In the present study, TSB levels were significantly higher in infants born during the cold season (October to March), and only in the male population, the bilirubin level was found to have a weak but significant negative correlation with mean daily air temperature at birth. Therefore, season of birth appears to be an etiological factor in neonatal jaundice. Furthermore, there also appears to be an influence of sex.
In 1969, Milby et al. described seasonal variations in the incidence of neonatal hyperbilirubinemia for the first time [7]. In their study, the incidence of neonatal unconjugated hyperbilirubinemia was significantly high during the fourth quarter of each year. However, climatic information was not described, and the cause of the seasonal fluctuation was unclear. Subsequently, eight other studies have been conducted to investigate the possible impact of the season of birth on serum bilirubin levels of neonates or pathological hyperbilirubinemia [8–14,17] (Table 3). Two of these studies demonstrated that TSB levels were higher in the cold season, as shown in the present study [8,17], although the study by Hojat et al. did not confirm the presence of a statistically significant difference. Anttolainen et al. suggested that the short duration of daylight experienced during the cold season could increase the incidence of hyperbilirubinemia [8]. Sunlight can prevent hyperbilirubinemia [18] because the sun emits blue-green light in the spectrum needed to most effectively convert bilirubin to its water-soluble isomers for excretion. Hojat et al. also described that there is less sunlight in the winter and the decomposition of bilirubin decreases during this time [17]. In addition, they suggested that parents often increase a baby’s room temperature to prevent hypothermia in winter, and this can cause dehydration and increase serum bilirubin levels. In the present study, there was no statistical significance in the seasonal and monthly variations of sunshine duration, and no significant correlation between serum bilirubin level and sunshine duration was found. On the other hand, six previous studies have demonstrated that serum bilirubin levels and the incidence of pathologic hyperbilirubinemia were significantly higher in warm seasons [9–14] (Table 3); González et al. suggested that high temperatures during the summer and the associated higher dehydration rate may be the main cause [9]. Additionally, they suggested that the seasonal differences could be due to breast milk jaundice. Ahmady et al. also suggested that, during the summer season, increased temperature led to increased breastfeeding rates to compensate for dehydration and elevated bilirubin levels [13]. Breastfeeding has been recognized as a contributing factor for the development of neonatal hyperbilirubinemia, as the breastmilk of some women contains a metabolite of progesterone called 3α,20β-pregnanediol, which inhibits UDP-glucuronosyltransferase (UGT) bilirubin glucuronidation activity [4]. Moreover, breastfed babies, particularly those who have difficulty nursing or getting enough nutrition from breastfeeding, are at a higher risk of jaundice. Besides dehydration, a low caloric intake through inadequate levels of breast feeding may contribute to the onset of jaundice. In the present study, room temperature was not included in the evaluated environmental factors and daily feeding volume was also not investigated. However, weight loss rate in the first 4 days after birth was not significantly different between the warm and cold seasons. Therefore, dehydration of the newborn during the warm season is unlikely. Our previously published paper reported that room temperature in the neonatal ward was unchanged throughout the year [19]. Moreover, in the present study, the rate of breastfed neonates was not different between those born in the warm and cold seasons.
