infants also had jaundiced brains, and among these 28 pairs of eyes were jaundiced. However, the relationship between TSB/TcB levels and jaundice of the conjunctiva in live infants was only studied recently (54-56). Importantly for clinical practice, the absence of conjunctival icterus helps to rule out significant HB (55,56). Also, parents may be advised to have their baby evaluated for NJ if they observe jaundice of the eyes (56). However, although the presence of conjunctival icterus is more common at intermediate-to-high TSB/TcB levels, in one of the studies it was also observed in ~20% of infants with TcB levels <171 µmol/L (<10 mg/dL) (55).

Clinical course

The clinical course of NJ is characterized by the absence of jaundice at birth in the majority of infants, however with TSB values that exceed the normal range for adults (50,57). This is followed by an increase in TSB which eventually manifests with detectable jaundice, typically on the 2nd–3rd day of life. However, infants with blood group isoimmunization may present with NJ on the very first day of life and then will require close follow-up and often therapeutic interventions (11,58). Historical data, before the advent of therapies that remove most of the higher TSB values, show that in the absence of interventions the peak of NJ as well as HB is reached later in those infants who go on to become very jaundiced (4,58). Thus, in Davidson’s study from 1941, the infants on the 10th centile reached a peak TSB of ~27 µmol/L (1.6 mg/dL) on the second day of life, while infants on the 90th centile peaked at TSB ~220 µmol/L (12.8 mg/dL) on the fourth day of life (4). HB also lasts longer in infants at the higher centiles, resulting in a greater ‘area under the curve’ as far as exposure to bilirubin. This may be predicted by early measurement of TSB and/or TcB and charting the values on a nomogram relative to an infant’s age in hours (26,59). Similar findings were made by Fouzas et al. who constructed a nomogram based on TcB measurements taken twice daily during the first 5 days of life in late preterm infants (60). TcB values peaked on the 3rd day of life in infants on the 5th and 25th centile, between the 3rd and 4th day of life in infants on the 50th centile, and on the 4th day of life in infants on the 75th and 95th centile. In a larger study that also included many term infants ≥37 weeks GA, TcB values for both the 50th, 75th, and 95th centiles peaked at 4.5 days of life (61). Postl et al. compared the course of neonatal HB in Inuit vs. Caucasian infants, and found that the former had higher peak TSB values than the latter, and reached these on day 3 of life, vs. day 2 for the Caucasian infants (62).

Recently, Kaplan and Maisels used pooled readings from 19 published TcB nomogram reports from predominantly breastfed newborns ≥35 weeks gestation to construct a ‘universal’ TcB nomogram which included the 25th, 50th, 75th, and 95th percentiles from 12 to 120 h (63). Studies included >119,000 TcB measurements from 44,392 infants and had been performed in the Americas, Europe, Africa, and Asia. This large data set confirms the relationships between percentiles and the age at which bilirubin values reach their peak, as discussed above. Thus, factors that modulate the clinical course of NJ may also impact on the epidemiology of NJ as well the risk for bilirubin-related sequelae.

Factors that influence the epidemiology of NJ


Infants of Southeast and Far East Asian descent have, on average, higher TSB concentrations and more NJ than infants of Caucasian or African descent (27,36,44,64-67), as do some American First Nation peoples (68) and Inuits (62,69). A comparison of the different ethnic groups in Singapore in the 1960s found clinical NJ in 90% of Chinese infants in the 1st week of life compared to 70% in Malays, and 30% in European infants (70). In the same study 99% of Chinese infants reached a peak TSB of ≥70 µmol/L (≥4 mg/dL), while 69% had levels of >170 µmol/L (>10 mg/dL). Peak TSB values were reached between the 2nd–3rd days of life in European infants vs. between the 4th–5th days of life in Asian infants. Of note, NJ/HB due to Rhesus iso-immunization is very rare among Chinese neonates since more than 99.9% of Chinese are Rhesus positive (71). In a study in Nepal (n=18,985) Infants of Madeshi ethnicity (originating from the plains) had a decreased risk of jaundice compared to infants of Pahadi (originating from the hills) ethnicity [RR =0.21 (95% CI: 0.18–0.25)]. However, it should be noted that infants in Madeshi households were significantly less likely to be exclusively breastfed, to be started on feeding early, or be given colostrum compared with Pahadi infants, all of which may confound the interpretation of the role of ethnicity (72).

In infants of mixed Asian-Caucasian parentage, only having a Caucasian mother and an Asian father was associated with increased probability of having a discharge diagnosis of NJ (67). Among 2,272 Nigerian infants examined daily for NJ during the first week of life, 35% of males and 30% of females were found to be jaundiced (73). The onset of NJ was on the 1st day of life in 12.8%, and between the 2nd–4th days in 72.4% of the cases. In cases with NJ, TSB was >170 µmol/L (>10 mg/dL) in 32.4%, less than half of the incidence in the Chinese infants, as mentioned above. Etiologic factors were sought in the 125 infants who had TSB >257 µmol/L (>15 mg/dL), the leading contributory cause was G-6-PD-deficiency in 49/125 cases, 37/125 had AB0-incompatibility (in combination with G-6-PD-deficiency in 11), while only 2/125 had Rhesus-incompatibility (73). Newman et al. compared the incidence of ‘non-physiologic’ HB in infants discharged from a hospital in San Francisco, CA, USA and found that the incidence was 31% in infants of Asian parentage, 16% in Caucasians, and 9% in African-Americans (66). The timing of presentation of HB differed between ethnic groups. Thus, while almost 80% of African-American infants with ‘non-physiologic’ HB had these values noted during the first 2 days of life, this occurred in 64% of Caucasians and 55% of Asians respectively (66).


In infants born on the island Lesbos in Greece NJ was found to be more frequent and more pronounced in both normal and in G-6-PD-deficient infants than in similar infants on the island of Rhodes as well as in a general Greek cohort of infants (74,75). This phenomenon may not present in infants of Greek parentage born elsewhere in the world (76). It has been suggested, but apparently not as yet documented or agreed, that an environmental factor may contribute to this phenomenon (77-81). It is interesting that a high incidence of NJ was also found on another Mediterranean island, Sardinia (51). In the study from Lesbos ‘severe NJ’ was defined at TSB >274 µmol/L (>16 mg/dL), and the incidence can be calculated from their table II to be 10.9%, while the incidence in Sardinia was 8.8%, excluding cases of G-6-PD-deficiency and blood group incompatibility (51,74).

