Ethical Publication Statement
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Neonatal jaundice is a common condition that occurs during the transitional period after birth.1-3. This unpreventable condition occurrs in 60% of term and 80% of preterm neonates all over the word. Jaundice is one of the most common causes of neonatal readmission to hospital.1 It usually begins on the second day after birth and lasts two to three days to reach normal levels of bilirubin in most cases without treatments.4,5 On the other hand, neonate population may show severe jaundice, or even jaundice that develops into acute bilirubin encephalopathy or kernicterus.6,7 Hyperbilirubinemia is primarily important because there is a close relationship between the increase in unconjugated bilirubin levels and neurotoxic effects that can lead to long-term complications such as cerebral palsy, kernicterus and hearing impairment.8-10 Severe jaundice is a serious life-threatening problem, and several factors interfere with the development of severe jaundice, which can be related to genetic and/or geographic variables.7 Early diagnosis of infants at high risk of severe hyperbilirubinemia plays an important role in facilitating the timely and appropriate prevention of disease within the first 14 days of birth.7,11 Clinical symptoms of hyperbilirubinemia are primarily seen in the head and face, and then affect the organs of the trunk and the limb due to increased serum levels of bilirubin. It is noteworthy that increasing hemoglobin release from breakdown of red cells due to high hemoglobin leads to jaundice at birth.12,13. This disease may also be due to decreased hepatic excretion of bilirubin.14,15 Since jaundice may have serious side effects on the health of infants, consideration should be given to its associated factors in newborns. Kernicterus is one of the most important diseases that complications of the disease are sometimes so dangerous. Considering the fact that jaundice is one of the common causes of hospitalization of newborns, attention can be paid to timely diagnosis and prevention of it. On the other hand, the rapid treatment of jaundice or timely prevention will be cost-effective in annual costs due to reduced hospitalization of newborns. To the best of our knowledge, the evaluation of the causes and risk factors of neonatal jaundice in newborns has not been comprehensively performed in Iran, while we are confronted with the spread of the disease among the newborns. Therefore, it is advisable to have a systematic and effective program for evaluation of causes and risk factors of jaundice in newborns. Prevention of jaundice risks requirs extensive and accurate analyses that should be continuously and repeatedly peformed. The present study was set out to assess the effects of maternal factors on neonatal jaundice with the aim of determining modifiable risk factors to reduce occurrence and consequences of severe jaundice in newborns.
Materials and Methods
All ethical principles of the Helsinki II declaration were followed. Newborns’ parents were informed and written consent forms were collected.
This cross-sectional study was performed on 2207 term newborns (<15 days) with hyperbilirubinemia (>15 mg/dl), who admitted to the neonatal intensive unit of the Ziaeean and Imam Khomeini Hospitals, Tehran, Iran, from April 2010 to May 2016. The records of all infants in terms of the maternal risk factors for neonatal jaundice have been investigated. Neonates born with jaundice in the birth admission were selected based on the neonatal outcome indicator. Data were obtained from medical records and interview sessions with the mothers by study staff. A checklist consisting of maternal demographic data and other data was provided for collecting data. Maternal information
Maternal information, including maternal age during pregnancy (over 35 and under the age of 18), first pregnancy, number of pregnancy, inter-pregnancy intervals of 3 years, type of delivery, Oxytocin Induction of labor, premature rupture of membranes (PROM), prolonged labor, cesarean section, multiple birth in the current pregnancy, respiratory rate during pregnancy, number of heart beats during pregnancy, maternal weight during pregnancy, body mass index, losing weight during pregnancy, history of abortion, were obtained from all mothers.
Inclusion criteria: Getting jaundice.
Exclusion criteria: Exclusion criteria included incomplete medical records that were beyond the control of the researcher; however, the additional sample size was considered to be about 20%.
Sample size calculation
An additional 20 percent sample size was added to prevent loss and withdrawal. p = first pregnancy as previously described.24,25 The sample size was finally calculated as 200. The data were subsequently collected and entered in the questionnaire, followed by statistical analysis based on SPSS software version 19. the obtained data was entered into cod sheet and master sheet. Qualitative variables were presented as frequency, while quantitative variables were calculated as mean, range, and standard deviation. Chi-square test was applied to examine qualitative data, while quantitative data were statically analyzed by T-test, p < 0.05 was considered statistically significant.
