PRENATAL FACTORS FOR NEONATAL JAUNDICE

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INTRODUCTION:
Neonatal jaundice (NJ) is a visual manifestation of yellow coloration of the skin, mucous membranes and sclera of the newborn (NB) due to increased levels of total bilirubin (BR) [1,2]. Demographic, environmental and genetic factors have been identified as being at risk of developing severe neonatal hyperblirubinaemia (HB) [3]. Prenatal, intranatal, and postnatal effects may influence the evolution of NJ. Mother's knowledge, attitude, and behavior about the various aspects of NJ are significantly better in older than in younger women and significantly better with increasing birth rates, as well as in mothers with higher levels of education [4].

PURPOSE:
To establish the role of prenatal factors (sequence of pregnancy and childbirth, history of NJ in siblings and diseases during pregnancy) for the manifestation of NJ in NBs.

MATERIAL AND METHODS:
The study is retrospective, includes 566 mothers and their full-term infants who were patients of the Department of Obstetrics and Department of Neonatology of University Hospital Medica Ruse, Bulgaria, from January 2017 to October 2020. Data on the pathology of pregnancy were obtained from the documentation submitted in admission and medical history. Data on the manifestation of NJ are derived from the medical history of NBs. A transcutaneous measurement of total BR with a bilirubinometer KJ-8000 was performed as follows: from about 12th postnatal hour daily until discharge, on the 12-14th and 28th-30th postnatal day. Patient'spersonal data and test results were stored, processed, and presented in accordance with the Personal Data Protection Act.
The statistical processing was performed using the statistical processing program IBM SPSS Statistics version 23 and spreadsheet program, part of the MS Office package -Microsoft Excel version 2016. For the significance level, which rejects the null hypothesis, p≤0.05 was chosen. https://doi.org/10.5272/jimab.2022284.4660

RESULTS:
The age distribution of mothers is shown in Table  1. Significantly higher levels of BR from the second to the fifth day (p=0.022, p=0.016, p=0.006, p=0.055) were registered in the group of mothers aged ≤20 years. We proved a statistically significant inverse weak linear re-lationship between the levels of BR on the second day in NBs and the age of the mother (r (362) = -0.112, p=0.033). No difference was found in the levels of BR in NBs when compared based on marital status, educational qualifications of the mother and place of residence. (Table 1, Fig. 1). A moderately strong association was found between the history of NJ in siblings and the presence of HB in the next NB. Spearman rank correlation coefficient was calculated: Table 2. Maternal diseases during pregnancy (*p≤0.05;R² -coefficient of determination) (r› )-r› (98)=0.227, p=0.025. NB with previous siblings with NJ required phototherapy in 59.8% of cases, while those without such history -only in 29.5%. 71.9% of NBs were first born children. They had significantly lower BR levels on the fourth postnatal day (155.30±33.0 µmol/L) compared to those from second or consecutive births (163.7±30.9 µmol/L, p=0.037). Despite the established difference, the need for phototherapy in both groups was similar -46.2% and 49.1%, respectively. Multifactorial linear regression analysis between BR levels in NBs and pregnancy sequence, birth sequence and history of HB showed significant values on the second (R², 8.90%; p=0.032) and fourth postnatal day (R², 8.2%; p=0.040).

Fig. 2. Mean level of total bilirubin values in newborns (µmol/L) according to a history of NJ in the previous sibling
Pathology of pregnancy with imminent premature birth in the last trimester, which required hospital treatment, was registered in 5.1% of mothers (Table 2). 34.6% of these mothers gave birth of children with HB. Mean BR values of these NB were significantly higher than in the other groups on the second (156.1±39.7 µmol/L) and third (174.2 ±47.6 µmol/L) postnatal day. The correlation between HB in NB and pathology with imminent premature birth is weakly positive (2nd day: r(360)=0.115, p=0.029; 3rd day: r(468)=0.103, p=0.025). (  Fig. 3. Mean level of total bilirubin values in newborns (µmol/L) according to maternal diseases during pregnancy.
Mothers who received therapy during pregnancy due to established hypertension or Preeclampsia consist 8.5% of the group. Their children have a lower incidence of HB (33.3%).
Pathology of the thyroid gland requiring thyroid hormone replacement therapy was found in 7.2% of the mothers. The incidence of HB in this group was 39%. We proved a statistically significant weak negative linear relationship between both indicators on the first day (r=-0.140, p=0.027).
2.8% of mothers suffered from urinary system pathology during pregnancy (hydronephrosis, calculosis, renal colic). HB was observed in 48.1% of their NBs. The correlation analysis showed a weak positive relationship between renal pathology during maternal pregnancy and the manifestation of HB in NB (r=0.116, p=0.014 on day 5).
Anemic conditions requiring treatment were found in 4.8% of the mothers, and 37% of their children suffered from HB. A weak negative correlation was observed between maternal anemic conditions during pregnancy and HB of NBs(r=-0.089, p=0.027 on day 3; r=-0.112, p=0.051 on day 5). No significant difference was found in mean bilirubin levels in newborns of anemic mothers (Fig.3), although they were lower compared to the other groups.
Inflammatory diseases of the female reproductive system, requiring systemic and local antimicrobial treatment, have been documented in 3% of cases. The NBs of these mothers had significantly higher BR levels on the third postnatal day (p=0.023). The performed correlation analysis showed a weak positive relationship (r=0.114, p=0.007 on the third day).

