Phenobarbital is Associated with Cholestasis in Low Birth Weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus

Phenobarbital is Associated with Cholestasis in Low Birth Weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Phenobarbital is Associated with Cholestasis in Low Birth Weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus Xintian Shen, Yie Huang, Haibo Peng, Ping Zhou, Lin Hung-Chih This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1599063/v3 This work is licensed under a CC BY 4.0 License Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Abstract Objectives This retrospective study aimed to assess whether phenobarbital was associated with cholestasis in low birth weight (LBW) infants with hemo-dynamically significant patent ductus arteriosus (hsPDA). Methods This study included 148 LBW infants (24 ~ 34 weeks, birth weight < 2000 g) diagnosed with hsPDA, admitted to a level III neonatal intensive care unit (NICU) from September 2016 to September 2019. Of the 148 infants, twenty infants were diagnosed with cholestasis. To assess the independent association with cholestasis or direct bilirubin, binary logistic or multivariable linear regression was done, adjusting for major confounders (birth weight, gestational age, critical risk index for babies, invasive mechanical ventilation, any sepsis onset in 28 days and etc). Result Binary logistic regression analysis was done adjusting for 12 related confounders. The “delay of full enteral feeding” was still associated with “duration of phenobarbital” (DOP) (OR: 1.571; P = 0.015) or “duration of phenobarbital before cholestasis onset” (DOPBCO) (OR: 1.662; P = 0.014). Cholestasis was still associated with “DOP” (OR: 1.553; P = 0.005) or “DOPBCO” (OR: 1.353; P = 0.088). “High direct bilirubin peak” (> 1.5 mg/dl) was still associated with “DOP” (OR: 1.686; P = 0.003) or “DOPBCO” (OR: 1.511; P = 0.021). Multivariate linear regression revealed that “persist time of cholestasis” was associated with “DOB” (B: 2.254; P = 0.050) after adjustment of “delay of full enteral feeding”. Conclusion This study found that phenobarbital was associated with neonatal cholestasis in LBW infants with hsPDA. Phenobarbital should be used cautiously in this population. neonatal cholestasis phenobarbital patent ductus arteriosus low birth weight infants Figures Figure 1 Key Points Controversy of phenobarbital exists in treatment of cholestasis in neonatal intensive care unit. This study found that phenobarbital was associated with cholestasis in low birth weight (LBW) infants with hemo-dynamically significant patent ductus arteriosus (hsPDA). Phenobarbital should be used cautiously in this population. Introduction Phenobarbital has been extensively used in neonates for treatment of seizure, hypoxic ischaemic encephalopathy (HIE), and prophylaxis of intraventricular hemorrhage (IVH). Phenobarbital is still the first-line therapy for neonatal seizures, because of extensive clinical experience, despite limited clinical effectiveness and potential neurotoxicity [ 1 – 3 ]. Furthermore, phenobarbital is used in combination with therapeutic hypothermia for seizure control and neuroprotection in neonates with HIE. The neuroprotective benefits of phenobarbital have been described in animal [ 4 ] and clinical studies of HIE [ 5 ]. Postnatal administration of phenobarbital is also used to prevent IVH in low birth weight (LBW) infants, whereas is associated with an increased need for mechanical ventilation [ 6 ]. Notably, phenobarbital is also used in treatment of hyperbilirubinemia, cholestasis and its complication, pruritus. Phenobarbital regulates constitutive androstane receptor (CAR) and/or the pregnane X receptor (PXR), which further regulates hepatocellular metabolism enzymes and transporters, including UDP-glucuronosyltransferase (UGT1A1) and multidrug-resistance-associated protein 2 (MRP2) [ 7 – 9 ], responsible for the detoxification of bilirubin. Phenobarbital is reported to reduce the serum bile acid in cholestasis [ 10 ]. Furthermore, phenobarbital improves neonatal unconjugated hyperbilirubinemia in the liver [ 11 ]. Phenobarbital also increases the accuracy of hepatobiliary scintigraphy by enhancing bile isotope excretion [ 12 ]. Case reports indicated that phenobarbital is useful for treatment of Dubin-Johnson syndrome with conjugated hyperbilirubinemia [ 13 , 14 ], which is caused by deficit of MRP2 [ 15 ]. Additionally, phenobarbital is useful in controlling cholestatic pruritus in children [ 16 ]. Controversially, growing evidences suggest that phenobarbital may aggravate neonatal cholestasis. A study found that 60% of phenobarbital-treated infants developed parenteral nutrition (PN) associated cholestasis, as compared to 33% of the untreated patients[ 17 ]. A retrospective cohort study suggested that phenobarbital has limited efficacy for the reduction of direct bilirubin in neonates and young infants with cholestasis in the neonatal intensive care unit (NICU), and advocated to avoid phenobarbital in the treatment of neonatal cholestasis [ 18 ]. Additionally, case reports indicated phenobarbital can aggravate the cholestatic bile acid pattern in infants with cholestasis [ 19 ]. Interestingly, some evidences indicate hemo-dynamically significant patent ductus arteriosus (hsPDA) is associated with increased risk of cholestasis in LBW infants. An epidemiological study with multiple logistic regression analysis identifies that patent ductus arteriosus (PDA) is an independent risk factor for PN associated cholestasis in infants [ 20 ]. Neonates with cholestasis is associated with hsPDA (76.9% vs 42.4%, P = 0.04) than neonates without cholestasis [ 21 ]. Our previous study found that LBW neonates with hsPDA is associated with increased risk of cholestasis than neonates without significant PDA (19.0% vs 3.4%, P = 0.007), this result is still significant even after adjustment with multiple logistic regression (OR: 6.730; P = 0.024) [ 22 ]. Therefore, this retrospective cohort study aimed to explore whether phenobarbital was associated with cholestasis in LBW infants with hsPDA. Materials And Methods Study design In this study, LBW infants (24~34 weeks, birth weight<2000 g) diagnosed with hsPDA, admitted to the NICU of our hospital in 48 hours after birth between September 2016 to September 2019, were included. Clinical and demographic data were collected from medical records of the patients until discharge. Exclusion criteria were as follows: malformations, genetic defects, severe asphyxia (defined as a blood pH<6.8), admitted to NICU at ≥48 hours of postnatal age, hospital stay <21 days, and death or abandon rescue. Finally, a total of 148 LBW infants were included in the analysis (Fig. 1). If there were any signs of cardiomegaly or pulmonary edema on chest radiograph, respiratory difficulty, hypotension, decreased urine output or metabolic acidosis suggesting hsPDA, we checked the echocardiography for the confirmation of hsPDA, which was defined as a PDA with a transductal diameter ≥1.4 mm/kg with significant left to right shunt[23, 24]. Feeding protocol Enteral feeding was started mostly on the first day of life at 10-20 ml/kg/day divided into 8 meals with own mother’s milk or donor milk. Human milk fortifier was added when enteral feeding reached 80-100 ml/kg. Aspirate residual from an orogastric tube and abdominal aspect were checked before each meal. In the absence of signs of feeding intolerance for 24 hours, enteral feeding was increased daily by 10~20 ml/kg. Enteral nutrition was discontinued in the case of erythematic abdominal wall, absence of bowel sounds, blood in the stools, or bile or blood in aspirates associated with a radiologic marker of NEC-Bell stage II. PN was maintained through a central line in all infants to ensure adequate intake of fluids, electrolytes, and nutrients until full enteral feeding was reached. Iron was supplemented orally according to recommendations. PN solutions Common PN solutions for LBW infants were composed of Sodium Glycerophosphate Injection (Glycophos, Fresenius kabi sspc), 10% and 50% glucose injection, 10% sodium chloride injection, 10% potassium chloride injection, Multi-trace Elements Injection (II) (Addamel, Fresenius kabi sspc.), Pediatric Compound Amino Acid Injection (19AA-I) (taurine included, China Resources Double-Crane Pharma.), Magnesium Sulfate Injection, Calcium Gluconate Injection, and 20% Soybean Oil, Fat Emulsions (Intralipid, Fresenius Kabi). Once neonatal cholestasis diagnosed, fat emulsion were replaced immediately with 20% Multi-oil Fat Emulsion Injection (SMOFlipid, Fresenius Kabi Austria GmbH) to protect the infants from cholestasis[25]. There was no change during the period of retrospective study in terms of new generation lipid emulsion, carnitine, taurine, etc. No cyclic PN had been adopted in included cases [25]. Outcome measures The main outcomes were neonatal cholestasis (conjugated hyperbilirubinemia, direct bilirubin ≥2 mg/dL and persistent duration ≥20 days, without other causes of hepatic dysfunction), persist time of cholestasis (days of direct bilirubin persisting above 2 mg/dl), direct bilirubin peak (the highest concentration of direct bilirubin) during hospital stay. Secondary outcomes were time to reach full enteral feeding and hospital stay. Data collection Data regarding gestational age, weight at birth, mode of delivery, multiple birth, sex, Apgar score, critical risk index for babies[26], presence of mechanical ventilation, time to reach full enteral feeding, time-to-discharge, occurrence of late-onset sepsis, NEC≥stage 2, were collected by researchers not in charge of the clinical management of the participants. Discharge was decided with criteria indicated by the American Academy of Pediatrics. Cholestasis associated risk factors were also recorded, including cytomegalovirus (CMV) infection during hospital stay. The drugs associated with cholestatic injury were scrutinized thoroughly in included cases, the usage of potential hepatotoxic antibiotics (such as ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin) and other potential hepatotoxic agents (phenobarbital and cimetidine)[27] were recorded as confounders. The presence of any sepsis onset (early or late onset sepsis clinically diagnosed or cuture-proven) in 28 days of hospital stay may affect the onset of cholestasis, therefore were recorded as confounders. Statistical analysis The Kolmogorov-Smirnov test was used to determine whether variables were normally distributed. For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test. For continuous variables of normal distribution, groups were compared with the independent-sample t-test. The chi-square test and Fisher’s exact test were used for categorical variables. To assess the independent association of treatment or duration of