Results and Discussion
A list of maternal data is provided in Table 1. Regarding the mean age of the mother, the maternal age was significantly associated with different levels of bilirubin (p = 0.02), indicating a significant correlation of maternal age with incidence of jaundice. Maternal weight, and BMI showed also significant differences among different levels of bilirubin (p = 0.001; p = 0.01). As matter of fact, our findings suggest that the aforementioned variables were associated with neonatal jaundice. Respiratory rate at delivery, maternal heart rate and height had a significant difference at various levels of bilirubin, and were found to be linked to incidence of jaundice (p = 0.44; p = 0.85 p = 0.19). Table 2 shows the association of some maternal blood factors with jaundice. The statistical analysis revealed that maternal WBC, PLT and Hb had a significant relationship with jaundice (p = 0.001; p = 0.001; p = 0.04), but maternal MCV, and HCT did not show significant correlation with bilirubin levels (p = 0.77; P = 0.88). There is a significant difference in terms of birth in the first pregnancy among neonates with different levels of bilirubin (p = 0.01; Table 2). Our findings also indicate that the numbers of pregnancies were more likely to be referred for bilirubin levels (p=0.00; Table 3). In addition, interpregnancy interval of less than 3 years was not found to be linked to hyperbilirubinemia (p= 0.9; Table 3). Table 4 shows that 30.1% of infants in the first maternal delivery had a bilirubin level of 10 to 14.9, followed by bilirubin levels of 15-19.9 (58.1%) and bilirubin levels of 20-24.9 (33.3%). Table 4 demonstrates that 38.7% of natural childbirth (Vaginal delivery) was categorized to the bilirubin level, where ranged from 10-14.9; while the bilirubin level in the range of 15-19.9 mg/dL was attributed to a frequency of 54.8% ; Furthermore, bilirubin values ranged from 20-24.9 mg/dL in 33.3% of neonates. The delivery mode was not associated with the incidence of hyperbilirubinemia (p = 0.2; Table 4). Regarding to oxytocin infusion, there was no significant difference between oxytocin infusion and disease incidence (p = 0.5; Table 4). According to the data of this study, there was a significant relationship between prolonged delivery and the incidence of neonatal jaundice (p= 0.03, Table 4). Moreover, 46.6% of infants, who showed premature rupture of membranes (PROM), had a bilirubin level in the range of 10-14.9 mg/dL, followed by bilirubin levels in the range of 15-19.9 (61.3%) and 20-24.9 mg/dL (33.3%). No association was found between PROM and different levels of bilirubin (p = 0.2, Table 4). Om the ther hand, neonates with different levels of bilirubin had no significant difference in maternal cesarean section (p = 0.1, Table 5). As shown in Table 5, 16% of infants delivered by a multiple pregnancy showed a bilirubin level between 10-14 mg/dL. 10-14.9; while the bilirubin level in the range of 15-19.9 mg/dL was attributed to a frequency of 6.5% and bilirubin values ranged from 20-24.9 mg/dL in 0% of neonates. It is noteworthy that no significant difference was found between twins and disease incidence among neonates with different levels of bilirubin (p= 0.2). The history of abortion did not show a significant relationship with the incidence of disease (p = 0.2; Table 5).
