Perinatal bile acid metabolism: analysis of urinary unsaturated ketonic bile acids in preterm and full-term infants

AIM: To compare urinary concentrations of unsaturated ketonic bile acids in preterm and full-term infants. METHODS: Urinary unsaturated ketonic bile acids were determined using gas chromatography-mass spectrometry. RESULTS: Urinary concentrations of total bile acids in early preterm infants (of less than 29wk gestational age) exceeded concentrations in late preterm (between 30 and 37 wk) and full-term infants (between 38 and 41 wk; p < 0.01). The percentage of ketonic bile acids (7alpha, 12alpha-dihydroxy-3-oxo-4-cholenoic acid and 7alpha-hydroxy-3-oxo-4-cholenoic acid) among total urinary bile acids in full-term infants (20.2 +/- 14.1%) was higher than that in early preterm infants (8.94 +/- 8.1%; p < 0.05). The percentage of unsaturated bile acids (3beta-hydroxy-delta5-bile acids) among total bile acids in urine did not differ greatly between groups. CONCLUSION: The percentage of 3-oxo-delta4 bile acids among total bile acids in urine gradually increased from early to late preterm infants, while healthy full-term infants excreted large amounts of 3-oxo-delta4 bile acids in urine at delivery.     

Developmental pattern of urinary bile acid profile in preterm infants

Background:  Bile acid metabolism in preterm infants is yet to be fully characterized. We compared the developmental pattern of urinary bile acid profiles in ten infants born at gestational ages from 25 to 33 weeks with previous data from full-term infants from birth to about 7 months of age.
Methods:  Gas chromatography–mass spectrometry was performed on serial samples.
Results:  Total urinary bile acid concentrations gradually increased until 1 to 2 months of age. After this peak of excretion (30 to 60 µmol/mmol creatinine), total urinary bile acid concentrations gradually decreased to less than 20 µmol/mmol creatinine. The percentage of usual bile acids (mainly cholic acid) relative to total urinary total bile acids gradually deceased from approximately 30% at birth to less than 15% at 7 months of age. On the other hand, 1β-hydroxylated bile acids (mainly 1β,3α,7α,12α-tetrahydroxy-5β-cholan-24-oic acid) relative to total urinary bile acids were increased gradually from 60% at birth to reach 70% to 80% at 1 month of age. The percentage of 1β-hydroxylated bile acids relative to total urinary bile acids then remained stable at a high percentage (70% to 90%) until the age of 7 months.
Conclusion:  Physiological cholestasis in preterm infants persists longer than in full-term infants. Moreover, as large amounts of cholic and 1β,3α,7α,12α-tetrahydroxy-5β-cholan-24-oic acids were detected in urine from preterm infants during this study, the 25-hydroxylation pathway may be particularly important for bile acid synthesis in early preterm infants.     

Disturbances in bile acid metabolism of infants with the Zellweger (cerebro-hepato-renal) syndrome

The bile acid pattern in bile and serum from two infants with the cerebro-hepato-renal syndrome of Zellweger was severely disturbed. An increased concentration particularly of trihydroxycoprostanic acid and also of dihydroxycoprostanic acid could be demonstrated. A generalized mitochondrial defect could explain these increased concentrations. This hypothesis is supported by the abnormal structure of the mitochondria in the liver biopsy of one of our patients. It is possible that the abnormal bile acids contribute to the liver damage of infants with Zellweger syndrome.     

早产儿胃肠道外营养总胆汁酸的变化

目的　探讨胃肠道外营养早产儿总胆汁酸 (TBA)的变化。方法　分析 5 2例进行胃肠道外营养的早产儿在胃肠道外营养前及胃肠道外营养停止后TBA的变化 ;比较胎龄 <32周与≥ 32周早产儿胃肠道外营养前后TBA变化的差别。结果　早产儿胃肠道外营养前TBA(15 9± 9 9) μmol/L与对照组TBA(2 2 9± 16 2 ) μmol/L无显著性差别 ,胃肠道外营养后TBA(32 5± 18 9) μmol/L较胃肠道外营养前TBA明显增高 (P <0 0 1) ;胎龄 <32周早产儿胃肠道外营养后TBA(40 6± 2 3 2 ) μmol/L较胎龄≥ 32周早产儿胃肠道营养后TBA(2 7 7± 14 3)μmol/L明显增高。 结论　目前使用的胃肠道外营养方法仍存在着影响早产儿肝胆系统功能的情况 ;胎龄越小 ,影响越明显     

早产儿血清总胆汁酸升高的危险因素分析

目的 探讨早产儿血清总胆汁酸（TBA）升高的危险因素。方法 回顾性分析入住新生儿重症监护病房的216例早产儿的临床资料。以是否发生TBA升高（TBA > 24.8 μmol/L）,将早产儿分为TBA升高组（53例）和非TBA升高组（163例）。对可能导致TBA升高的影响因素进行单因素分析和非条件多因素logistic回归分析。结果 单因素分析显示,TBA升高和非TBA升高两组出生胎龄、出生体重、小于胎龄儿比例、呼吸机辅助通气比例、禁食时间、静脉营养时间以及新生儿呼吸衰竭、新生儿败血症的发生率的比较差异有统计学意义（P < 0.05）。非条件多因素logistic回归分析显示,低出生体重（OR=3.84,95% CI：1.53~9.64）、新生儿败血症（OR=2.56,95% CI：1.01~6.47）是早产儿TBA升高的独立危险因素。结论 低出生体重及新生儿败血症可导致TBA升高。     

Ascorbic acid and tyrosine metabolism in preterm and small-for-dates infants.