A comparison of infants born at 3,100 vs. 1,600 m altitude in Colorado showed that the incidence of HB >205 µmol/L (>12 mg/dL) was 32.7% at the higher vs. 13% at the lower altitude, and about 4 times that of data from sea level (16). A comparison of factors that influence serum bilirubin levels did not point to any factor(s) other than altitude that could explain the higher incidence of HB at 3,100 m. Although hematocrit values were significantly higher at 3,100 vs. 1,600 m, the differences were rather small, and in both cohorts hematocrit values were actually higher in infants without HB than in infants with HB. Thus, a higher Hgb load leading to greater bilirubin production does not seem a likely explanation for the difference in HB incidence. The authors speculated that uptake or conjugation, but not excretion, might be impaired by high altitude exposure (16,82).

Ding et al. followed 875 newborns from three different geographical areas of China (North, Northeast, and South) with TSB measurements during the first 7 days of life (27). In all areas peak TSB values were reached on the 5th day of life. However, with the exception of day 1 of life, infants from the South had significantly higher TSB values throughout the period of observation, while those from the Northeast had the lowest values and those from the North occupied an intermediate position (27). The study did not bring to light any concrete explanations for these differences, but the authors speculated that differences in local customs and heredity might contribute.


Milby et al. first reported seasonal variations in the incidence of neonatal HB (14). A retrospective review of nursery records in a small California community hospital revealed a significantly higher number of cases of HB exceeding 170 µmol/L (10 mg/dL) in the 4th quarter (October–December) of each of 4 succeeding years. The authors speculated on a number of hypothetical explanations for their findings without identifying a specific cause. A prospective study was undertaken and alluded to in later correspondence, but no data have been published (83).

Lee et al. studied neonatal HB in Hong Kong, defined as TSB >257 µmol/L (>15 mg/dL), over a period of 4 years, and found that HB was significantly more common in summer (April–September) than in winter (October–March) (71). Friedman et al. retrospectively analyzed the occurrence of HB [≥205 µmol/L (≥12 mg/dL) and ≥291 µmol/L (≥17 mg/dL)] among 12,461 neonates over a 5-year period in a London birthing hospital (84). Although their data were collected by month and shown in their figure 1, they apparently did not perform a statistical assessment of seasonal variation. Nevertheless, an inspection of that figure shows that with the exception of the 3rd year, the peak incidence of HB occurred mid-year, while in the 3rd year the peak incidence looks to be shifted a couple of months toward early fall (84).

In a study of 875 newborns from three geographical regions of China, Ding et al. found that mean TSB values on the first 4 days of life were significantly higher during the months of April–June than during the other quartiles of the year (27). González de Dios et al. in Alicante, Spain studied NICU admissions and found significantly higher rates of ‘severe HB’ in the summer, speculating that temperatures might have an influence (85). Cerna et al. compared two groups of healthy neonates born in June and December respectively for HB >205 µmol/L (>12 mg/dL) and use of phototherapy (86). Both HB as defined and phototherapy use were significantly more prevalent in June than in December (27.5% vs. 22.9%, P<0.05, and 14.3% vs. 10.0%, P<0.05, respectively).

Similarly, in Nepal birth during the “hot season” (March–October) was significantly associated with NJ (72). This was further validated by the recorded minimum ambient air temperature on the infant’s birthdate, which indicated a significant 3% increase in risk of NJ for each 1 °C increase in temperature. Identification of NJ was by visual inspection by study case workers (72).

Thus, several studies seem to suggest that the incidence of NJ may vary with season, and with the exception of one study (14), all appear to find a higher incidence in summer or warm season. However, all studies except for the one in Nepal (72) were small and/or retrospective and their criteria for case inclusion differed. In conclusion, the data that show a seasonal variation in the incidence of NJ are suggestive but limited, and further prospective studies with well-defined criteria are needed to answer this question.


Lower birth order and an older sibling with NJ have both been shown to be associated with increased risk of NJ (24,51,72,87). Nielsen et al. found that when a woman had born a severely jaundiced infant, the risk of a recurrence in her next pregnancy was 2–3 times greater (88). Almost identical observations were made by Khoury et al., i.e., the risk of NJ in newborns who had older sibling(s) with NJ was 3.1 times greater than for those without such family history (89). Further, the risk of severe HB (defined as peak TSB >257 µmol/L) in newborns who had older sibling(s) with severe HB was 12.5 times higher than that of control newborns (89).


Both the ethnic and familial factors discussed above are likely to have genetic causes. A number of well-described syndromes are associated with NJ, such as hemolytic anemias, variants in bilirubin metabolism, and Down syndrome. As the genetics of NJ is reviewed in another paper in the present issue of Pediatric Medicine, this topic will not be discussed further here.

Events during pregnancy

Maternal smoking

Hardy and Mellits first suggested that maternal smoking reduced NJ, however the sample size was small and they did not control for other factors that might influence TSB levels (90). Similar claims were made shortly thereafter by Nymand, but no details of the study were reported (91). Also, in a large retrospective study based on interviews and record reviews Linn et al. found a significant negative correlation between maternal smoking and HB ≥171 µmol/L (≥10 mg/dL) (19). The findings were sustained in a logistic regression controlling for other potential contributing factors (OR: 0.77, 95% CI: 0.68–0.87). Interestingly, a very similar odds ratio, using the same cutoff value for TSB to define NJ, was found by Diwan et al. (OR: 0.81, 95% CI: 0.66–0.99), although they started by identifying infants with NJ, then selecting controls (23). In a recent large Swedish registry-based study of 1,019,220 singleton live births between 1987–2002, Lee et al. showed that maternal smoking was significantly associated with a reduced incidence of both hemolytic and non-hemolytic NJ, with odds ratios between 0.73–0.88, perhaps providing the most convincing evidence for this association (92).

In a population of 10,122 singleton Israeli newborns Gale et al. identified 1,154 infants with TSB >221 µmol/L (>12.9 mg/dL) (24). An equal number of controls were selected at random from the remaining infants who all had lower TSB values. There was no difference in the number of mothers who smoked during pregnancy between the two groups. However, <4% of mothers in both groups reported smoking in pregnancy—a significantly lower proportion than in other populations. Thus, in a smaller study from Denmark performed at the same time as the study from Israel, 43% of mothers reported smoking during pregnancy (93). The median increase in TSB during the first 24 h of postnatal life was significantly higher in the group of neonates born to smokers compared to non-smokers (P<0.02), while in contrast the median increase in TSB from the 1st to the 3rd postnatal day was significantly lower among the neonates born to smokers compared to non-smoking mothers (P<0.04). Thus, on the 3rd postnatal day the overall frequency of clinical jaundice and the frequency of neonates with TSB >175 µmol/L was almost identical in the two groups (93).