Jaundice is a complication that may lead to death in the first month of birth and infants who are still alive suffer from many disorders including mental retardation (Intellectual disability), mobility and balance disorders, seizures, hearing loss at high frequencies, and speech impairment. Protecting and promoting the health of infants as a vulnerable group in the health services has a special place. Therefore, evaluation of neonatal jaundice in health care services should always be considered as a fundamental policy. Nearby, early detection of its risk factors can be effective in preventing disease in high-risk mothers-infants. Our study showed that maternal age, weight, BMI, WBC, Hb, PLT, birth in the first pregnancy, numbers of pregnancies and prolonged delivery were significantly correlated with bilirubin levels. Maternal age was found to be statistically significant in statistical analysis. Srivastav et al., found higher serum bilirubin levels in neonates of younger mothers.16 A previous study has also suggested that maternal age ≥30 years can be linked to increased risk for neonates.17 Another study by Özdek et al. demonstrated that mothers who have more weight than the advised amount may be at risk of neonatal jaundice.18 Conversely, many studies have reported that this variable was not correlated with hyperbilirubinemia.19,20 In the present study, the mean age of mothers in patients was determined as 28.8 years (Maximum: 43 years; Minimum: 17 years). Based on the findings, the mean age of mothers in newborns with moderate jaundice was lower than other forms of disease and the most cases of jaundice were observed in the first pregnancy (34.5%, 69 cases). In other studies, CBC level and its related parameters have not been studied in the mother. One of the strengths of this study is to examine the level of maternal blood parameters. It seems that the levels of WBC, Hb, and PLT have a significant correlation with the incidence of neonatal jaundice. However, it was found that that there was not an increasing risk for neonatal jaundice with maternal MCV, and HCT. Nevertheless, conversely, a study indicated that maternal haemoglobin was not demonstrated to affect the bilirubin levels in physiological jaundice.19 Further studies are needed to clarify the role of blood factors mentioned in the current study. Our finding suggested that birth in the first pregnancy, numbers of pregnancies and prolonged labor could be important risk factors in current study population. In our study population, some factors such as delivery mods, twins, interpregnancy interval of less than 3 years were found to be associated with neonatal jaundice. In agreements with previous studies, there was no an increasing risk for neonatal jaundice with the delivery mode, where was not correlated with the incidence of hyperbilirubinemia.
It has been previously reported that mode of delivery could be liked to jaundice and its severity 19,20-24 Contrary, it has been previously revealed that naturally delivered subjects are likely to be at higher risk for neonatal jaundice, when comparing with those born by cesarean section, indicating the importance of delivery mode as a risk factors for jaundice.25,26 The conflicting findings could be linked to types of variables, types of study, sample size and study condition, where can affect to data analysis. On the other hand, no significant difference was found between oxytocin infusion and disease incidence, while oxytocin is involved in bilirubin metabolism and has been described to be a risk factor for the development of neonatal jaundice, induction of labor with oxytocin may associated with hypoosmotic and lytic effects (increased red blood cell lysis), resulting in hyperbilirubinemia 26-28. However, it is recommended that this factor be assessed with a higher sample size. Excessive application of oxytocin during labor and cesarean section have been defined as risk factors.25, 26 In the present study, cesarean section was not found to be associated with hyperbilirubinemia. Hyperbilirubinemia might be exacerbated by cesarean section, in comparison to natural births 11. On the other hand, mode of delivery has been not found to be significantly associated with incidence of hyperbilirubinemia.29 As mentioned in results, prolonged labor remained obviously linked to neonatal jaundice in our study population. In consist with the current study, Scrafford, et al, reported a significant association of prolonged labor with jaundice, possibly the clinical relationship between longer labor and cephalohematoma may play a role in this event.10,30 Furthermore, no significant association was found between PROM and neonatal jaundice, however PROM has been described to affect some of the parameters involved in the health of fetuses and infants, such as neonatal jaundice, platelet parameters and erythrocyte parameters 31, Further evaluation are required to clarify the role some of mentioned variable that were not showed correlation with neonatal jaundice. Twins was not important risk factors in the current study, several reported risk factors were not found in the current study to be correlated with jaundice in neonates such as twins 32-35. As matter of fact twins was found to be correlated with hyperbilirubinemia in some investigations, but we did not find such association in our studies. In consist with our study, Scrafford et al. did not demonstrate correlation between twins and hyperbilirubinemia.10 The number of multiple births was very low in the current study (N=28), whereas caution should be observed in its interpretation; thereby, may reduce the statistical power for determining the statistically strong association between twins and jaundice in newborns.10 Preventing the risk correlated with maternal factors or identifying neonates with these risk factors is firstly important in effective management of infants, which can be taken into account by improving maternal and public health education.10, 36, 37.
The findings of this study indicated that there is a need for more epidemiological studies on characteristics of infants, and identifying the risk factors for hyperbilirubinemia. The history of abortion stillbirth or abortion did not show a significant relationship with the incidence of disease. History of stillbirth or abortion has been previously reported to be associated risk factor for neonatal hyperbilirubinemia,38,39 which are in agreement with our study. Further assessment of community-based detection of abortion history should be investigated in neonates. In future studies, the variables should be further evaluated in higher sample size. Finally, in order to promote health of infants, evaluation of neonatal jaundice should always be considered at all levels of health services.