DISCUSSION:
The relationship between maternal age at birth and the occurrence of neonatal HB is insignificant, according to some studies [5]. Younger mothers, especially those under the age of 20, represent a higher risk of HB for their NB compared to the rest of the population [6]. Our study also demonstrated an inverse correlation between maternal age and BR levels in NBs.
According to our data, the mother's demographics (place of residence, marital status and education) are not related to the incidence of HB in their NBs. The organization of healthcare in Bulgaria assumes that births take place in hospitals, as the latter is available to all patients, and the newborns are monitored during the first three days in neonatology units.
There is a slight correlation between BR levels and maternal parity [5]. In our group of patients, the share of those born from the second or subsequent pregnancy is 1/ 3 of the total, and from the second or subsequent birth, slightly less than 1/3. We found significantly higher levels of total BR in children born from second or consecutive birth. However, the sequence of pregnancy did not correlate with bilirubin levels.
In NBs, whose larger siblings suffer from HB (BR>205 µmol/L), the risk of developing HB was 3.1 times higher. If the previous sibling expressed significant HB (BR >257 µmol/L), the risk in the next child increases to 12.5 times [7]. Najib K, et al. puts the history of severe HB in previous siblings in second place as a risk factor for the development of NJ [8]. A Danish study of a large number of births (19809) found a significant correlation between the incidence of NJ and peak levels of BR in siblings [9]. We found a moderate correlation with higher mean levels of BR and a higher proportion of phototherapy in NB whose older siblings had NJ.
Preeclampsia hypertension and Preeclampsia during pregnancy often lead to NJ (4.7-19%) because high maternal blood pressure is an important factor for premature birth and premature babies are at high risk of developing jaundice due to hepatic immaturity and polyglobulia [12]. On the other hand, Preeclampsia stimulates the maturation of the fetal liver function. Therefore, full-term infants born to mothers with such pathology expressed lower levels of BR.
Uncontrolled maternal hyperthyroidism in the second half of pregnancy can lead to transient central hypothyroidism in NB [13]. Most, if not all, cases of transient congenital hypothyroidism are due to maternal autoimmune thyroid disease [13]. We did not find a difference in bilirubin levels in the NB of mothers treated for thyroid pathology; all mothers were in a euthyroid condition at birth. We registered a child with transient hypothyroidism who suffered from prolonged NJ. Íis mother had elevated antithyroglobulin antibodies.
Anemia in pregnant women is a high-risk factor for the pathological course of HB in NBs [14]. High doses of iron supplementation in pregnant women increase the incidence of physiological jaundice in NBs [15].Excess of iron influences hemoxygenase-1, which is responsible for converting heme to biliverdin. The latter, in turn, becomes BR and may increase the likelihood of NJ [16].
Delayed umbilical cord clamping is associated with increased iron transfer to the NB and also increased NJ frequency [17]. Children of anemic pregnant women in our group did not suffer more often from severe jaundice, which indicates adequate therapy. A weak negative correlation was observed between the presence of anemia in pregnant women and HB in the NB.
Manifestation of maternal infection during pregnancy is strongly associated with neonatal HB [5]. Premature rupture of the amniotic membranes is a significant factor in the manifestation of NJ [17,18], and 2.7% [13] of NJ cases are explained by it. Newborns whose mothers had an infection during pregnancy are more likely to suffer from NJ [19]. The incidence of NJ in such neonates is 3.45% [12] -4% [20]. We reported a higher than average incidence of hyperbilirubinemia in children of mothers with inflammatory diseases of the female reproductive system (58.8% of NBs in this group), urinary system pathology (48.1% of NBs in this group) and infectious pathology (48.2% of all inflammatory diseases during pregnancy).

CONCLUSION:
According to our data, prenatal factors that may increase the incidence of NJ and BR levels in NB are parity, the history of jaundice in siblings, the younger age of the mother. Inflammatory diseases of the female reproductive system affect the severity of neonatal bilirubinemia, and pathology of the urinary system increases its frequency. Well-controlled thyroid function, as well as balanced iron supplementation of the pregnant woman, contribute to a better balance of neonatal BR metabolism. Preeclampsia and hypertension during pregnancy decrease the rate of HB in full-term infants.