phenobarbital with the main outcomes and the secondary outcomes, binary logistic regression analysis was done, adjusting for indicated major confounders. The statistical analysis was done with IBM SPSS Statistics version 19.0 (IBM Corp., Amarok, NY, USA). P values less than 0.05 (2-sided) were considered statistically significant. Results 1. Main demographic and clinical characteristics of the study population Among 148 LBW infants (< 34 weeks, birth weight < 2000 g) with hsPDA, 20 infants were diagnosed with cholestasis (see Table 1 ). Cholestasis was associated with “small for gestational age” and “time to reach full enteral feeding”. The cholestasis diagnosed persisted for 20–107 days before discharge. Direct bilirubin peak reached 2.3–17.6 mg/dl during hospital stay. Table 1 Main demographic and clinical characteristics of the study population Characteristics before discharge No cholestasis (n = 128) Cholestasis (n = 20) P Direct bilirubin peak [mg/dl, M (P25, P75)] § 0.89(0.74, 1.17) 4.99(3.34, 9.16) 0.000 Direct bilirubin at dicharge [mg/dl, M (P25, P75)] § 0.51(0.29, 0.79) 3.06(1.78, 7.95) 0.000 Persist time of cholestasis [day, M (P25, P75)] § 0(0, 0) 45(30, 60) 0.000 birth weight(g, mean ± sd)† 1193.71 ± 308.11 1069.00 ± 233.33 0.085 gestational age(wk, mean ± sd)† 29.01 ± 2.07 28.83 ± 1.83 0.707 twins [n(%)]‡ 51 (39.8%) 10(50%) 0.391 male [n(%)]‡ 72 (56.3%) 13 (65.0%) 0.462 antenatal dexamethasone [n (%)]‡ 102 (79.7%) 13(65.0%) 0.239 cesarean delivery [n(%)]‡ 77 (60.2%) 9 (45.0%) 0.126 small for gestational age [n(%)]‡ 12 (9.4%) 6 (30.0%) 0.024 Apgar score at 1 min [M (P25, P75)]§ 8(7, 10) 9(8, 10) 0.333 Apgar score at 5 min [M (P25, P75)]§ 10(9, 10) 10(9, 10) 0.478 critical risk index for babies [M (P25, P75)]§ 7(5, 9) 8(6, 9) 0.130 time to reach full enteral feeding [days, M (P25, P75)]§ 21(14.25, 28) 35(25, 47) 0.000 invasive mechanical ventilation [n (%)]‡ 81 (63.3%) 16 (80.0%) 0.143 hospital stay [day, M (P25, P75)] § 65(51.5, 78.75) 72.5(65.25, 88.75) 0.021 †. For continuous variables of normal distribution, groups were compared with the independent-sample t-test. ‡. The chi-square test and Fisher’s exact test were used for categorical variables. §. For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test. 2. Possible cholestasis associated risk factors. CMV infection and necrotising enterocolitis during hospital stay were included as confounders. The drugs associated with cholestatic injury were scrutinized thoroughly, the usage of risk drugs (phenobarbital, cimetidine) and whether use the risk antibiotics (ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin) were recorded as confounders. Possible cholestasis associated risk factors are listed in Table 2 . Cholestasis was associated with duration of phenobarbital (DOP) and duration of phenobarbital before cholestasis onset (DOPBCO). Table 2 Possible cholestasis associated risk factors Risk factors No cholestasis (n = 128) Cholestasis (n = 20) P Phenobarbital [n (%)]‡ 61 (47.7%) 15 (75.0%) 0.023 DOP [days, M (P25, P75)] § 0 (0, 2) 1.5 (0, 4) 0.001 DOPBCO [days, M (P25, P75)] § 0 (0, 2) 1 (0, 3) 0.041 cimetidine [n (%)]‡ 6 (4.7%) 7 (35.0%) 0.000 duration of cimetidine [days, M (P25, P75)] § 0 (0, 0) 0 (0, 3) 0.000 whether use the risk antibiotics* [n (%)]‡ 27 (21.1%) 6 (30.0%) 0.548 CMV infection [n (%)]‡ 1 (0.8%) 3 (15.0%) 0.004 necrotising enterocolitis [n (%)]‡ 1 (0.8%) 2 (10.0%) 0.062 any sepsis onset in 28 days [n (%)]‡ 38 (29.7%) 12 (60.0%) 0.008 ‡. The chi-square test and Fisher’s exact test were used for categorical variables. § .For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test.. * The risk antibiotics included ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin; DOP, duration of Phenobarbital; DOPBCO, Duration of Phenobarbital before cholestasis onset; CMV, cytomegalovirus; 3. Exploring factors and confounding factors associated with phenobarbital Phenobarbital was associated with factors “cholestasis”, “time to reach full enteral feeding”, “High direct bilirubin peak” (> 1.5mg/dl), “High direct bilirubin at discharge” (> 1.5mg/dl), and “persist time of cholestasis”. Phenobarbital was also associated with confounding factors “male”, “whether use the risk antibiotics”, “any sepsis onset in 28 days” and “invasive mechanical ventilation”. (See Table 3 .) Table 3 factors and confounding factors associated with Phenobarbital Characteristics before discharge No use of Phenobarbital (n = 72) Use of Phenobarbital(n = 76) P Cholestasis [n(%)]‡ 5(6.9%) 15(19.7%) 0.023 Direct bilirubin peak[mg/dl, M (P25, P75)] § 0.94(0.78, 1.20) 1.01(0.76, 2.09) 0.092 High direct bilirubin peak (> 1.5mg/dl) [n(%)]‡ 7(9.9%) 26(35.1%) 0.000 Direct bilirubin at discharge[mg/dl, M (P25, P75)] § 0.52(0.35, 0.73) 0.68(0.29, 1.39) 0.162 High direct bilirubin at discharge (> 1.5mg/dl) [n(%)]‡ 0(0.0%) 44(57.9%) 0.000 Persist time of cholestasis [day, M (P25, P75)] § 0(0, 0) 0(0, 0) 0.020 birth weight(g, mean ± sd)† 1179.93 ± 311.44 1173.95 ± 293.74 0.904 gestational age(wk, mean ± sd)† 29.20 ± 2.11 28.78 ± 1.96 0.207 twins [n(%)]‡ 34 (47.2%) 27(35.5%) 0.149 male [n(%)]‡ 31 (43.1%) 54(71.1%) 0.001 antenatal dexamethasone [n (%)]‡ 57 (79.2%) 58(76.3%) 0.677 cesarean delivery [n(%)]‡ 42 (58.3%) 44 (57.9%) 0.957 small for gestational age [n(%)]‡ 11 (15.3%) 7 (9.2%) 0.259 Apgar score at 1 min [M (P25, P75)]§ 9(7, 10) 8(7, 10) 0.116 Apgar score at 5 min [M (P25, P75)]§ 10(9, 10) 10(9, 10) 0.863 critical risk index for babies [M (P25, P75)]§ 8(5, 9) 8(5, 9) 0.261 time to reach full enteral feeding [days, M (P25, P75)]§ 20(14, 27) 35(25, 47) 0.013 invasive mechanical ventilation [n (%)]‡ 33 (45.8%) 64 (84.2%) 0.000 hospital stay [day, M (P25, P75)] § 63(51, 78) 58(69, 84) 0.087 whether use the risk antibiotics* [n (%)]‡ 11(15.3%) 22 (28.9%) 0.046 CMV infection [n (%)]‡ 1 (1.4%) 3 (3.9%) 0.651 necrotising enterocolitis [n (%)]‡ 2 (2.8%) 1 (1.3%) 0.962 any sepsis onset in 28 days [n (%)]‡ 17 (23.6%) 33 (43.4%) 0.011 †. For continuous variables of normal distribution, groups were compared with the independent-sample t-test. ‡. The chi-square test and Fisher’s exact test were used for categorical variables. §. For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test. * The risk antibiotics included ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin; CMV, cytomegalovirus. 4. “Delay of full enteral feeding” was associated with phenobarbital in LBW infants with hsPDA. The risk of PN associated cholestasis was independently increased by the prolongation of PN, which means the “delay of full enteral feeding”, defined as “reach full enteral feeding at 28 days or later” in this study. To explore whether the “delay of full enteral feeding” (40 cases) was associated with “DOP” or “DOPBCO”, binary logistic regression analysis was done adjusting for 12 related confounders “male”, “gestational age”, “birth weight”, “Apgar score at 5 min”, “critical risk index for babies”, “small for gestational age”, “invasive mechanical ventilation”, “CMV infection”, “necrotising enterocolitis”, “any sepsis onset in 28 days”, “duration of cimetidine”, and “whether use the risk antibiotics”. After adjustment, the “delay of full enteral feeding” was still associated with “DOP” (OR: 1.571; 95% CI: 1.091, 2.262; P = 0.015) or “DOPBCO” (OR: 1.662; 95% CI: 1.108, 2.493; P = 0.014), as listed in Table 4 and Table 5 . Table 4 logistic analysis of factors for “delay of full enteral feeding” against “DOP” Factors OR 95%CI P DOP (days) 1.571 1.091 ~ 2.262 0.015 gestational age(wk) 0.368 0.160 ~ 0.847 0.019 birth weight(g) 0.994 0.989 ~ 0.999 0.022 invasive mechanical ventilation 2.904 0.840 ~ 10.040 0.092 any sepsis onset in 28 days 4.464 1.555 ~ 12.821 0.005 duration of cimetidine (days) 2.159 1.186 ~ 3.932 0.012 DOP, duration of Phenobarbital; Table 5 logistic analysis of factors for “delay of full enteral feeding” against “DOPBCO” Factors OR 95%CI P DOPBCO (days) 1.662 1.108 ~ 2.493 0.014 gestational age(wks) 0.356 0.155 ~ 0.817 0.015 birth weight(g) 0.994 0.989 ~ 0.999 0.021 any sepsis onset in 28 days 4.525 1.582 ~ 12.99 0.005 duration of cimetidine(days) 2.436 1.319 ~ 4.496 0.004 DOPBCO, Duration of Phenobarbital before cholestasis onset 5. The risk of cholestasis was associated with phenobarbital in LBW infants with hsPDA. To explore whether the risk of cholestasis was independently increased by “DOP” or “DOPBCO”, binary logistic regression analysis was done adjusting for the same 12 confounders listed in result 4. Notably, “delay of full enteral feeding” was not included, because it is interrelated to the DOP or DOPBCO, as revealed in result 4. After adjustment, cholestasis was still associated with “DOP” (OR: 1.553; 95% CI: 1.143, 2.110; P = 0.005) and “CMV infection” (OR: 43.478; 95% CI: 1.506, 1000; P = 0.028). Furthermore, cholestasis was still associated with “DOPBCO” (OR: 1.353; 95% CI: 0.956, 1.917; P = 0.088) and “CMV infection” (OR: 29.413; 95% CI: 1.381, 500; P = 0.030) after adjustment. 6. “High direct bilirubin peak” was associated with phenobarbital in LBW infants with hsPDA. To explore whether “high direct bilirubin peak” (> 1.5 mg/dl) was associated with “DOP” or “DOPBCO”, binary logistic regression analysis was done adjusting for the same 12 confounders listed in result 4. After adjustment, “high direct bilirubin peak” was still associated with “DOP” (OR: 1.686; 95% CI: 1.189, 2.392; P = 0.003) and “duration of cimetidine” (OR: 2.648; 95% CI: 1.396, 5.023; P = 0.003). Furthermore, cholestasis was also associated with “DOPBCO” (OR: 1.511; 95% CI: 1.064, 2.146; P = 0.021), “duration of cimetidine” (OR: 2.660; 95% CI: 1.415, 5.001; P = 0.002), and “small for gestational age” (OR: 7.633; 95% CI: 1.131, 52.631; P = 0.037) after adjustment. 