Table 3
Reported articles investigating seasonal variation of serum bilirubin levels in neonates or neonatal hyperbilirubinemia
Study and country | Study type | Inclusion criteria | Sample size | Age at study | Seasonality | Sex difference | Summary |
Milby et al., 1969, USA [7] | R | Serum indirect bilirubin, > 171 µmol/L | 170 | Unknown | Yes | Yes | Incidence of hyperbilirubinemia was high during the fourth quarter of each year. Elevated bilirubin levels were more frequent in male infants. |
Anttolainen et al., 1975, Finland [8] | P | BW, < 2500 g | 76 | 0–10 d | Yes | NA | Total bilirubin levels were lower from March to August than from September to February. |
González et al., 1996, Spain [9] | P | Serum total bilirubin, > 274 µmol/L | 161 | Unknown | Yes | NA | Pathologic hyperbilirubinemia was commoner in fall and less common in winter (not a statistically significant difference). Pathologic hyperbilirubinemia due to breastmilk jaundice was significantly commoner in summer. |
Bottini et al., 2000, Italy [10] | P | Unknown | 343 | 23–25 h | Yes | Yes | The rise of serum bilirubin was minimal in autumn (September-November). The rise of serum bilirubin showed a tendency to decrease from winter to autumn. The rise of serum bilirubin level in spring and summer was significantly higher in female infants than in male infants. |
Bottini et al., 2003, Italy [11] | P | Unknown | 5540 | Unknown | Yes | Yes | The maximum incidence of phototherapy was observed from May to August. The proportion of infants undergoing phototherapy was lower in female infants. |
Cerna et al., 2010, Czech [12] | R | Healthy, term | 565 | Unknown | Yes | NA | The incidence of hyperbilirubinemia was higher in summer. The frequency of phototherapy use was higher during summer. |
Ahmady et al., 2015, Egypt [13] | P | GA, 37 weeks | 500 | Unknown | Yes | Yes | Total and unconjugated bilirubin were higher in newborns born in summer. Increased unconjugated bilirubin was more common in male infants born in summer. Total and unconjugated bilirubin in female infants were significantly raised in summer. Conjugated bilirubin was elevated in winter. |
Bala et al., 2016, India [14] | P | GA, 37 weeks | 1000 | Unknown | Yes | Yes | Total and indirect bilirubin were higher in summer. Indirect bilirubin level was higher in male infants in summer. In female infants, total and indirect bilirubin were significantly raised in winter. Direct bilirubin level was raised in winter. |
Hojat et al., 2018, Iran [17] | P | GA, 38–42 weeks BW, 2500–3400 g | 400 | 7 d | No | NA | The highest bilirubin level was observed in winter (not statistically significant). |
R, retrospective study; P, prospective study; GA, gestational age; BW, birthweight; NA, not analyzed |
Regarding sex differences, five of nine studies refer to a role of sex in seasonal variation of bilirubin levels [7,10,11,13,14] (Table 3). Four of them reported that serum bilirubin levels or the incidence of pathological hyperbilirubinemia were higher in male infants [7,11,13,14]. Meanwhile, Bottini et al. reported that the rise of serum bilirubin levels in the warm season was significantly higher in female infants, whereas in the cold season, no significant differences between male infants and female infants were observed [10]. In addition, two studies reported that conjugated bilirubin was more common in female infants [13,14]. Sex divergent glucuronidation rates were observed in humans, and sex differences in UGT mRNA have also been observed in animal studies [20,21]. Sex hormones may be an important regulator of conjugation. In a previous study, the phenomenon of protection from oxidative stress was shown to be much more marked in male than in female newborn infants [10].
Several other clinical factors may influence neonatal hyperbilirubinemia. As bilirubin has a protective effect against secondary oxidative stress [2,6], seasonal variation of birth stress may influence bilirubin levels during the first few days of life [10]. In one study, the highest number of births leading to cerebral palsy occurred in spring, with the lowest number occurring in winter [22]. Low birthweight and prematurity are well-recognized as being major risk factors for exaggerated hyperbilirubinemia [1]. Seasonal patterns of low birthweight and preterm births have been found [23]. As pregnant women are particularly sensitive to meteorological conditions and environmental exposure [5], the period before delivery could be a critical window influencing fetal growth when high or low ambient temperature exposure occurs [23]. In summer, heat stress can damage antioxidant defense systems and lead to increased oxytocin secretion [24]. In winter, decreased sunlight exposure may lead to lower levels of vitamin D [25], which is essential for normal placental function and fetal growth [26]. The mode of delivery may also influence the jaundice risk. In previous studies, lower bilirubin levels were observed after cesarean section (CS) and this is supposedly explained by placental transfusion or the timing of cord clamping [27,28]. However, other studies comparing CS with vaginal delivery did not show a difference in hyperbilirubinemia risk [15,29]. In the present study, birthweight, gestational age, 1-min and 5-min Apgar scores (as an indicator of birth stress), and delivery mode were not associated with significant seasonal variations.
The present study has limitations. First, the retrospective study design restricted the appropriate assessment of potential confounders. Second, the meteorological data used for the statistical analyses were not available at the time that the neonate was born or the blood was sampled. In addition, data on the indoor temperature in the maternity ward were not available. For mothers, personal exposure to meteorological indicators may be modified by the duration of time spent indoors before delivery. Actual exposure of individuals to meteorological conditions might not always be the same as the recorded data of a specific geographical region. As a result, this may lead to some degree of evaluation error.
The present study also has strengths. Information about seasonal variation in neonatal jaundice is limited because most other studies are based on a small sample size, a limited number of variables, and a short study period. Unlike previous studies, this study evaluated the association between serum bilirubin levels and meteorological data in early neonatal period with a relatively large sample size.