In conclusion, several studies suggest that maternal smoking may reduce NJ/neonatal HB, although not all studies concur. Several mechanisms for this effect have been suggested, but no direct experimental evidence for these appears to have been published. Future studies need to control better for breast-feeding as a possible confounder, as smoking mothers may breastfeed less than nonsmokers (94).

Maternal age and illness

Studies are divided as far as the effect of maternal age on the incidence of NJ. Thus, while some found the incidence to be increased in older mothers (24,92,95,96), others found the highest risk in infants of younger mothers (72,97,98), particularly in those <20 years of age (72,98).

A higher incidence of NJ/neonatal HB is associated with maternal diabetes, pregnancy-induced hypertension, maternal obesity, and 1st trimester bleeding (19-22,24,92).

Maternal pharmacotherapy

Drugs may induce liver enzymes (99,100). When given to pregnant women phenobarbital has been shown induce hepatic processing of bilirubin in the fetus (101,102). In Malawi infants born to HIV-positive mothers who had received a 6-week course of nevirapine to reduce mother-to-infant virus transfer, were shown to have significantly reduced incidence of NJ compared to infants of mothers who were HIV negative and had not received nevirapine (103). Nevirapine is known to interact with cytochrome P450 enzymes both as a substrate and as an inducer, and the latter probably explains the effects noted (104). Oxytocin administered at delivery has been shown by some to be associated with NJ, however the effects were small and not replicated by others (19,21,84).

Blood group incompatibility

Because bilirubin is the end product of heme catabolism, increased breakdown of erythrocytes, as occurs in all kinds of hemolytic anemias, increases bilirubin production causing NJ (105). Hereditary hemolytic anemias are dealt with elsewhere in this issue of the journal. However, hemolysis through immune mechanisms elicited by maternal-fetal blood group incompatibilities is a more common contributor to NJ, and among these ABO incompatibility has become the most frequent in clinical practice (24,37,106,107). The incidence of Rh isoimmunization has declined significantly since the advent of Rhesus prophylaxis in pregnancy, however it remains an important cause of neonatal morbidity and mortality (36,108,109). Among less common blood group incompatibilities Kell, s, C, Jka, S, Lub, and N isoimmunization may cause significant hemolytic disease of the newborn (110,111).

Labor and delivery

Several events related to labor and delivery have been found to be associated with increased NJ/HB, including placenta previa, placental abruption, PROM, prolonged labor, breech presentation, forceps, vacuum, caesarean delivery, epidural anesthesia, and cephalohematoma (19,24,51,72,84,107,109). However, some nuances should be noted. Thus, Bracci et al. found higher TSB after spontaneous delivery vs. emergency caesarean, and after planned vs. emergency caesarean delivery (107). Also, Friedman et al. found that general anesthesia reduced the risk for NJ/HB (84).

Gestational age/prematurity

Lower gestational age increases the risk for NJ (19,24,37,60,84,107,112-116). Thus, for each week of gestation below 40 weeks, the risk for significant HB increases significantly (96,117-119). Prediction is further improved by including predischarge TSB/TcB (118). Although low gestational age predicts an increased need for PT, this is likely, at least in part, also an effect of chart construction (24,120,121).

Birth weight

Low birth weight is also associated with increased risk for NJ (18,19,21,24,72,84,107,109,113).


The risk of NJ is increased in male newborns compared to females, as has been shown in multiple studies (19,24,51,60,72,76,84,107,111). However, the mechanism for this phenomenon appears not to have been discussed.

Nutrition, caloric intake, fluids, weight loss

A proportion of breast-fed infants exhibit exaggerated and prolonged HB during the first days and weeks of life (12,15,18-20,28,39,107,109), and breastfed infants had significantly greater need for PT than controls (18,37). It may take from 1–4 months of slowly declining TSB levels before values normalize (12). In one study, among infants with feeding difficulties exclusive breastfeeding was a risk factor for NJ, whereas exclusive breastfeeding was protective among infants with no report of feeding difficulties (72).

The degree of NJ/HB in the neonatal period is associated with percent postnatal weight loss (24,51,122), and maximum dehydration as well as time to maximum dehydration is greater in jaundiced infants vs. controls (18).

Meconium retention vs. passage

Corchia et al. showed that delayed first passage of meconium is associated with greater risk of NJ (51).


Any extravasation of blood, as in fractures, hematomas, and closed hemorrhages increases the likelihood of NJ/HB (24,37,112).


High hematocrit during the first days of life is associated with increased risk of NJ/HB (12,107,109,123). However, late cord clamping had no effect on TSB course or the need for PT, though the hematocrit increased by only 2.7 percentage points (124).


NJ may on rare occasions be the presenting sign of infection such as sepsis and UTI (19,33,112,125-128).

‘Pronounced’, ‘severe’, ‘extreme’, and ‘hazardous’ HB

With some variations depending on the complexities of the birth population and/or the conformation of therapeutic guidelines, about 5% of healthy term and near-term infants receive PT for NJ/HB. Certain risk factors have been shown to be strongly predictive of such ‘pronounced’ NJ, including lower GA, bruising, blood type incompatibility with or without positive DAT, Asian ethnicity, exclusive breastfeeding, and extent of jaundice in Kramer zones (37). The same is true for TSB ≥100 µmol/L (≥6 mg/dL) during the first 24 h of life and TcB values above the 75th centile on the Bhutani nomogram between 24–72 h of life (26,129). Re-hospitalization for NJ is associated with a need for phototherapy in the majority of infants (130). Risk factors associated with re-hospitalization include ethnicity (Caucasian or Asian), primiparity, preterm birth, breast-feeding, feeding difficulties and suspicion of jaundice during the birth hospitalization, and early discharge (<48 h) compared to later discharge, particularly for infants of 37 and 38 weeks GA compared to those of 39–41 weeks GA (40,130,131).