7. “Persist time of cholestasis” was associated with phenobarbital in LBW infants with hsPDA. To explore whether “persist time of cholestasis” was associated with “DOP”, linear regression analysis was done adjusting for phenobarbital associated confounders including “male”, “invasive mechanical ventilation”, “any sepsis onset in 28 days”, “delay of full enteral feeding”, and “whether use the risk antibiotics” listed in result 3. However, “time to reach full enteral feeding” is replaced with category variable “delay of full enteral feeding”, because there is only 20 cases of cholestasis in this study, if “time to reach full enteral feeding” put in the linear equation then the linear model became insignificant. After adjustment, “persist time of cholestasis” was still associated with “DOP” (B: 2.254; 95% CI: 0.002, 4.506; P = 0.050) and “delay of full enteral feeding” (OR: 35.161; 95% CI: 13.544, 56.778; P = 0.004). Discussion This study revealed that DOP was associated with cholestasis in LBW infants with hsPDA, even after adjustment for 12 related confounders “male”, “gestational age”, “birth weight”, “Apgar score at 5 min”, “critical risk index for babies”, “small for gestational age”, “invasive mechanical ventilation”, “CMV infection”, “necrotising enterocolitis”, “any sepsis onset in 28 days”, “duration of cimetidine”, and “whether use the risk antibiotics”. Accordingly, several case reports suggested that phenobarbital caused hepatoxicity and conjugated hyperbilirubinemia in infants and children [ 28 – 30 ]. The most common liver disturbances induced by phenobarbital include elevated aminotransferases, conjugated hyperbilirubinemia, prolonged prothrombin time, decreased vitamin K dependent clotting factors, even fulminant hepatic falure and death[ 28 – 30 ]. Prompt and permanent cessation of phenobarbital results in resolution of symptoms in most patients. [ 30 ]. Notably, Phenobarbital is used in 51.35% (76/148) of LBW infants in our study, mostly for controlling seizure, partly for sedation during invasive mechanical ventilation, which are common practices in NICU in China and some western countries [ 31 ]. It is reported that very preterm infants given opioids for sedation took significantly longer to reach full enteral feeding than those in control groups [ 32 ]. Coincidentally, “delay of full enteral feeding” was associated with DOP (OR: 1.629; P = 0.003) and DOPBCO (OR: 1.629; P = 0.003), would increase the risk of parenteral nutrition associated cholestasis. Accordingly, a study found that 60% of phenobarbital-treated infants developed parenteral nutrition (PN) associated cholestasis, as compared to 33% of the untreated patients[ 17 ]. After the adjustment with 12 related confounders including “invasive mechanical ventilation”, cholestasis was still associated with “DOP” (OR: 1.553; P = 0.005) and “DOPBCO” (OR: 1.353; P = 0.088); “high direct bilirubin peak” (> 1.5 mg/dl) was still associated with “DOP” (OR: 1.686; P = 0.003) and “DOPBCO” (OR: 1.511; P = 0.021). Furthermore, Multivariate linear regression revealed that “persist time of cholestasis” was associated with “DOB” (B: 2.254; P = 0.050), even after adjustment of “delay of full enteral feeding”. Those results indicate that phenobarbital increases the risk of cholestasis in LBW infants with hsPDA. In other respects, phenobarbital induces neuronal apoptosis, which involves the cortex, hypothalamus, thalamus, basal ganglia, and developing white matter [ 1 , 33 , 34 ], and causes long-term behavioral toxicity and impaired cognitive development in neonates [ 35 – 37 ]. In order to reduce the risk of neurotoxicity and hepatoxicity in LBW infants, phenobarbital should be used cautiously and conservatively. Furthermore, phenobarbital is reported to has limited efficacy for reduction of direct bilirubin in neonates and young infants with cholestasis[ 18 ], therefore phenobarbital is suggested not to be used to treat neonatal cholestasis in LBW infants with hsPDA. Increasing evidences indicate that phenobarbital is associated with direct hepatoxicity. By analyzing 2.6 million adverse event reports made from the FDA Adverse Event Reporting System (FAERS) database between July 1, 2018 and March 31, 2020 for drug-induced liver injury (DILI) due to antiseizure medications (ASMs), the reporting odds ratio (ROR) of DILI for phenobarbital versus all non-ASM reports is 2.91 (CI:2.24–3.77, p < 0.0001) [ 38 ]. Mitochondrial toxicity and oxidative stress is involved in the hepatotoxicity induced by phenobarbital [ 39 , 40 ]. Laboratory animal studies have reported the hepatotoxicity of high dose phenobarbital in juvenile male rats [ 41 ]. The hepatoxicity is suggested to be related to defect in phenobarbital detoxification and hypersensitivity[ 28 ]. Notably, accumulation of phenobartbital is not uncommon in LBW neonates with immature liver and kidney. The mean half-life of phenobarbital is very long in neonates, about 115 hours after 1 week and about 67 hours after 4 weeks of administration[ 42 ]. The main reasons of phenobarbital poisoning in infants and children were therapeutic intoxication when phenobarbital therapy performed according to the recommended dosage in guidelines[ 28 ]. Drug accumulation may occur at the recommended maintenance dose during the first 2 weeks of life [ 43 ]. To our best knowledge, this study suggested for the first time that phenobarbital duration-dependently increased the risk of cholestasis in LBW infants with hsPDA. The limitation of this retrospective cohort study is obvious that the sample size was as small as 148 cases in total, and the cholestasis group includes only 20 cases. Furthermore, the sickest infants who might have the longest period of time until full enteral feedings also are more likely to be in need of phenobarbital for sedation. Whereas, after the adjustment of 12 related critical risk factors including “critical risk index for babies” and “invasive mechanical ventilation”, DOP is still associated with cholestasis; and even after adjustment of “delay of full enteral feeding”, “persist time of cholestasis” was associated with “DOB”, indicating phenobarbital might even prolong the established cholestasis in LBW infants, therefore should be used cautiously in LBW infants with hsPDA or cholestasis. List Of Abbreviations hsPDA, hemo-dynamically significant patent ductus arteriosus; LBW, low birth weight; NICU, neonatal intensive care unit; DOPBCO, “duration of phenobarbital before cholestasis onset” ; DOP, “duration of phenobarbital”; CMV, cytomegalovirus. Declarations Ethics approval and consent to participate : This study was approved by the Institutional Review Board of Shenzhen Baoan women’s and Children’s Hospital (LLSCHY-2019-10-32), which had waived the need of informed consent for this retrospective study. The institutional ethics committees approved this research comply with Declaration of Helsinki. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication : Not applicable. Availability of data and materials: All data generated or analysed during this study are included in this published article and its supplementary information files. Competing interests: None. Funding : This study is supported by Research Foundation of Shenzhen Baoan Women’s and Children’s Hospital, Jinan University (BAFY 2022001) Authors' contributions: Xintian Shen designed the retrospective study, Xintian Shen supervised this study in pharmacy and medicine fields. Yie Huang analyzed the data and Xintian Shen wrote the manuscript. Haibo Peng and Ping Zhou retrieved and checked the data. Lin Hung-Chih provided constructive advice on manuscript writing. Acknowledgements : The authors thank professor Lin Hung-Chih from China Medical University Children Hospital, Taichung, Taiwan for providing constructive advice on manuscript writing. References Bittigau, P., et al., Antiepileptic drugs and apoptotic neurodegeneration in the developing brain . Proc Natl Acad Sci U S A, 2002. 99 (23): p. 15089–94. Painter, M.J., et al., Phenobarbital compared with phenytoin for the treatment of neonatal seizures . N Engl J Med, 1999. 341 (7): p. 485–9. El-Dib, M. and J.S. Soul, The use of phenobarbital and other anti-seizure drugs in newborns . Semin Fetal Neonatal Med, 2017. 22 (5): p. 321–327. Barks, J.D., et al., Phenobarbital augments hypothermic neuroprotection . Pediatr Res, 2010. 67 (5): p. 532–7. Hall, R.T., F.K. Hall, and D.K. Daily, High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up . J Pediatr, 1998. 132 (2): p. 345–8. Smit, E., D. Odd, and A. Whitelaw, Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants . Cochrane Database Syst Rev, 2013(8): p. CD001691. Kodama, S. and M. Negishi, Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car . Drug Metab Rev, 2006. 38 (1–2): p. 75–87. Sueyoshi, T. and M. Negishi, Phenobarbital response elements of cytochrome P450 genes and nuclear receptors . Annu Rev Pharmacol Toxicol, 2001. 41 : p. 123–43. Tien, E.S. and M. Negishi, Nuclear receptors CAR and PXR in the regulation of hepatic metabolism . Xenobiotica, 2006. 36 (10–11): p. 1152–63. Stiehl, A., M.M. Thaler, and W.H. Admirand, The effects of phenobarbital on bile salts and bilirubin in patients with intrahepatic and extrahepatic cholestasis . N Engl J Med, 1972. 286 (16): p. 858–61. Sugatani, J., et al., The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR . Hepatology, 2001. 33 (5): p. 1232–8. Majd, M., R.C. Reba, and R.P. Altman, Hepatobiliary scintigraphy with 99mTc-PIPIDA in the evaluation of neonatal jaundice . Pediatrics, 1981. 67 (1): p. 140–5. Kimura, A., et al., Neonatal Dubin-Johnson syndrome with severe cholestasis: effective phenobarbital therapy . Acta Paediatr Scand, 1991. 80 (3): p. 381–5. Merdler, C., et al., The effect of phenobarbital on patients with Dubin-Johnson syndrome . Digestion, 1976. 14 (5–6): p. 394–9. Paulusma, C.C., et al., A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome . Hepatology, 1997. 25 (6): p. 1539–42. Cies, J.J. and J.N. Giamalis, Treatment of cholestatic pruritus in children . Am J Health Syst Pharm, 2007. 64 (11): p. 1157–62. Gleghorn, E.E., et al., Phenobarbital does not prevent total parenteral nutrition-associated cholestasis in noninfected neonates . JPEN J Parenter Enteral Nutr, 1986. 10 (3): p. 282–3. Lewis, T., S. Kuye, and A. Sherman, Ursodeoxycholic acid versus phenobarbital for cholestasis in the Neonatal Intensive Care Unit . BMC Pediatr, 2018. 18 (1): p. 197. Nemeth, A., S.A. Wikstrom, and B. Strandvik, Phenobarbital can aggravate a cholestatic bile acid pattern in infants with obstructive cholangiopathy . J Pediatr Gastroenterol Nutr, 1990. 10 (3): p. 290–7. Bell, R.L., et al., Total parenteral nutrition-related cholestasis in infants . JPEN J Parenter Enteral Nutr, 1986. 10 (4): p. 356–9. Steinbach, M., et al., Demographic and nutritional factors associated with prolonged cholestatic jaundice in the premature infant . J Perinatol, 2008. 28 (2): p. 129–35. Shen, X., et al., Oral ibuprofen promoted cholestatic liver disease in very low birth weight infants with patent ductus arteriosus . Clin Res Hepatol Gastroenterol, 2021. 45 (2): p. 101495. Kluckow, M. and N. Evans, Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation . J Pediatr, 1995. 127 (5): p. 774–9. McNamara, P.J. and A. Sehgal, Towards rational management of the patent ductus arteriosus: the need for disease staging . Arch Dis Child Fetal Neonatal Ed, 2007. 92 (6): p. F424-7. Orso, G., et al., Pediatric parenteral nutrition-associated liver disease and cholestasis: Novel advances in pathomechanisms-based prevention and treatment . Dig Liver Dis, 2016. 48 (3): p. 215–22. Parry, G., J. Tucker, and W. Tarnow-Mordi, CRIB II: an update of the clinical risk index for babies score . Lancet, 2003. 361 (9371): p. 1789–91. Mohi-ud-din, R. and J.H. Lewis, Drug- and chemical-induced cholestasis. Clin Liver Dis, 2004. 