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From Pediatric Critical Care Medicine Does Gender Affect Neonatal Hyperbilirubinemia in Low-Birth-Weight Infants?

Jennifer A. Tioseco MD; Hany Aly MD; Josh Milner MD; Kantilal Patel PhD; Ayman A. E. El-Mohandes MD, MPH

Abstract Background: Neonatal mortality and morbidity are gender-biased in low-birthweight (LBW) infants. The male disadvantage theory has been suggested to be responsible for these maturational differences.

Objective: To examine the impact of gender on neonatal hyperbilirubinemia.

Design/Methods: A retrospective observational study. Data on all LBW infants admitted to George Washington University neonatal intensive care unit and surviving for > 48 hrs from January 1992 to March 2003 were analyzed. Males and females were compared for gestational age, birth weight, race, Apgar scores at 1 and 5 mins, peak bilirubin levels, sepsis, and intraventricular hemorrhage (IVH). Significant differences were entered in a regression model to detect the influence of gender on bilirubin (Bili). Analysis was repeated after stratification of infants into: group A, < 1000 g; group B, 1000-1499 g; and group C, 1500-2499 g.

Results: A total of 840 infants were included in this study. When comparing males (n = 407) with females (n = 433), significant differences were detected in birth weight (1,539 ± 541 vs. 1,428 ± 549 g; p = .003), IVH (14.2% vs. 9%; p = .025), and Bili (10.1 ± 3.0 vs. 9.2 ± 2.8 mg%; p < .001). No differences were detected in gestational age, sepsis, or Apgar 1 and 5. Difference in Bili for the entire group remained significant in the regression model (regression coefficient [RC] = 0.79 ± 0.22; p < .001). In subgroup analyses: group A Bili (8.4 ± 2.3 vs. 8.0 ± 2.0; p = .14) and group B Bili (9.0 ± 2.1 vs. 9.2 ± 2.2; p = .51) did not differ in bivariate or multivariate analyses. In group C, Bili was (11.3 ± 3.1 vs. 10.1 ± 3.3; p < .001) and remained the only significant difference in the regression model (RC = 1.19 ± 0.37; p = .001). Conclusions: Bili in LBW infants is significantly higher in males when compared with females. After stratification to birth weight subgroups, significance is retained in the 1500- to 2499-g group after logistic regression analysis. Bili levels in infants < 1500 g are influenced more significantly by factors other than gender, such as sepsis and IVH.

Recent studies have estimated incidence of 6% to 10%[1. Apgar scores . race. conjugation.[1. NC). We also examined the strength of this correlation after stratification of the population into various weight subcategories. In this study. sepsis. and sepsis. race.[12] Whether this gender bias is still pertinent for hyperbilirubinemia in the lower-birth-weight categories is a question that remains unanswered. neonatal sepsis. there are a couple of studies that do not show this relationship. Data on gestational age (GA). instrumental delivery. Different clinical entities presenting with neonatal jaundice include physiological jaundice. and is in compliance with the new Health Information Privacy and Portability Act (HIPAA) regulations. Apgar scores.9-11] The Ychromosome effect has been suggested to be responsible in general for the male disadvantage in mortality and morbidity of premature infants. Univariate analyses were done to compare the two groups regarding GA. Methods Patients and Design This retrospective observational study was approved by the Institutional Review Board at the George Washington University Hospital.[5-8] Although most previous studies on this issue favor an increased incidence in males. and oxytocin use during labor. peak serum Bili levels.Introduction Neonatal hyperbilirubinemia is a commonly diagnosed phenomenon in the neonate with potential serious consequences. birth weight (BW). bruising. including gestational age. All LBW infants admitted to the neonatal intensive care unit (NICU) from January 1992 to March 2003 and who survived beyond the first 48 hrs of life were included in the study. immaturity. Asian race. Apgar scores. and IVH were collected from the hospital records and entered into a local database. low birth weight. epidural anesthesia. intraventricular hemorrhage (IVH).[4] Common clinical risk factors associated with neonatal jaundice include prematurity. or genetic deficiency of enzyme systems among others. and excretion cause this transitional elevation during the neonatal period. BW. previous sibling with a history of jaundice. breast feeding. blood group iso-immunization.[3] The pathophysiology of this condition may vary according to the etiology. Bili levels were compared between the two gender groups using a two-tailed t -test.2] in the general population. Statistical Analysis Statistical analyses were performed using the SAS software (Cary. Alterations in the equilibrium between bilirubin (Bili) production. we investigated the correlation of peak Bili levels with gender in a population of low-birth-weight (LBW) infants while controlling for variables that influence Bili production and metabolism.5-7.