Worldwide the incidence of ‘severe’ NJ, defined as jaundice associated with acute bilirubin encephalopathy (ABE)/kernicterus and/or exchange transfusions (ET) and/or jaundice-related death, has been estimated by Slusher et al. to be 99/100,000 live births (95% CI: 28–356) (132). No TSB values were available for this study, but given the severity of the clinical symptoms included in the study, it seems very likely that a large proportion of these infants will have had TSB values in the ‘extreme’ and even ‘hazardous’ range (12). The study demonstrated very significant disparities between parts of the world, from a low estimate of 37/100,000 (95% CI: 17–80) in Europe to a high of 6,678/100,000 (95% CI: 6,033–7,385) in Africa (132). During the past 60+ years several studies have estimated the incidence of ‘severe’ NJ, starting with the reanalysis of data from the US Collaborative Perinatal Project that showed an incidence of 707/100,000 live births (133). The methods for detecting patients have varied between studies, from clinical detection of NJ in single centers leading to TSB testing, to TSB screening of complete cohorts in multiple hospitals (32,112,116,119,131,134-143). Not surprisingly, the incidence range has been very wide, from 10.4/100,000 (140) to 6,600/100,000 (141), though the latter was based on the rate of ET.

Bhutani et al. estimated that the incidence of ‘extreme’ NJ [defined as TSB >428 µmol/L (>25 mg/dL)] worldwide was 359/100,000 live births, and that about 24% of the affected infants died, while 13% were left with moderate-to-severe long-term neurological impairments (36). In other studies the incidence of ‘extreme’ NJ varied from 9.4/100,000 to 233/100,000 (32,43,49,116,119,133,134,136,139,140,143,144). The incidence of ‘hazardous’ HB [TSB >510 µmol/L (>30 mg/dL)] ranged from 2/100,000 to 15/100,000 (32,49,131,134,139,140,145-147).

Applying even the moderate estimate of ‘severe’ NJ from Slusher et al. (132) to the 130 million births per year in the world translates into ~130,000 newborn infants each year who are exposed to significant risk of bilirubin-induced brain damage or death. Therefore, as the risk factors for ‘severe’ NJ may vary between countries and regions, depending both on biological differences and different ways of organizing health care, each region, country, and/or institution should analyze their risk profile and educate their caregivers as well as their birthing population to these to reduce the risk of kernicterus spectrum syndrome and death (147). Some risk factors are global, such as blood group incompatibility, prematurity, breast-feeding jaundice, extravasation of blood, male gender, family history (previous sibling with NJ), and hospital readmission (47). Others may show significant variation between regions, such as ethnicity (Southeast Asian) and G-6-PD-deficiency (47). However, in a significant proportion of cases no specific etiology is found, highlighting the need for vigilance and an ‘open door’ policy for expedient management of all infants with NJ (148,149).


Funding: None.


Provenance and Peer Review: This article was commissioned by the Guest Editors (David K. Stevenson and Ronald J. Wong) for the series “Neonatal Jaundice” published in Pediatric Medicine. The article has undergone external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at The series “Neonatal Jaundice” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See:


  1. Kramer LI. Advancement of dermal icterus in the jaundiced newborn. Am J Dis Child 1969;118:454-8. [PubMed]
  2. Ebbesen F. The relationship between the cephalo-pedal progress of clinical icterus and the serum bilirubin concentration in newborn infants without blood type sensitization. Acta Obstet Gynecol Scand 1975;54:329-32. [Crossref] [PubMed]
  3. Riskin A, Abend-Weinger M, Bader D. How accurate are neonatologists in identifying clinical jaundice in newborns? Clin Pediatr (Phila) 2003;42:153-8. [Crossref] [PubMed]
  4. Davidson LT, Merritt KK, Weech AA. Hyperbilirubinemia in the newborn. Am J Dis Child 1941;61:958-80.
  5. Szabo P, Wolf M, Bucher HU, et al. Detection of hyperbilirubinaemia in jaundiced full-term neonates by eye or by bilirubinometer? Eur J Pediatr 2004;163:722-7. [Crossref] [PubMed]
  6. Knudsen A, Brodersen R. Skin colour and bilirubin in neonates. Arch Dis Child 1989;64:605-9. [Crossref] [PubMed]
  7. Madlon-Kay DJ. Recognition of the presence and severity of newborn jaundice by parents, nurses, physicians, and icterometer. Pediatrics 1997;100:E3. [Crossref] [PubMed]
  8. Moyer VA, Ahn C, Sneed S. Accuracy of clinical judgment in neonatal jaundice. Arch Pediatr Adolesc Med 2000;154:391-4. [Crossref] [PubMed]
  9. Riskin A, Kugelman A, Abend-Weinger M, et al. In the eye of the beholder: how accurate is clinical estimation of jaundice in newborns? Acta Paediatr 2003;92:574-6. Erratum in: Acta Paediatr 2005;94:1168. [Crossref] [PubMed]
  10. Urdal P, Bolann B, Marstein S, et al. Updated reference intervals for clinical chemical components. Tidsskr Nor Laegeforen 2004;124:1515-7. [PubMed]
  11. Lee KS, Gartner LM. Management of unconjugated hyperbilirubinemia in the newborn. Semin Liver Dis 1983;3:52-64. [Crossref] [PubMed]
  12. Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004;24:650-62. [Crossref] [PubMed]
  13. Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn. Pediatrics 2006;118:805-7. [Crossref] [PubMed]
  14. Milby TH. Seasonal neonatal hyperbilirubinemia. Pediatrics 1969;43:601-5. [PubMed]
  15. Maisels MJ, Gifford K. Neonatal jaundice in full-term infants. Role of breast-feeding and other causes. Am J Dis Child 1983;137:561-2. [Crossref] [PubMed]
  16. Moore LG, Newberry MA, Freeby GM, et al. Increased incidence of neonatal hyperbilirubinemia at 3,100 m in Colorado. Am J Dis Child 1984;138:157-61. [PubMed]
  17. Clarkson JE, Cowan JO, Herbison GP. Jaundice in full term healthy neonates--a population study. Aust Paediatr J 1984;20:303-8. [Crossref] [PubMed]
  18. Osborn LM, Reiff MI, Bolus R. Jaundice in the full-term neonate. Pediatrics 1984;73:520-5. [PubMed]
  19. Linn S, Schoenbaum SC, Monson RR, et al. Epidemiology of neonatal hyperbilirubinemia. Pediatrics 1985;75:770-4. [PubMed]
  20. Maisels MJ, Gifford K. Normal serum bilirubin levels in the newborn and the effect of breast-feeding. Pediatrics 1986;78:837-43. [PubMed]
  21. Maisels MJ, Gifford K, Antle CE, et al. Jaundice in the healthy newborn infant: a new approach to an old problem. Pediatrics 1988;81:505-11. [PubMed]
  22. Jährig D, Jährig K, Stiete S, et al. Neonatal jaundice in infants of diabetic mothers. Acta Paediatr Scand Suppl 1989;360:101-7. [Crossref] [PubMed]
  23. Diwan VK, Vaughan TL, Yang CY. Maternal smoking in relation to the incidence of early neonatal jaundice. Gynecol Obstet Invest 1989;27:22-5. [Crossref] [PubMed]
  24. Gale R, Seidman DS, Dollberg S, et al. Epidemiology of neonatal jaundice in the Jerusalem population. J Pediatr Gastroenterol Nutr 1990;10:82-6. [Crossref] [PubMed]
  25. Ho NK. Neonatal jaundice in Asia. Baillieres Clin Haematol 1992;5:131-42. [Crossref] [PubMed]
  26. Bhutani VK, Gourley GR, Adler S, et al. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2000;106:E17. [Crossref] [PubMed]
  27. Ding G, Zhang S, Yao D, et al. An epidemiological survey on neonatal jaundice in China. Chin Med J (Engl) 2001;114:344-7. [PubMed]
  28. Gourley GR. Breast-feeding, neonatal jaundice and kernicterus. Semin Neonatol 2002;7:135-41. [Crossref] [PubMed]
  29. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396-403. [Crossref] [PubMed]
  30. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316. Erratum in: Pediatrics 2004;114:1138. [Crossref] [PubMed]
  31. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of > or = 35 weeks' gestation. Pediatrics 2006;117:1169-73. [Crossref] [PubMed]
  32. Kuzniewicz MW, Escobar GJ, Newman TB. Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. Pediatrics 2009;124:1031-9. [Crossref] [PubMed]
  33. Chen HT, Jeng MJ, Soong WJ, et al. Hyperbilirubinemia with urinary tract infection in infants younger than eight weeks old. J Chin Med Assoc 2011;74:159-63. [Crossref] [PubMed]
  34. McGillivray A, Evans N. Severe neonatal jaundice: is it a rare event in Australia? J Paediatr Child Health 2012;48:801-7. [Crossref] [PubMed]
  35. Maisels MJ, Newman TB. Chapter 6: The epidemiology of neonatal hyperbilirubinemia. In: Stevenson DK, Maisels MJ, Watchko JF. editors. Care of the jaundiced neonate. New York: McGraw-Hill, 2012:97-113.
  36. Bhutani VK, Zipursky A, Blencowe H, et al. Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels. Pediatr Res 2013;74:86-100. [Crossref] [PubMed]
  37. Bhutani VK, Stark AR, Lazzeroni LC, et al. Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. J Pediatr 2013;162:477-82.e1. [Crossref] [PubMed]
  38. Huang L, Bao Y, Xu Z, et al. Neonatal bilirubin levels and childhood asthma in the US Collaborative Perinatal Project, 1959-1965. Am J Epidemiol 2013;178:1691-7. [Crossref] [PubMed]
  39. Maisels MJ, Clune S, Coleman K, et al. The natural history of jaundice in predominantly breastfed infants. Pediatrics 2014;134:e340-5. [Crossref] [PubMed]
  40. Lain SJ, Roberts CL, Bowen JR, et al. Early discharge of infants and risk of readmission for jaundice. Pediatrics. 2015;135:314-21. [Crossref] [PubMed]
  41. Bhutani VK, Wong RJ, Stevenson DK. Hyperbilirubinemia in preterm neonates. Clin Perinatol 2016;43:215-32. [Crossref] [PubMed]
  42. Greco C, Arnolda G, Boo NY, et al. Neonatal jaundice in low- and middle-income countries: lessons and future directions from the 2015 Don Ostrow Trieste Yellow Retreat. Neonatology 2016;110:172-80. [Crossref] [PubMed]