8 (1): p. 95–132, vii. Ghorani-Azam, A., et al., Acute phenobarbital poisoning for the management of seizures in new-borns and children; A systematic literature review . CNS Neurol Disord Drug Targets, 2020. Roberts, E.A., et al., Phenobarbital hepatotoxicity in an 8-month-old infant . J Hepatol, 1990. 10 (2): p. 235–9. Mockli, G., et al., Massive hepatic necrosis in a child after administration of phenobarbital . Am J Gastroenterol, 1989. 84 (7): p. 820–2. Trends in narcotics and sedative use during mechanical ventilation of preterm infants in Canadian neonatal intensive care units . Zhongguo Dang Dai Er Ke Za Zhi, 2018. 20 (1): p. 5–11. Bellu, R., K. de Waal, and R. Zanini, Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis . Arch Dis Child Fetal Neonatal Ed, 2010. 95 (4): p. F241-51. Forcelli, P.A., et al., Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain . Epilepsia, 2011. 52 (12): p. e207-11. Kaushal, S., et al., Anticonvulsant drug-induced cell death in the developing white matter of the rodent brain . Epilepsia, 2016. 57 (5): p. 727–34. Reinisch, J.M., et al., In utero exposure to phenobarbital and intelligence deficits in adult men . JAMA, 1995. 274 (19): p. 1518–25. Yaffe, S.J. and L.D. Dorn, Effects of prenatal treatment with phenobarbital . Dev Pharmacol Ther, 1990. 15 (3–4): p. 215–23. Gutherz, S.B., et al., Brief postnatal exposure to phenobarbital impairs passive avoidance learning and sensorimotor gating in rats . Epilepsy Behav, 2014. 37 : p. 265–9. Kamitaki, B.K., et al., Drug-induced liver injury associated with antiseizure medications from the FDA Adverse Event Reporting System (FAERS) . Epilepsy Behav, 2021. 117 : p. 107832. Santos, N.A., et al., Aromatic antiepileptic drugs and mitochondrial toxicity: effects on mitochondria isolated from rat liver . Toxicol In Vitro, 2008. 22 (5): p. 1143–52. Santos, N.A., et al., Involvement of oxidative stress in the hepatotoxicity induced by aromatic antiepileptic drugs . Toxicol In Vitro, 2008. 22 (8): p. 1820–4. Yamaguchi, T., et al., The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats . J Toxicol Sci, 2019. 44 (7): p. 459–469. Pitlick, W., M. Painter, and C. Pippenger, Phenobarbital pharmacokinetics in neonates . Clin Pharmacol Ther, 1978. 23 (3): p. 346–50. Pacifici, G.M., Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics . Curr Pediatr Rev, 2016. 12 (1): p. 48–54. Additional Declarations No competing interests reported. Supplementary Files neonatalcholestasisphenobarbital2022.06.17.xls Cite Share Download PDF Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1599063","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":130484908,"identity":"9c7c8f12-0328-4f9b-8c7b-a52dec9baec2","order_by":0,"name":"Xintian Shen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYBACAziLmYHxQUJFDdFaDEBamA0enDlGihYGBjbJhy3MhLWYs3cnPvjw54+8fDv7s4rEBjYG/vbuBLxaLHvObjac2WZguOEwj9mNxB0yDBJnzm7A77AbudukeRsMGDcw87DdSDzDxmAgkUtQy/bfPH8M7Oc3sz8rSGxjJkrLNqD5BokNhxnMGIjTcubsZsmZbcbJQL8YSyScOcZD2C/Hezd++PBHznZ+//GHH39U1Mjxt/fi14IBeEhTPgpGwSgYBaMAKwAAVKVJwqEUQXgAAAAASUVORK5CYII=","orcid":"","institution":"Shenzhen Baoan Women's and Children's Hospital, Jinan University","correspondingAuthor":true,"prefix":"","firstName":"Xintian","middleName":"","lastName":"Shen","suffix":""},{"id":130484909,"identity":"79c4b525-bd59-432b-a797-7908aba7ef1e","order_by":1,"name":"Yie Huang","email":"","orcid":"","institution":"Shenzhen Baoan Women's and Children's Hospital, Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Yie","middleName":"","lastName":"Huang","suffix":""},{"id":130484910,"identity":"e6ca84ca-02af-4579-a678-4e76660f0849","order_by":2,"name":"Haibo Peng","email":"","orcid":"","institution":"Shenzhen Baoan Women's and Children's Hospital, Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Haibo","middleName":"","lastName":"Peng","suffix":""},{"id":130484911,"identity":"70d1e268-b7a5-4e9f-8756-60c3bcb032c4","order_by":3,"name":"Ping Zhou","email":"","orcid":"","institution":"Shenzhen Baoan Women's and Children's Hospital, Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Zhou","suffix":""},{"id":130484912,"identity":"8e506611-d8b2-436c-927b-0b866f8b7e26","order_by":4,"name":"Lin Hung-Chih","email":"","orcid":"","institution":"China Medical University Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Hung-Chih","suffix":""}],"badges":[],"createdAt":"2022-04-27 02:29:10","currentVersionCode":3,"declarations":"","doi":"10.21203/rs.3.rs-1599063/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-1599063/v3","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":25509668,"identity":"4deb71f6-ec85-43d2-8152-e59ed2472153","added_by":"auto","created_at":"2022-08-22 18:27:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":78154,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the study population. LBW infants (24~34 weeks, birth weight\u0026lt;2000 g) admitted to the NICU of our hospital in 48 hours after birth, and diagnosed with hemo-dynamically significant patent ductus arteriosus (hsPDA) between September 2016 to September 2019, were included. Included infants were categorized into the infants with cholestasis or without cholestasis.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-1599063/v3/9b1c0099fef96a7398f381d3.png"},{"id":27984672,"identity":"2923fd80-0d1d-440a-bc0f-fd4ff7b38271","added_by":"auto","created_at":"2022-10-19 12:14:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":676676,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1599063/v3/732a809a-90ed-47ed-ac63-5ff500dc92cb.pdf"},{"id":25509667,"identity":"179b2e16-42bd-40a6-b303-0b2a78364d18","added_by":"auto","created_at":"2022-08-22 18:27:08","extension":"xls","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":78848,"visible":true,"origin":"","legend":"","description":"","filename":"neonatalcholestasisphenobarbital2022.06.17.xls","url":"https://assets-eu.researchsquare.com/files/rs-1599063/v3/02fceb32502872d3e84dc589.xls"}],"financialInterests":"No competing interests reported.","formattedTitle":"Phenobarbital is Associated with Cholestasis in Low Birth Weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus","fulltext":[{"header":"Key Points","content":"\u003cp\u003eControversy of phenobarbital exists in treatment of cholestasis in neonatal intensive care unit. This study found that phenobarbital was associated with cholestasis in low birth weight (LBW) infants with hemo-dynamically significant patent ductus arteriosus (hsPDA). Phenobarbital should be used cautiously in this population.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003ePhenobarbital has been extensively used in neonates for treatment of seizure, hypoxic ischaemic encephalopathy (HIE), and prophylaxis of intraventricular hemorrhage (IVH). Phenobarbital is still the first-line therapy for neonatal seizures, because of extensive clinical experience, despite limited clinical effectiveness and potential neurotoxicity [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Furthermore, phenobarbital is used in combination with therapeutic hypothermia for seizure control and neuroprotection in neonates with HIE. The neuroprotective benefits of phenobarbital have been described in animal [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and clinical studies of HIE [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Postnatal administration of phenobarbital is also used to prevent IVH in low birth weight (LBW) infants, whereas is associated with an increased need for mechanical ventilation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNotably, phenobarbital is also used in treatment of hyperbilirubinemia, cholestasis and its complication, pruritus. Phenobarbital regulates constitutive androstane receptor (CAR) and/or the pregnane X receptor (PXR), which further regulates hepatocellular metabolism enzymes and transporters, including UDP-glucuronosyltransferase (UGT1A1) and multidrug-resistance-associated protein 2 (MRP2) [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], responsible for the detoxification of bilirubin. Phenobarbital is reported to reduce the serum bile acid in cholestasis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, phenobarbital improves neonatal unconjugated hyperbilirubinemia in the liver [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Phenobarbital also increases the accuracy of hepatobiliary scintigraphy by enhancing bile isotope excretion [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Case reports indicated that phenobarbital is useful for treatment of Dubin-Johnson syndrome with conjugated hyperbilirubinemia [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], which is caused by deficit of MRP2 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Additionally, phenobarbital is useful in controlling cholestatic pruritus in children [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eControversially, growing evidences suggest that phenobarbital may aggravate neonatal cholestasis. A study found that 60% of phenobarbital-treated infants developed parenteral nutrition (PN) associated cholestasis, as compared to 33% of the untreated patients[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A retrospective cohort study suggested that phenobarbital has limited efficacy for the reduction of direct bilirubin in neonates and young infants with cholestasis in the neonatal intensive care unit (NICU), and advocated to avoid phenobarbital in the treatment of neonatal cholestasis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Additionally, case reports indicated phenobarbital can aggravate the cholestatic bile acid pattern in infants with cholestasis [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInterestingly, some evidences indicate hemo-dynamically significant patent ductus arteriosus (hsPDA) is associated with increased risk of cholestasis in LBW infants. An epidemiological study with multiple logistic regression analysis identifies that patent ductus arteriosus (PDA) is an independent risk factor for PN associated cholestasis in infants [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Neonates with cholestasis is associated with hsPDA (76.9% vs 42.4%, P\u0026thinsp;=\u0026thinsp;0.04) than neonates without cholestasis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our previous study found that LBW neonates with hsPDA is associated with increased risk of cholestasis than neonates without significant PDA (19.0% vs 3.4%, P\u0026thinsp;=\u0026thinsp;0.007), this result is still significant even after adjustment with multiple logistic regression (OR: 6.730; P\u0026thinsp;=\u0026thinsp;0.024) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, this retrospective cohort study aimed to explore whether phenobarbital was associated with cholestasis in LBW infants with hsPDA.