001).[12] This male disadvantage or the Y-chromosome effect has been postulated to be responsible for these differences. Variables that differed significantly between the two groups were identified and entered into a logistic regression model to detect the influence of gender on Bili levels.79 ± 0. Bili was significantly higher in males in group C ( p < . After controlling for race. a higher metabolic rate in the male fetuses may be another contributing factor. GA. p < . and C are shown in Table 1 .at 1 and 5 mins. and group C. 407 males and 433 females. There were no differences in GA or Apgars at 1 and 5 mins. reports continue to demonstrate higher rates of morbidity and mortality in males. significant differences were detected in BW.9% vs.001) and remained significant after controlling for confounders in regression analysis (regression coefficient = +1.22. B. sepsis. < 1000 g. Characteristics of the study population are shown in Table 1 . BW. females were significantly lower in BW. Mortality rate in males was significantly higher than females (7. and Bili.14 and . respectively). and only two infants had a documented elevated direct bilirubinemia during their hospitalization. respectively. and IVH. and Table 7 . Dysfunction of the placenta can be a factor. Table 6 .51. As expected. Despite technologic advances in neonatal medicine such as the use of surfactant and improved ventilators and ventilation strategies. Table 4 .37. IVH.[16] In addition. Fourteen infants required exchange transfusion (six males and eight females). Table 5 . These analyses were repeated after stratifying subjects into three BW subcategories: group A. Discussion Many clinically observable differences have been reported to be subject to gender bias in the newborn: Apgar scores. respiratory distress syndrome. group B. When comparing males with females. were included in the study. p < .001). IVH. In BW stratified analyses. the increased Bili in males remained significant (regression coefficient. No significant differences in Bili were detected between genders in groups A and B ( p = . and IVH in a multiple regression model. Table 2 . Results A total of 885 infants were born during the study period. 1000-1499. This theory is enforced by the fact that XY blastocysts and embryos grow at an accelerated rate when compared with XX chromosome bearers. The prevalence in IVH was significantly lower in females as was Bili. + 0. as described in association with male fetus pregnancies.3%. 1500-2499 g. There was a trend toward a lower incidence of sepsis in females. ie. and urinary tract infection .[17] An inverse relationship . pulmonary disease. although the difference did not reach statistical significance.001). 2. Forty-five infants did not survive beyond the first 48 hrs and were excluded from the analysis. Table 3 .19 ± 0.[13-15] The role that various gender-biased biologic mechanisms contribute to the observed male disadvantage can only be speculated. p = . the characteristics of groups A. sepsis. A total of 840 LBW survivors.

The study has some limitations because it did not correlate peak Bili levels with initiation and type of feed.4%. In the smaller-weight categories. these differences cannot alone explain the difference in Bili because they were controlled for in the logistic model. albeit with a new application.001). The incidence of IVH in males was strikingly increased in group A (33. and elimination of serum bilirubin in the LBW male newborn. it may play a protective role against oxidative stress and in males may be physiologically beneficial. the analyses indicate that other risk variables such as sepsis and IVH may supersede gender in influencing Bili. whereas females only at a rate of 5% ( p < . early use of phototherapy could have potentially obscured larger differences within the lower-weight groups. In addition.025). males died at a rate of 2% compared with 0% in the female cohort ( p < . When stratified into three BW groups. However. Although higher Bili in the hospitalized LBW male infant may be a reflection of various maturational and genetically determined pathophysiological characteristics.5%.2% vs.[19. similarly in infants between 1000 and 1499 g.between lifespan and metabolic rate has been established and may reflect significant differences in associated physiological mechanisms[18] Nonetheless.9% vs. Deficiency in enzyme system maturation or secondary effects resulting from higher acuity of illness in newborn males may influence the generation. or with the use of . 9%. may appear clinically trivial. the prevalence of IVH grades III and IV was higher in males when compared with females (3. p = . 1.9% and 1. metabolism. such an effect can only be supported in the future through the analysis of a more comprehensive data set. male infants <1000 g died at a rate of 27%. p = . In our study. p = .5% for females ( p = . More of the sicker males may have died in the first 2 days curtailing their opportunity to demonstrate their peak Bili levels.033) and group B (19. The small difference in Bili noted between male and female infants. 1500-2499 g). there is no proposed mechanism that specifically addresses the male vulnerability to increased bilirubin levels.3% vs. As demonstrated by the results of this study. 19.0001). Similarly. p < . the difference in Bili remained significantly higher only in the larger BW category (weight. One of the findings in the analysis of our population was the significant difference in the prevalence of IVH in males when compared with females (14.001). The differences in Bili in the smaller-weight categories could also have been influenced by the discrepancy in mortality rates between males and females. and there is no concrete evidence to support these theories. 4%. This study demonstrates a higher peak serum Bili in male LBW infants.5). Nonetheless.20] Unfortunately. These differences were not remarkable for the weight group =1500 g in which male mortality was 0.029). serum Bili is not an exception to the rule. namely the super-female newborn. The difference in IVH prevalence is worth further analysis and could be attributed to differences in severity of illness in the male group.1% vs. the results of this study rekindle the interest in a topic studied in the past. although statistically significant.

This is especially true in the lower-weight categories that have not been available for adequate investigation in the past. gender influences on neonatal illnesses and outcomes should remain a topic of debate and investigation. In summary. The value of this current study is in its role in completing a larger and more complicated jigsaw puzzle. It would have also been beneficial to determine whether differences in serum albumin concentrations existed between male and female newborns. hematocrit levels were not controlled for in this study. Moreover. . Physiological and pathologic phenomena associated with male gender must be integrated in the frame of understanding of both susceptibility and protection of the male newborn. hence impacting on the potential susceptibility of the central nervous system to the effects of elevated serum Bili levels. but it is unlikely that caregivers were influenced by gender in their management of these infants.phototherapy.