  43. McGillivray A, Polverino J, Badawi N, et al. Prospective surveillance of extreme neonatal hyperbilirubinemia in Australia. J Pediatr 2016;168:82-7.e3. [Crossref] [PubMed]
  44. Bentz MG, Carmona N, Bhagwat MM, et al. Beyond "Asian": Specific East and Southeast Asian races or ethnicities associated with jaundice readmission. Hosp Pediatr 2018;8:269-73. [Crossref] [PubMed]
  45. Brits H, Adendorff J, Huisamen D, et al. The prevalence of neonatal jaundice and risk factors in healthy term neonates at National District Hospital in Bloemfontein. Afr J Prim Health Care Fam Med 2018;10:e1-6. [Crossref] [PubMed]
  46. Taylor JA, Burgos AE, Flaherman V, et al. Discrepancies between transcutaneous and serum bilirubin measurements. Pediatrics 2015;135:224-31. [Crossref] [PubMed]
  47. Olusanya BO, Kaplan M, Hansen TWR. Neonatal hyperbilirubinaemia: a global perspective. Lancet Child Adolesc Health 2018;2:610-20. [Crossref] [PubMed]
  48. Adamkin DH. Late preterm infants: severe hyperbilirubinemia and postnatal glucose homeostasis. J Perinatol 2009;29:S12-7. [Crossref] [PubMed]
  49. Mah MP, Clark SL, Akhigbe E, et al. Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics 2010;125:e1143-8. [Crossref] [PubMed]
  50. Hirsch A. Die physiologische Ikterusbereitschaft des Neugeborenen. Zeitschr Kinderheilk 1913;9:196-207. [Crossref]
  51. Corchia C, Sanna MC, Serra C, et al. 'Idiopathic' jaundice in Sardinian full-term newborn infants: a multivariate study. Paediatr Perinat Epidemiol 1993;7:55-66. [Crossref] [PubMed]
  52. Keren R, Tremont K, Luan X, et al. Visual assessment of jaundice in term and late preterm infants Arch Dis Child Fetal Neonatal Ed 2009;94:F317-22. [Crossref] [PubMed]
  53. Hervieux JFE. De l’Ictère des Nouveau-nés. Paris: University of Paris, 1847.
  54. Azzuqa A, Watchko JF. Bilirubin concentrations in jaundiced neonates with conjunctival icterus. J Pediatr 2015;167:840-4. [Crossref] [PubMed]
  55. Maisels MJ, Coffey MP, Gendelman B, et al. Diagnosing jaundice by eye -outpatient assessment of conjunctival icterus in the newborn. J Pediatr 2016;172:212-4.e1. [Crossref] [PubMed]
  56. Azzuqa A, Watchko JF. Conjunctival icterus - an important but neglected sign of clinically relevant hyperbilirubinemia in jaundiced neonates. Curr Pediatr Rev 2017;13:169-75. [PubMed]
  57. Ylppö A. Icterus neonatorum (incl. I. n. gravis) und Gallenfarbstoffsekretion beim Foetus und Neugeboren. Ztschr Kinderheilk 1913;9:208. [Crossref]
  58. Furuhjelm U, Nevanlinna HR, Usterlund K. Early neonatal jaundice and hyperbilirubinaemia and their relation to AB0 incompatibility. Acta Paediatr Scand 1967;56:477-84. [Crossref] [PubMed]
  59. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999;103:6-14. [Crossref] [PubMed]
  60. Fouzas S, Karatza AA, Skylogianni E, et al. Transcutaneous bilirubin levels in late preterm neonates. J Pediatr 2010;157:762-6.e1. [Crossref] [PubMed]
  61. Fouzas S, Mantagou L, Skylogianni E, et al. Transcutaneous bilirubin levels for the first 120 postnatal hours in healthy neonates. Pediatrics 2010;125:e52-7. [Crossref] [PubMed]
  62. Postl BD, Nelson N, Carson J. Hyperbilirubinemia in Inuit neonates. Can Med Assoc J 1982;126:811-3. [PubMed]
  63. Kaplan M, Maisels MJ. Natural history of early neonatal bilirubinemia: a global perspective. J Perinatol 2021; Epub ahead of print. [Crossref] [PubMed]
  64. Yeung CY. Neonatal hyperbilirubinemia in Chinese. Trop Geogr Med 1973;25:151-7. [PubMed]
  65. Horiguchi T, Bauer C. Ethnic differences in neonatal jaundice: comparison of Japanese and Caucasian newborn infants. Am J Obstet Gynecol 1975;121:71-4. [Crossref] [PubMed]
  66. Newman TB, Easterling MJ, Goldman ES, et al. Laboratory evaluation of jaundice in newborns. Frequency, cost, and yield. Am J Dis Child 1990;144:364-8. [Crossref] [PubMed]
  67. Setia S, Villaveces A, Dhillon P, et al. Neonatal jaundice in Asian, white, and mixed-race infants. Arch Pediatr Adolesc Med 2002;156:276-9. [Crossref] [PubMed]
  68. Saland J, McNamara H, Cohen MI. Navajo jaundice: a variant of neonatal hyperbilirubinemia associated with breast feeding. J Pediatr 1974;85:271-5. [Crossref] [PubMed]
  69. Fisher Q, Cohen MI, Curda L, et al. Jaundice and breast-feeding among Alaskan Eskimo newborns. Am J Dis Child 1978;132:859-61. [PubMed]
  70. Brown WR, Boon WH. Ethnic group differences in plasma bilirubin levels of full-term, healthy Singapore newborns. Pediatrics 1965;36:745-51. [PubMed]
  71. Lee KH, Yeung KK, Yeung CY. Neonatal jaundice in Chinese newborns. J Obstet Gynaecol Br Commonw 1970;77:561-4. [PubMed]
  72. Scrafford CG, Mullany LC, Katz J, et al. Incidence and risk factors for neonatal jaundice among newborns in Southern Nepal. Trop Med Int Health 2013;18:1317-28. [PubMed]
  73. Effiong CE, Aimaku VE, Bienzle U, et al. Neonatal jaundice in Ibadan. Incidence and etiologic factors in babies born in hospital. J Natl Med Assoc 1975;67:208-13. [PubMed]
  74. Valaes T, Karaklis A, Stravrakakis D, et al. Incidence and mechanism of neonatal jaundice related to glucose-6-phosphate dehydrogenase deficiency. Pediatr Res 1969;3:448-58. [Crossref] [PubMed]
  75. Valaes T, Petmezaki S, Doxiadis SA. Effect on neonatal hyperbilirubinemia of phenobarbital during pregnancy or after birth: practical value of the treatment in a population with high risk of unexplained severe neonatal jaundice. Birth Defects Orig Artic Ser 1970;6:46-54. [PubMed]
  76. Drew JH, Barrie J, Horacek I, et al. Factors influencing jaundice in immigrant Greek infants. Arch Dis Child 1978;53:49-52. [Crossref] [PubMed]
  77. Doxiadis SA, Karaklis A, Valaes T, et al. Risk of severe jaundice in glucose-6-phosphate-dehydrogenase deficiency of the newborn. Differences in population groups. Lancet 1964;2:1210-2. [Crossref] [PubMed]
  78. Drew JH, Kitchen WH. Jaundice in infants of Greek parentage: the unknown factor may be environmental. J Pediatr 1976;89:248-52. [Crossref] [PubMed]
  79. Drew JH, Smith MB, Kitchen WH. Glucose-6-phosphate dehydrogenase deficiency in immigrant Greek infants. J Pediatr 1977;90:659-60. [Crossref] [PubMed]
  80. Valaes T. Neonatal jaundice in Greek immigrants. J Pediatr 1977;91:1030-2. [Crossref] [PubMed]