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, LBW infants (24~34 weeks, birth weight\u0026lt;2000 g) diagnosed with hsPDA, admitted to the NICU of our hospital in 48 hours after birth between September 2016 to September 2019, were included. Clinical and demographic data were collected from medical records of the patients until discharge. Exclusion criteria were as follows: malformations, genetic defects, severe asphyxia (defined as a blood pH\u0026lt;6.8), admitted to NICU at \u0026ge;48 hours of postnatal age, hospital stay \u0026lt;21 days, and death or abandon rescue. Finally, a total of 148 LBW infants were included in the analysis (Fig. 1). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIf there were any signs of cardiomegaly or pulmonary edema on chest radiograph, respiratory difficulty, hypotension, decreased urine output or metabolic acidosis suggesting hsPDA, we checked the echocardiography for the confirmation of hsPDA, which was defined as a PDA with a transductal diameter \u0026ge;1.4 mm/kg with significant left to right shunt[23, 24].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFeeding protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEnteral feeding was started mostly on the first day of life at 10-20 ml/kg/day divided into 8 meals with own mother\u0026rsquo;s milk or donor milk. Human milk fortifier was added when enteral feeding reached 80-100 ml/kg. Aspirate residual from an orogastric tube and abdominal aspect were checked before each meal. In the absence of signs of feeding intolerance for 24 hours, enteral feeding was increased daily by 10~20 ml/kg. Enteral nutrition was discontinued in the case of erythematic abdominal wall, absence of bowel sounds, blood in the stools, or bile or blood in aspirates associated with a radiologic marker of NEC-Bell stage II. PN was maintained through a central line in all infants to ensure adequate intake of fluids, electrolytes, and nutrients until full enteral feeding was reached. Iron was supplemented orally according to recommendations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePN solutions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCommon PN solutions for LBW infants were composed of Sodium Glycerophosphate Injection (Glycophos, Fresenius kabi sspc), 10% and 50% glucose injection, 10% sodium chloride injection, 10% potassium chloride injection, Multi-trace Elements Injection (II) (Addamel, Fresenius kabi sspc.), Pediatric Compound Amino Acid Injection (19AA-I) (taurine included, China Resources Double-Crane Pharma.), Magnesium Sulfate Injection, Calcium Gluconate Injection, and 20% Soybean Oil, Fat Emulsions (Intralipid, Fresenius Kabi).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOnce neonatal cholestasis diagnosed, fat emulsion were replaced immediately with 20% Multi-oil Fat Emulsion Injection (SMOFlipid, Fresenius Kabi Austria GmbH) to protect the infants from cholestasis[25]. There was no change during the period of retrospective study in terms of new generation lipid emulsion, carnitine, taurine, etc. No cyclic PN had been adopted in included cases [25].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main outcomes were neonatal cholestasis (conjugated hyperbilirubinemia, direct bilirubin \u0026ge;2 mg/dL and persistent duration \u0026ge;20 days, without other causes of hepatic dysfunction), persist time of cholestasis (days of direct bilirubin persisting above 2 mg/dl), direct bilirubin peak (the highest concentration of direct bilirubin) during hospital stay. Secondary outcomes were time to reach full enteral feeding and hospital stay.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData regarding gestational age, weight at birth, mode of delivery, multiple birth, sex, Apgar score, critical risk index for babies[26], presence of mechanical ventilation, time to reach full enteral feeding, time-to-discharge, occurrence of late-onset sepsis, NEC\u0026ge;stage 2, were collected by researchers not in charge of the clinical management of the participants. Discharge was decided with criteria indicated by the American Academy of Pediatrics.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCholestasis associated risk factors were also recorded, including cytomegalovirus (CMV) infection during hospital stay. The drugs associated with cholestatic injury were scrutinized thoroughly in included cases, the usage of potential hepatotoxic antibiotics (such as ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin) and other potential hepatotoxic agents (phenobarbital and cimetidine)[27] were recorded as confounders. The presence of any sepsis onset (early or late onset sepsis clinically diagnosed or cuture-proven) in 28 days of hospital stay may affect the onset of cholestasis, therefore were recorded as confounders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Kolmogorov-Smirnov test was used to determine whether variables were normally distributed. For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test. For continuous variables of normal distribution, groups were compared with the independent-sample t-test. The chi-square test and Fisher\u0026rsquo;s exact test were used for categorical variables. To assess the independent association of treatment or duration of phenobarbital with the main outcomes and the secondary outcomes, binary logistic regression analysis was done, adjusting for indicated major confounders. The statistical analysis was done with IBM SPSS Statistics version 19.0 (IBM Corp., Amarok, NY, USA). P values less than 0.05 (2-sided) were considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e1. Main demographic and clinical characteristics of the study population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 148 LBW infants (\u0026lt;\u0026thinsp;34 weeks, birth weight\u0026thinsp;\u0026lt;\u0026thinsp;2000 g) with hsPDA, 20 infants were diagnosed with cholestasis (see Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Cholestasis was associated with \u0026ldquo;small for gestational age\u0026rdquo; and \u0026ldquo;time to reach full enteral feeding\u0026rdquo;. The cholestasis diagnosed persisted for 20\u0026ndash;107 days before discharge. Direct bilirubin peak reached 2.3\u0026ndash;17.6 mg/dl during hospital stay. \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMain demographic and clinical characteristics of the study population\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics before discharge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo cholestasis (n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCholestasis (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDirect bilirubin peak [mg/dl, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.89(0.74, 1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.99(3.34, 9.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDirect bilirubin at dicharge [mg/dl, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.51(0.29, 0.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.06(1.78, 7.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePersist time of cholestasis [day, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0, 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45(30, 60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ebirth weight(g, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1193.71\u0026thinsp;\u0026plusmn;\u0026thinsp;308.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1069.00\u0026thinsp;\u0026plusmn;\u0026thinsp;233.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egestational age(wk, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.01\u0026thinsp;\u0026plusmn;\u0026thinsp;2.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.83\u0026thinsp;\u0026plusmn;\u0026thinsp;1.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.707\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etwins [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (39.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.391\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (65.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.462\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eantenatal dexamethasone [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e102 (79.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13(65.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.239\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecesarean delivery [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77 (60.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (45.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.126\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esmall for gestational age [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApgar score at 1 min [M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(7, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(8, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.333\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApgar score at 5 min [M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(9, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(9, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.478\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecritical risk index for babies [M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(5, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(6, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.130\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etime to reach full enteral feeding [days, M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21(14.25, 28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35(25, 47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvasive mechanical ventilation [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81 (63.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehospital stay [day, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65(51.5, 78.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72.5(65.25, 88.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u0026dagger;. For continuous variables of normal distribution, groups were compared with the independent-sample t-test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u0026Dagger;. The chi-square test and Fisher\u0026rsquo;s exact test were used for categorical variables.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026sect;. For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Possible cholestasis associated risk factors.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCMV infection and necrotising enterocolitis during hospital stay were included as confounders. The drugs associated with cholestatic injury were scrutinized thoroughly, the usage of risk drugs (phenobarbital, cimetidine) and whether use the risk antibiotics (ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin) were recorded as confounders. Possible cholestasis associated risk factors are listed in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Cholestasis was associated with duration of phenobarbital (DOP) and duration of phenobarbital before cholestasis onset (DOPBCO).