  81. Drew JH, Kitchen WH. Neonatal jaundice in Greek immigrants – In reply. J Pediatr 1977;91:1031-2. [Crossref]
  82. Newberry MA, Moore LG, Crnic LS. Bilirubin metabolism in the rat at high altitude. Aviat Space Environ Med 1984;55:377-80. [PubMed]
  83. Milby TH, Mitchell JE, Freeman TS. Seasonal neonatal hyperbilirubinemia. Pediatrics 1969;43:601-5. [PubMed]
  84. Friedman L, Lewis PJ, Clifton P, et al. Factors influencing the incidence of neonatal jaundice. BMJ 1978;1:1235-7. [Crossref] [PubMed]
  85. González de Dios J, Moya Benavent M, Sirvent Mayor MC, et al. Diferencias estacionales en la ictericia neonatal. An Esp Pediatr 1996;45:403-8. [PubMed]
  86. Cerna M, Vitek L, Mala K, et al. Seasonal nature of neonatal jaundice. Pediatr Res 2010;68:586. [Crossref]
  87. Fok TF, Lau SP, Hui CW. Neonatal jaundice: its prevalence in Chinese babies and associating factors. Aust Paediatr J 1986;22:215-9. [Crossref] [PubMed]
  88. Nielsen HE, Haase P, Blaabjerg J, et al. Risk factors and sib correlation in physiological neonatal jaundice. Acta Paediatr Scand 1987;76:504-11. [Crossref] [PubMed]
  89. Khoury MJ, Calle EE, Joesoef RM. Recurrence risk of neonatal hyperbilirubinemia in siblings. Am J Dis Child 1988;142:1065-9. [PubMed]
  90. Hardy JB, Mellits ED. Does maternal smoking during pregnancy have a long-term effect on the child? Lancet 1972;2:1332-6. [Crossref] [PubMed]
  91. Nymand G. Letter: Maternal smoking and neonatal hyperbilirubinaemia. Lancet 1974;2:173. [Crossref] [PubMed]
  92. Lee BK, Le Ray I, Sun JY, et al. Haemolytic and nonhaemolytic neonatal jaundice have different risk factor profiles. Acta Paediatr 2016;105:1444-50. [Crossref] [PubMed]
  93. Knudsen A. Maternal smoking and the bilirubin concentration in the first three days of life. Eur J Obstet Gynecol Reprod Biol 1991;40:123-7. [Crossref] [PubMed]
  94. van Rossem L, Oenema A, Steegers EA, et al. Are starting and continuing breastfeeding related to educational background? The generation R study. Pediatrics 2009;123:e1017-27. [Crossref] [PubMed]
  95. Seidman DS, Ergaz Z, Paz I, et al. Predicting the risk of jaundice in full-term healthy newborns: a prospective population-based study. J Perinatol 1999;19:564-7. [Crossref] [PubMed]
  96. Newman TB, Xiong B, Gonzales VM, et al. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000;154:1140-7. [Crossref] [PubMed]
  97. Wood BS, Culley PE, Waterhouse JA, et al. Factors influencing neonatal jaundice. Arch Dis Child 1962;37:371-7. [Crossref] [PubMed]
  98. Walker AR, Waites BT, Caughey AB. The impact of extremes of maternal age on maternal and neonatal pregnancy outcomes in women with pregestational diabetes mellitus. J Matern Fetal Neonatal Med 2020;33:437-41. [Crossref] [PubMed]
  99. Catz C, Yaffe SJ. Pharmacological modification of bilirubin conjugation in newborn. Am J Dis Child 1962;104:516.
  100. Yaffe SJ, Levy G, Matsuzawa T, et al. Enhancement of glucuronide-conjugating capacity in a hyperbilirubinemic infant due to apparent enzyme induction by phenobarbital. N Engl J Med 1966;275:1461-6. [Crossref] [PubMed]
  101. Valaes T, Kipouros K, Petmezaki S, et al. Effectiveness and safety of prenatal phenobarbital for the prevention of neonatal jaundice. Pediatr Res 1980;14:947-52. [Crossref] [PubMed]
  102. Valaes TN, Harvey-Wilkes K. Pharmacologic approaches to the prevention and treatment of neonatal hyperbilirubinemia. Clin Perinatol 1990;17:245-73. [Crossref] [PubMed]
  103. Nakanga W, Patel P, Panjwani S, et al. Supra-treatment threshold neonatal jaundice: Incidence in HIV-exposed compared to non-exposed neonates at Queen Elizabeth Central Hospital in Blantyre, Malawi. Malawi Med J 2015;27:104-8. [Crossref] [PubMed]
  104. Milinkovic A, Martínez E. Nevirapine in the treatment of HIV. Expert Rev Anti Infect Ther 2004;2:367-73. [Crossref] [PubMed]
  105. Hansen TWR, Wong RJ, Stevenson DK. Molecular physiology and pathophysiology of bilirubin handling by the blood, liver, intestine, and brain in the newborn. Physiol Rev 2020;100:1291-346. [Crossref] [PubMed]
  106. Solheim B, Grønn M, Hansen TWR. Chapter 45: Hemolytic disease of the fetus and newborn. In: Simon TL, McCullough JM, Snyder EL, et al. editors. Rossi’s principles of transfusion medicine. 5th ed. Hoboken: John Wiley & Sons, Ltd., 2016:528-34.
  107. Bracci R, Buonocore G, Garosi G, et al. Epidemiologic study of neonatal jaundice. A survey of contributing factors. Acta Paediatr Scand Suppl 1989;360:87-92. [Crossref] [PubMed]
  108. Girish N, Santosh S, Keshavamurthy SR. Evolving trends: hyperbilirubinemia among newborns delivered to Rh negative mothers in southern India. J Clin Diagn Res 2013;7:2508-10. [PubMed]
  109. Asefa GG, Gebrewahid TG, Nuguse H, et al. Determinants of neonatal jaundice among neonates admitted to neonatal intensive care unit in Public General Hospitals of Central Zone, Tigray, Northern Ethiopia, 2019: a case-control study. Biomed Res Int 2020;2020:4743974. [Crossref] [PubMed]
  110. Liley HG, Gardener G, Lopriore E. et al. Immune hemolytic disease. In: Orkin SH, Fisher DE, Ginsburg D, et al. editors. Nathan & Oski's hematology and oncology of infancy and childhood. Philadelphia: Saunders Elsevier, 2015:76-100.e5.
  111. Orgun A, Çalkavur Ş, Olukman Ö, et al. Role of minor erythrocyte antigens on alloimmunızation in neonatal indirect hyperbilirubinemia background. Turk Arch Ped 2013;48:23-9. [Crossref]
  112. Palmer DC, Drew JH. Jaundice: a 10 year review of 41,000 live born infants. Aust Paediatr J 1983;19:86-9. [PubMed]
  113. Narang A, Gathwala G, Kumar P. Neonatal jaundice: an analysis of 551 cases. Indian Pediatr 1997;34:429-32. [PubMed]
  114. Tan KL. Neonatal jaundice in 'healthy' very low birthweight infants. Aust Paediatr J 1987;23:185-8. [Crossref] [PubMed]
  115. Visruthan NK, Agarwal P, Sriram B, et al. Neonatal outcome of the late preterm infant (34 to 36 weeks): the Singapore story. Ann Acad Med Singap 2015;44:235-43. [PubMed]
  116. Campbell Wagemann S, Mena Nannig P. Severe hyperbilirubinemia in newborns, risk factors and neurological outcomes. Rev Chil Pediatr 2019;90:267-74. [Crossref] [PubMed]
  117. Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmission. Pediatrics 1998;101:995-8. [Crossref] [PubMed]