\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePossible cholestasis associated risk factors\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRisk factors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo cholestasis (n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCholestasis (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhenobarbital [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (47.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDOP [days, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0, 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5 (0, 4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDOPBCO [days, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0, 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0, 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecimetidine [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (4.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (35.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eduration of cimetidine [days, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0, 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0, 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ewhether use the risk antibiotics* [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (21.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.548\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCMV infection [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (15.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enecrotising enterocolitis [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (10.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eany sepsis onset in 28 days [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (29.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u0026Dagger;. The chi-square test and Fisher\u0026rsquo;s exact test were used for categorical variables.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u0026sect; .For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test..\u003c/p\u003e\n\u003cp\u003e* The risk antibiotics included ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin;\u003c/p\u003e\n\u003cp\u003eDOP, duration of Phenobarbital; DOPBCO, Duration of Phenobarbital before cholestasis onset; CMV, cytomegalovirus;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Exploring factors and confounding factors associated with phenobarbital\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePhenobarbital was associated with factors \u0026ldquo;cholestasis\u0026rdquo;, \u0026ldquo;time to reach full enteral feeding\u0026rdquo;, \u0026ldquo;High direct bilirubin peak\u0026rdquo; (\u0026gt;\u0026thinsp;1.5mg/dl), \u0026ldquo;High direct bilirubin at discharge\u0026rdquo; (\u0026gt;\u0026thinsp;1.5mg/dl), and \u0026ldquo;persist time of cholestasis\u0026rdquo;. Phenobarbital was also associated with confounding factors \u0026ldquo;male\u0026rdquo;, \u0026ldquo;whether use the risk antibiotics\u0026rdquo;, \u0026ldquo;any sepsis onset in 28 days\u0026rdquo; and \u0026ldquo;invasive mechanical ventilation\u0026rdquo;. (See Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.)\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003efactors and confounding factors associated with Phenobarbital\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics before discharge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo use of Phenobarbital (n\u0026thinsp;=\u0026thinsp;72)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUse of Phenobarbital(n\u0026thinsp;=\u0026thinsp;76)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCholestasis [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(6.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(19.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDirect bilirubin peak[mg/dl, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.94(0.78, 1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.01(0.76, 2.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh direct bilirubin peak (\u0026gt;\u0026thinsp;1.5mg/dl) [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(9.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(35.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDirect bilirubin at discharge[mg/dl, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.52(0.35, 0.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.68(0.29, 1.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.162\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh direct bilirubin at discharge (\u0026gt;\u0026thinsp;1.5mg/dl) [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44(57.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePersist time of cholestasis [day, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0, 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0, 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ebirth weight(g, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1179.93\u0026thinsp;\u0026plusmn;\u0026thinsp;311.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1173.95\u0026thinsp;\u0026plusmn;\u0026thinsp;293.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.904\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egestational age(wk, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd)\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.20\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.207\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etwins [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (47.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27(35.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.149\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (43.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54(71.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eantenatal dexamethasone [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57 (79.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58(76.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.677\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecesarean delivery [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (58.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (57.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.957\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esmall for gestational age [n(%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (15.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.259\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApgar score at 1 min [M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(7, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(7, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.116\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApgar score at 5 min [M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(9, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(9, 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.863\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecritical risk index for babies [M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(5, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(5, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.261\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etime to reach full enteral feeding [days, M (P25, P75)]\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20(14, 27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35(25, 47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvasive mechanical ventilation [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (45.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (84.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehospital stay [day, M (P25, P75)] \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63(51, 78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58(69, 84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.087\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ewhether use the risk antibiotics* [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11(15.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (28.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCMV infection [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.651\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enecrotising enterocolitis [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.962\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eany sepsis onset in 28 days [n (%)]\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (23.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (43.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u0026dagger;. For continuous variables of normal distribution, groups were compared with the independent-sample t-test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u0026Dagger;. The chi-square test and Fisher\u0026rsquo;s exact test were used for categorical variables.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u0026sect;. For continuous variables of non-normal distribution, groups were compared with independent-sample Mann-Whitney test.\u003c/p\u003e\n\u003cp\u003e* The risk antibiotics included ampicillin, amoxicillin clavulanate, oxacillin, erythromycin, azithromycin and ciprofloxacin;\u003c/p\u003e\n\u003cp\u003eCMV, cytomegalovirus.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. \u0026ldquo;Delay of full enteral feeding\u0026rdquo; was associated with phenobarbital in LBW infants with hsPDA.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of PN associated cholestasis was independently increased by the prolongation of PN, which means the \u0026ldquo;delay of full enteral feeding\u0026rdquo;, defined as \u0026ldquo;reach full enteral feeding at 28 days or later\u0026rdquo; in this study. To explore whether the \u0026ldquo;delay of full enteral feeding\u0026rdquo; (40 cases) was associated with \u0026ldquo;DOP\u0026rdquo; or \u0026ldquo;DOPBCO\u0026rdquo;, binary logistic regression analysis was done adjusting for 12 related confounders \u0026ldquo;male\u0026rdquo;, \u0026ldquo;gestational age\u0026rdquo;, \u0026ldquo;birth weight\u0026rdquo;, \u0026ldquo;Apgar score at 5 min\u0026rdquo;, \u0026ldquo;critical risk index for babies\u0026rdquo;, \u0026ldquo;small for gestational age\u0026rdquo;, \u0026ldquo;invasive mechanical ventilation\u0026rdquo;, \u0026ldquo;CMV infection\u0026rdquo;, \u0026ldquo;necrotising enterocolitis\u0026rdquo;, \u0026ldquo;any sepsis onset in 28 days\u0026rdquo;, \u0026ldquo;duration of cimetidine\u0026rdquo;, and \u0026ldquo;whether use the risk antibiotics\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003eAfter adjustment, the \u0026ldquo;delay of full enteral feeding\u0026rdquo; was still associated with \u0026ldquo;DOP\u0026rdquo; (OR: 1.571; 95% CI: 1.091, 2.262; P\u0026thinsp;=\u0026thinsp;0.015) or \u0026ldquo;DOPBCO\u0026rdquo; (OR: 1.662; 95% CI: 1.108, 2.493; P\u0026thinsp;=\u0026thinsp;0.014), as listed in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003elogistic analysis of factors for \u0026ldquo;delay of full enteral feeding\u0026rdquo; against \u0026ldquo;DOP\u0026rdquo;\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDOP (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.571\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.091\u0026thinsp;~\u0026thinsp;2.262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egestational age(wk)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.160\u0026thinsp;~\u0026thinsp;0.847\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ebirth weight(g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.994\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.989\u0026thinsp;~\u0026thinsp;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvasive mechanical ventilation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.904\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.840\u0026thinsp;~\u0026thinsp;10.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eany sepsis onset in 28 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.555\u0026thinsp;~\u0026thinsp;12.821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eduration of cimetidine (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.186\u0026thinsp;~\u0026thinsp;3.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eDOP, duration of Phenobarbital;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab5\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003elogistic analysis of factors for \u0026ldquo;delay of full enteral feeding\u0026rdquo; against \u0026ldquo;DOPBCO\u0026rdquo;\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDOPBCO (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.662\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.108\u0026thinsp;~\u0026thinsp;2.493\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egestational age(wks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.356\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.155\u0026thinsp;~\u0026thinsp;0.817\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ebirth weight(g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.994\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.989\u0026thinsp;~\u0026thinsp;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eany sepsis onset in 28 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.525\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.582\u0026thinsp;~\u0026thinsp;12.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eduration of cimetidine(days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.436\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.319\u0026thinsp;~\u0026thinsp;4.496\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eDOPBCO, Duration of Phenobarbital before cholestasis onset\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. The risk of cholestasis was associated with phenobarbital in LBW infants with hsPDA.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo explore whether the risk of cholestasis was independently increased by \u0026ldquo;DOP\u0026rdquo; or \u0026ldquo;DOPBCO\u0026rdquo;, binary logistic regression analysis was done adjusting for the same 12 confounders listed in\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eresult 4. Notably, \u0026ldquo;delay of full enteral feeding\u0026rdquo; was not included, because it is interrelated to the DOP or DOPBCO, as revealed in result 4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter adjustment, cholestasis was still associated with \u0026ldquo;DOP\u0026rdquo; (OR: 1.553; 95% CI: 1.143, 2.110; P = 0.005) and \u0026ldquo;CMV infection\u0026rdquo; (OR: 43.478; 95% CI: 1.506, 1000; P = 0.028). Furthermore, cholestasis was still associated with \u0026ldquo;DOPBCO\u0026rdquo; (OR: 1.353; 95% CI: 0.956, 1.917; P = 0.088) and \u0026ldquo;CMV infection\u0026rdquo; (OR: 29.413; 95% CI: 1.381, 500; P = 0.030) after adjustment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6. \u0026ldquo;High direct bilirubin peak\u0026rdquo; was associated with phenobarbital in LBW infants with hsPDA.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo explore whether \u0026ldquo;high direct bilirubin peak\u0026rdquo; (\u0026gt;\u0026thinsp;1.5 mg/dl) was associated with \u0026ldquo;DOP\u0026rdquo; or \u0026ldquo;DOPBCO\u0026rdquo;, binary logistic regression analysis was done adjusting for the same 12 confounders listed in result 4.\u003c/p\u003e\n\u003cp\u003eAfter adjustment, \u0026ldquo;high direct bilirubin peak\u0026rdquo; was still associated with \u0026ldquo;DOP\u0026rdquo; (OR: 1.686; 95% CI: 1.189, 2.392; P\u0026thinsp;=\u0026thinsp;0.003) and \u0026ldquo;duration of cimetidine\u0026rdquo; (OR: 2.648; 95% CI: 1.396, 5.023; P\u0026thinsp;=\u0026thinsp;0.003). Furthermore, cholestasis was also associated with \u0026ldquo;DOPBCO\u0026rdquo; (OR: 1.511; 95% CI: 1.064, 2.146; P\u0026thinsp;=\u0026thinsp;0.021), \u0026ldquo;duration of cimetidine\u0026rdquo; (OR: 2.660; 95% CI: 1.415, 5.001; P\u0026thinsp;=\u0026thinsp;0.002), and \u0026ldquo;small for gestational age\u0026rdquo; (OR: 7.633; 95% CI: 1.131, 52.631; P\u0026thinsp;=\u0026thinsp;0.037) after adjustment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. \u0026ldquo;Persist time of cholestasis\u0026rdquo; was associated with phenobarbital in LBW infants with hsPDA.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo explore whether \u0026ldquo;persist time of cholestasis\u0026rdquo; was associated with \u0026ldquo;DOP\u0026rdquo;, linear regression analysis was done adjusting for phenobarbital associated confounders including \u0026ldquo;male\u0026rdquo;, \u0026ldquo;invasive mechanical ventilation\u0026rdquo;, \u0026ldquo;any sepsis onset in 28 days\u0026rdquo;, \u0026ldquo;delay of full enteral feeding\u0026rdquo;, and \u0026ldquo;whether use the risk antibiotics\u0026rdquo; listed in result 3. However, \u0026ldquo;time to reach full enteral feeding\u0026rdquo; is replaced with category variable \u0026ldquo;delay of full enteral feeding\u0026rdquo;, because there is only 20 cases of cholestasis in this study, if \u0026ldquo;time to reach full enteral feeding\u0026rdquo; put in the linear equation then the linear model became insignificant.\u003c/p\u003e\n\u003cp\u003eAfter adjustment, \u0026ldquo;persist time of cholestasis\u0026rdquo; was still associated with \u0026ldquo;DOP\u0026rdquo; (B: 2.254; 95% CI: 0.002, 4.506; P\u0026thinsp;=\u0026thinsp;0.050) and \u0026ldquo;delay of full enteral feeding\u0026rdquo; (OR: 35.161; 95% CI: 13.544, 56.778; P\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study revealed that DOP was associated with cholestasis in LBW infants with hsPDA, even after adjustment for 12 related confounders \u0026ldquo;male\u0026rdquo;, \u0026ldquo;gestational age\u0026rdquo;, \u0026ldquo;birth weight\u0026rdquo;, \u0026ldquo;Apgar score at 5 min\u0026rdquo;, \u0026ldquo;critical risk index for babies\u0026rdquo;, \u0026ldquo;small for gestational age\u0026rdquo;, \u0026ldquo;invasive mechanical ventilation\u0026rdquo;, \u0026ldquo;CMV infection\u0026rdquo;, \u0026ldquo;necrotising enterocolitis\u0026rdquo;, \u0026ldquo;any sepsis onset in 28 days\u0026rdquo;, \u0026ldquo;duration of cimetidine\u0026rdquo;, and \u0026ldquo;whether use the risk antibiotics\u0026rdquo;. Accordingly, several case reports suggested that phenobarbital caused hepatoxicity and conjugated hyperbilirubinemia in infants and children [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The most common liver disturbances induced by phenobarbital include elevated aminotransferases, conjugated hyperbilirubinemia, prolonged prothrombin time, decreased vitamin K dependent clotting factors, even fulminant hepatic falure and death[\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Prompt and permanent cessation of phenobarbital results in resolution of symptoms in most patients. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNotably, Phenobarbital is used in 51.35% (76/148) of LBW infants in our study, mostly for controlling seizure, partly for sedation during invasive mechanical ventilation, which are common practices in NICU in China and some western countries [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. It is reported that very preterm infants given opioids for sedation took significantly longer to reach full enteral feeding than those in control groups [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Coincidentally, \u0026ldquo;delay of full enteral feeding\u0026rdquo; was associated with DOP (OR: 1.629; P\u0026thinsp;=\u0026thinsp;0.003) and DOPBCO (OR: 1.629; P\u0026thinsp;=\u0026thinsp;0.003), would increase the risk of parenteral nutrition associated cholestasis. Accordingly, a study found that 60% of phenobarbital-treated infants developed parenteral nutrition (PN) associated cholestasis, as compared to 33% of the untreated patients[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. After the adjustment with 12 related confounders including \u0026ldquo;invasive mechanical ventilation\u0026rdquo;, cholestasis was still associated with \u0026ldquo;DOP\u0026rdquo; (OR: 1.553; P\u0026thinsp;=\u0026thinsp;0.005) and \u0026ldquo;DOPBCO\u0026rdquo; (OR: 1.353; P\u0026thinsp;=\u0026thinsp;0.088); \u0026ldquo;high direct bilirubin peak\u0026rdquo; (\u0026gt;\u0026thinsp;1.5 mg/dl) was still associated with \u0026ldquo;DOP\u0026rdquo; (OR: 1.686; P\u0026thinsp;=\u0026thinsp;0.003) and \u0026ldquo;DOPBCO\u0026rdquo; (OR: 1.511; P\u0026thinsp;=\u0026thinsp;0.021). Furthermore, Multivariate linear regression revealed that \u0026ldquo;persist time of cholestasis\u0026rdquo; was associated with \u0026ldquo;DOB\u0026rdquo; (B: 2.254; P\u0026thinsp;=\u0026thinsp;0.050), even after adjustment of \u0026ldquo;delay of full enteral feeding\u0026rdquo;. Those results indicate that phenobarbital increases the risk of cholestasis in LBW infants with hsPDA.\u003c/p\u003e \u003cp\u003eIn other respects, phenobarbital induces neuronal apoptosis, which involves the cortex, hypothalamus, thalamus, basal ganglia, and developing white matter [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and causes long-term behavioral toxicity and impaired cognitive development in neonates [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In order to reduce the risk of neurotoxicity and hepatoxicity in LBW infants, phenobarbital should be used cautiously and conservatively. Furthermore, phenobarbital is reported to has limited efficacy for reduction of direct bilirubin in neonates and young infants with cholestasis[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], therefore phenobarbital is suggested not to be used to treat neonatal cholestasis in LBW infants with hsPDA.