  118. Keren R, Luan X, Friedman S, et al. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics 2008;121:e170-9. [Crossref] [PubMed]
  119. Newman TB, Liljestrand P, Escobar GJ. Combining clinical risk factors with serum bilirubin levels to predict hyperbilirubinemia in newborns. Arch Pediatr Adolesc Med 2005;159:113-9. [Crossref] [PubMed]
  120. Mreihil K, Benth JS, Stensrud HJ, et al. Phototherapy is commonly used for neonatal jaundice but greater control is needed to avoid toxicity in the most vulnerable infants. Acta Paediatr 2018;107:611-9. [Crossref] [PubMed]
  121. Mreihil K, Nakstad B, Stensrud HJ, et al. Uniform national guidelines do not prevent wide variations in the clinical application of phototherapy for neonatal jaundice. Acta Paediatr 2018;107:620-7. [Crossref] [PubMed]
  122. Zaitsu M, Yoshihara T, Nakai H, et al. Optimal thermal control with sufficient nutrition may reduce the incidence of neonatal jaundice by preventing body-weight loss among non-low birth weight infants not admitted to neonatal intensive care unit. Neonatology 2018;114:348-54. [Crossref] [PubMed]
  123. Olusanya BO, Slusher TM. Infants at risk of significant hyperbilirubinemia in poorly-resourced countries: evidence from a scoping review. World J Pediatr 2015;11:293-9. [Crossref] [PubMed]
  124. Carvalho OMC, Augusto MCC, Medeiros MQ, et al. Late umbilical cord clamping does not increase rates of jaundice and the need for phototherapy in pregnancies at normal risk. J Matern Fetal Neonatal Med 2019;32:3824-9. [Crossref] [PubMed]
  125. Escobedo MB, Barton LL, Marshall RE, et al. The frequency of jaundice in neonatal bacterial infections: observation on 16 newborns without hemolytic disease. Clin Pediatr (Phila) 1974;13:656-7. [Crossref] [PubMed]
  126. Chavalitdhamrong PO, Escobedo MB, Barton LL, et al. Hyperbilirubinaemia and bacterial infection in the newborn. A prospective study. Arch Dis Child 1975;50:652-4. [Crossref] [PubMed]
  127. Linder N, Yatsiv I, Tsur M, et al. Unexplained neonatal jaundice as an early diagnostic sign of septicemia in the newborn. J Perinatol 1988;8:325-7. [PubMed]
  128. Shahian M, Rashtian P, Kalani M. Unexplained neonatal jaundice as an early diagnostic sign of urinary tract infection. Int J Infect Dis 2012;16:e487-90. [Crossref] [PubMed]
  129. Alpay F, Sarici SU, Tosuncuk HD, et al. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns. Pediatrics 2000;106:E16. [Crossref] [PubMed]
  130. Geiger AM, Petitti DB, Yao JF. Rehospitalisation for neonatal jaundice: risk factors and outcomes. Paediatr Perinat Epidemiol 2001;15:352-8. [Crossref] [PubMed]
  131. Lee KS, Perlman M, Ballantyne M, et al. Association between duration of neonatal hospital stay and readmission rate. J Pediatr 1995;127:758-66. [Crossref] [PubMed]
  132. Slusher TM, Zamora TG, Appiah D, et al. Burden of severe neonatal jaundice: a systematic review and meta-analysis. BMJ Paediatr Open 2017;1:e000105. [Crossref] [PubMed]
  133. Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long-term outcome: another look at the Collaborative Perinatal Project. Pediatrics 1993;92:651-7. [PubMed]
  134. Newman TB, Escobar GJ, Gonzales VM, et al. Frequency of neonatal bilirubin testing and hyperbilirubinemia in a large health maintenance organization. Pediatrics 1999;104:1198-203. [PubMed]
  135. Walston F, Manning D, Neithercut WD. Increasing incidence of moderate neonatal hyperbilirubinaemia in Wirral. Arch Dis Child Fetal Neonatal Ed 2004;89:F374. [Crossref] [PubMed]
  136. Ebbesen F, Andersson C, Verder H, et al. Extreme hyperbilirubinaemia in term and near-term infants in Denmark. Acta Paediatr 2005;94:59-64. [Crossref] [PubMed]
  137. Olusanya BO, Akande AA, Emokpae A, et al. Infants with severe neonatal jaundice in Lagos, Nigeria: incidence, correlates and hearing screening outcomes. Trop Med Int Health 2009;14:301-10. [Crossref] [PubMed]
  138. Tikmani SS, Warraich HJ, Abbasi F, et al. Incidence of neonatal hyperbilirubinemia: a population-based prospective study in Pakistan. Trop Med Int Health 2010;15:502-7. [Crossref] [PubMed]
  139. Zoubir S, Arlettaz Mieth R, Berrut S, et al. Incidence of severe hyperbilirubinaemia in Switzerland: a nationwide population-based prospective study. Arch Dis Child Fetal Neonatal Ed 2011;96:F310-1. [Crossref] [PubMed]
  140. Gotink MJ, Benders MJ, Lavrijsen SW, et al. Severe neonatal hyperbilirubinemia in the Netherlands. Neonatology 2013;104:137-42. [Crossref] [PubMed]
  141. Aletayeb SMH, Dehdashtian M, Kajbaf TZ, et al. Determination of hematologic causes of hyperbilirubinemia in neonates undergoing exchange transfusion in South West of Iran. Pak Pediatr J 2014;38:36-41.
  142. Thielemans L, Trip-Hoving M, Landier J, et al. Indirect neonatal hyperbilirubinemia in hospitalized neonates on the Thai-Myanmar border: a review of neonatal medical records from 2009 to 2014. BMC Pediatrics 2018;18:190. [Crossref] [PubMed]
  143. Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal hyperbilirubinemia in Canada. CMAJ 2006;175:587-90. [Crossref] [PubMed]
  144. Bjerre JV, Petersen JR, Ebbesen F. Surveillance of extreme hyperbilirubinaemia in Denmark. A method to identify the newborn infants. Acta Paediatr 2008;97:1030-4. [Crossref] [PubMed]
  145. Newman TB, Liljestrand P, Escobar GJ. Infants with bilirubin levels of 30 mg/dl or more in a large managed care organization. Pediatrics 2003;111:1303-11. [Crossref] [PubMed]
  146. Manning D, Todd P, Maxwell M, et al. Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed 2007;92:F342-6. [Crossref] [PubMed]
  147. Olusanya BO, Osibanjo FB, Slusher TM. Risk factors for severe neonatal hyperbilirubinemia in low and middle-income countries: a systematic review and meta-analysis. PLoS One 2015;10:e0117229. [Crossref] [PubMed]
  148. Smitherman H, Stark AR, Bhutani VK. Early recognition of neonatal hyperbilirubinemia and its emergent management. Semin Fetal Neonatal Med 2006;11:214-24. [Crossref] [PubMed]
  149. Hansen TWR. The role of phototherapy in the crash-cart approach to extreme neonatal jaundice. Semin Perinatol 2011;35:171-4. [Crossref] [PubMed]
doi: 10.21037/pm-21-4
Cite this article as: Hansen TWR. Narrative review of the epidemiology of neonatal jaundice. Pediatr Med 2021;4:18.

Download Citation