\u003c/p\u003e \u003cp\u003eIncreasing evidences indicate that phenobarbital is associated with direct hepatoxicity. By analyzing 2.6\u0026nbsp;million adverse event reports made from the FDA Adverse Event Reporting System (FAERS) database between July 1, 2018 and March 31, 2020 for drug-induced liver injury (DILI) due to antiseizure medications (ASMs), the reporting odds ratio (ROR) of DILI for phenobarbital versus all non-ASM reports is 2.91 (CI:2.24\u0026ndash;3.77, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Mitochondrial toxicity and oxidative stress is involved in the hepatotoxicity induced by phenobarbital [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Laboratory animal studies have reported the hepatotoxicity of high dose phenobarbital in juvenile male rats [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. The hepatoxicity is suggested to be related to defect in phenobarbital detoxification and hypersensitivity[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Notably, accumulation of phenobartbital is not uncommon in LBW neonates with immature liver and kidney. The mean half-life of phenobarbital is very long in neonates, about 115 hours after 1 week and about 67 hours after 4 weeks of administration[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. The main reasons of phenobarbital poisoning in infants and children were therapeutic intoxication when phenobarbital therapy performed according to the recommended dosage in guidelines[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Drug accumulation may occur at the recommended maintenance dose during the first 2 weeks of life [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo our best knowledge, this study suggested for the first time that phenobarbital duration-dependently increased the risk of cholestasis in LBW infants with hsPDA. The limitation of this retrospective cohort study is obvious that the sample size was as small as 148 cases in total, and the cholestasis group includes only 20 cases. Furthermore, the sickest infants who might have the longest period of time until full enteral feedings also are more likely to be in need of phenobarbital for sedation. Whereas, after the adjustment of 12 related critical risk factors including \u0026ldquo;critical risk index for babies\u0026rdquo; and \u0026ldquo;invasive mechanical ventilation\u0026rdquo;, DOP is still associated with cholestasis; and even after adjustment of \u0026ldquo;delay of full enteral feeding\u0026rdquo;, \u0026ldquo;persist time of cholestasis\u0026rdquo; was associated with \u0026ldquo;DOB\u0026rdquo;, indicating phenobarbital might even prolong the established cholestasis in LBW infants, therefore should be used cautiously in LBW infants with hsPDA or cholestasis.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003ehsPDA, hemo-dynamically significant patent ductus arteriosus; LBW, low birth weight; NICU, neonatal intensive care unit; DOPBCO, \u0026ldquo;duration of phenobarbital before cholestasis onset\u0026rdquo; ; DOP, \u0026ldquo;duration of phenobarbital\u0026rdquo;; CMV, cytomegalovirus.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis study was approved by the Institutional Review Board of\u0026nbsp;Shenzhen Baoan women\u0026rsquo;s and Children\u0026rsquo;s Hospital\u0026nbsp;(LLSCHY-2019-10-32), which had waived the need of informed consent for this retrospective study.\u0026nbsp;The institutional ethics committees approved this research comply with Declaration of Helsinki. All methods were carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e All data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This study is supported\u0026ensp;by\u0026ensp;Research\u0026ensp;Foundation\u0026ensp;of\u0026ensp;Shenzhen Baoan Women\u0026rsquo;s and Children\u0026rsquo;s Hospital, Jinan\u0026ensp;University (BAFY 2022001)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e Xintian Shen designed the retrospective study, Xintian Shen supervised this study in pharmacy and medicine fields. Yie Huang analyzed the data and Xintian Shen wrote the manuscript. Haibo Peng and Ping Zhou retrieved and checked the data.\u0026nbsp;Lin Hung-Chih provided constructive advice on manuscript writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: The authors thank professor Lin Hung-Chih from China Medical University Children Hospital, Taichung, Taiwan for providing constructive advice on manuscript writing.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBittigau, P., et al., \u003cem\u003eAntiepileptic drugs and apoptotic neurodegeneration in the developing brain\u003c/em\u003e. Proc Natl Acad Sci U S A, 2002. \u003cb\u003e99\u003c/b\u003e(23): p.\u0026nbsp;15089\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePainter, M.J., et al., \u003cem\u003ePhenobarbital compared with phenytoin for the treatment of neonatal seizures\u003c/em\u003e. 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Lancet, 2003. \u003cb\u003e361\u003c/b\u003e(9371): p.\u0026nbsp;1789\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohi-ud-din, R. and J.H. Lewis, \u003cem\u003eDrug- and chemical-induced cholestasis.\u003c/em\u003e Clin Liver Dis, 2004. \u003cb\u003e8\u003c/b\u003e(1): p.\u0026nbsp;95\u0026ndash;132, vii.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhorani-Azam, A., et al., \u003cem\u003eAcute phenobarbital poisoning for the management of seizures in new-borns and children; A systematic literature review\u003c/em\u003e. CNS Neurol Disord Drug Targets, 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoberts, E.A., et al., \u003cem\u003ePhenobarbital hepatotoxicity in an 8-month-old infant\u003c/em\u003e. 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Epilepsy Behav, 2021. \u003cb\u003e117\u003c/b\u003e: p.\u0026nbsp;107832.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantos, N.A., et al., \u003cem\u003eAromatic antiepileptic drugs and mitochondrial toxicity: effects on mitochondria isolated from rat liver\u003c/em\u003e. Toxicol In Vitro, 2008. \u003cb\u003e22\u003c/b\u003e(5): p.\u0026nbsp;1143\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantos, N.A., et al., \u003cem\u003eInvolvement of oxidative stress in the hepatotoxicity induced by aromatic antiepileptic drugs\u003c/em\u003e. Toxicol In Vitro, 2008. \u003cb\u003e22\u003c/b\u003e(8): p.\u0026nbsp;1820\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamaguchi, T., et al., \u003cem\u003eThe effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats\u003c/em\u003e. J Toxicol Sci, 2019. \u003cb\u003e44\u003c/b\u003e(7): p.\u0026nbsp;459\u0026ndash;469.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePitlick, W., M. Painter, and C. Pippenger, \u003cem\u003ePhenobarbital pharmacokinetics in neonates\u003c/em\u003e. Clin Pharmacol Ther, 1978. \u003cb\u003e23\u003c/b\u003e(3): p.\u0026nbsp;346\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePacifici, G.M., \u003cem\u003eClinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics\u003c/em\u003e. Curr Pediatr Rev, 2016. \u003cb\u003e12\u003c/b\u003e(1): p.\u0026nbsp;48\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"neonatal cholestasis, phenobarbital, patent ductus arteriosus, low birth weight infants","lastPublishedDoi":"10.21203/rs.3.rs-1599063/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1599063/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThis retrospective study aimed to assess whether phenobarbital was associated with cholestasis in low birth weight (LBW) infants with hemo-dynamically significant patent ductus arteriosus (hsPDA).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study included 148 LBW infants (24\u0026thinsp;~\u0026thinsp;34 weeks, birth weight\u0026thinsp;\u0026lt;\u0026thinsp;2000 g) diagnosed with hsPDA, admitted to a level III neonatal intensive care unit (NICU) from September 2016 to September 2019. Of the 148 infants, twenty infants were diagnosed with cholestasis. To assess the independent association with cholestasis or direct bilirubin, binary logistic or multivariable linear regression was done, adjusting for major confounders (birth weight, gestational age, critical risk index for babies, invasive mechanical ventilation, any sepsis onset in 28 days and etc).\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eBinary logistic regression analysis was done adjusting for 12 related confounders. The \u0026ldquo;delay of full enteral feeding\u0026rdquo; was still associated with \u0026ldquo;duration of phenobarbital\u0026rdquo; (DOP) (OR: 1.571; P\u0026thinsp;=\u0026thinsp;0.015) or \u0026ldquo;duration of phenobarbital before cholestasis onset\u0026rdquo; (DOPBCO) (OR: 1.662; P\u0026thinsp;=\u0026thinsp;0.014). Cholestasis was still associated with \u0026ldquo;DOP\u0026rdquo; (OR: 1.553; P\u0026thinsp;=\u0026thinsp;0.005) or \u0026ldquo;DOPBCO\u0026rdquo; (OR: 1.353; P\u0026thinsp;=\u0026thinsp;0.088). \u0026ldquo;High direct bilirubin peak\u0026rdquo; (\u0026gt;\u0026thinsp;1.5 mg/dl) was still associated with \u0026ldquo;DOP\u0026rdquo; (OR: 1.686; P\u0026thinsp;=\u0026thinsp;0.003) or \u0026ldquo;DOPBCO\u0026rdquo; (OR: 1.511; P\u0026thinsp;=\u0026thinsp;0.021). Multivariate linear regression revealed that \u0026ldquo;persist time of cholestasis\u0026rdquo; was associated with \u0026ldquo;DOB\u0026rdquo; (B: 2.254; P\u0026thinsp;=\u0026thinsp;0.050) after adjustment of \u0026ldquo;delay of full enteral feeding\u0026rdquo;.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study found that phenobarbital was associated with neonatal cholestasis in LBW infants with hsPDA. Phenobarbital should be used cautiously in this population.\u003c/p\u003e","manuscriptTitle":"Phenobarbital is Associated with Cholestasis in Low Birth Weight Infants with Hemo-dynamically Significant Patent Ductus Arteriosus","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2022-08-22 18:27:06","doi":"10.21203/rs.3.rs-1599063/v3","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2022-06-29 17:51:39","doi":"10.21203/rs.3.rs-1599063/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2022-05-05 16:28:12","doi":"10.21203/rs.3.rs-1599063/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3391a13e-5a6e-455b-8be5-7d0c9f821a8a","owner":[],"postedDate":"August 22nd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-10-19T12:14:16+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-22 18:27:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v3","identity":"rs-1599063","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1599063","identity":"rs-1599063","version":["v3"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}