Ascorbic acid levels in plasma and leucocytes and urinary excretion of tyrosyl derivatives (TD) were determined in 11 normal, 18 preterm, and 4 small-for-dates infants. Concentrations of ascorbic acid in both plasma and leucocytes were found to be similar in the 3 groups. There was no difference in the basal levels of TD between normal and small-for-dates infants, but preterms showed higher basal excretion of TD than the other two groups. After protein load the excretion of TD was higher than the basal level in preterms. It was concluded that the altered metabolism of tyrosine observed in preterms is not the result of poor ascorbic acid status; and that tyrosine metabolism is influenced by the period of gestation rather than the body weight of the infant.     

广西地区早产儿氨基酸代谢特点研究

目的 探讨广西地区早产儿的氨基酸代谢变化特点.方法 回顾性收集2018～2020年于广西新生儿疾病筛查中心进行遗传代谢病筛查且检测结果为阴性的30757例新生儿的临床资料,其中28611例正常足月儿为正常对照组.早产儿2146例,根据胎龄分为极早产组(n=209)、中期早产组(n=307)、晚期早产组(n=1630);...     

Urinary excretion of 5-L-oxoproline (pyroglutamic acid) during early life in term and preterm infants

Urinary 5-L-oxoproline was measured in term and preterm infants from shortly after birth until 6 weeks of postnatal age to determine their ability to synthesise glycine. In term infants the excretion was five to 10 times that seen in normal adults, increasing from 105 µmol/mmol creatinine in the first 72 hours after birth to 170 µmol/mmol creatinine at 6 weeks of age. There was a significant inverse linear correlation between the excretion of 5-L-oxoproline and length of gestation or birthweight. By 6 weeks of age there was no longer a significant difference in 5-L-oxoproline between term and preterm infants. There was no difference in the excretion of 5-L-oxoproline between boys and girls, or between infants fed on human milk or an artificial formula.  If, in part, variability in the excretion of 5-L-oxoproline is determined by the extent to which the endogenous formation of glycine is adequate, then glycine formation may be marginal during early life, more so in preterm than in term infants, providing additional evidence that glycine is a conditionally essential amino acid in the neonate.     

Postnatal urinary conductance measurement in preterm infants

The aim of this study was to determine whether serial urinary conductance measurements can be used to estimate reliably the end of the transition period of negative sodium balance in preterm infants. The relationship between urine conductance, measured by a conductance meter, and urine sodium concentration was determined in 109 pooled samples of urine obtained from 14 preterm infants during the transitional period of fluid balance. It was shown by linear regression analysis that urine sodium concentration (mmol l -1 ) = 0.78 ×urine conductance -1.25. Urine sodium concentrations derived from the above formula were concordant with urine sodium measured directly when used to calculate daily sodium balance in all 14 infants.

Conclusion: Urine conductance can be accurately measured at the cotside by neonatal nurses and used to identify the timing of the postnatal transition from negative to positive sodium balance in preterm infants. These findings can help in making decisions on the introduction of postnatal sodium administration to preterm infants.     

Developmental pattern of 3-oxo-Δ4 bile acids in neonatal bile acid metabolism

AIMS—To investigate whether a fetal pathway of bile acid synthesis persists in neonates and infants.
METHODS—3-oxo-Δ⁴ bile acids were determined qualitatively and quantitatively in the urine, meconium, and faeces of healthy neonates and infants, using gas chromatography-mass spectrometry.
RESULTS—The mean percentage of 3-oxo-Δ⁴ bile acids in total bile acids in urine at birth was significantly higher than that at 3 or 7 days, and at 1 or 3 months of age. The concentration of this component in meconium was significantly higher than that in faeces at 7 days and at 1 or 3 months of age.
CONCLUSIONS—The presence of large amounts of urinary 3-oxo-Δ⁴ bile acids may indicate immaturity in the activity of hepatic 3-oxo-Δ⁴-steroid 5β-reductase in the first week of postnatal life. Large amounts of this component in meconium may be due to the ingestion of amniotic fluid by the fetus during pregnancy.

     

Gastric acid secretory function in preterm infants

To establish normal values for gastric secretory function in preterm infants, we studied 34 healthy preterm infants once a week during hospitalization. Basal acid output, pentagastrin-stimulated acid output, fasting serum gastrin, and fasting serum pancreatic polypeptide were measured during each study. Basal acid output at 1 week of age was 12 mumol/kg/hr, increasing over the first 4 weeks to 30 mumol/kg/hr. Administration of pentagastrin 6 micrograms/kg subcutaneously increased acid output in all age groups. Pentagastrin-stimulated acid output at 1 week was 21 mumol/kg/hr, increasing over the first 4 weeks to 44 mumol/kg/hr. Acid secretion did not change significantly over the next 4 to 6 weeks. Fasting serum gastrin concentration was stable over the first 6 weeks of life, but doubled during the end of the second month. Pancreatic polypeptide was found at low levels throughout the study. These studies confirm that the majority of healthy preterm infants secrete acid in quantity sufficient to maintain the gastric pH less than or equal to 4, providing a barrier to bacteria and protein antigens.     

早产儿中性粒细胞活性氧代谢的研究

目的：该研究通过对于不同胎龄新生儿中性粒细胞活性氧代谢水平的检测研究,以了解新生儿中性粒细胞功能发育成熟的过程,并探讨早产儿对于细菌高易感性的部分原因。方法：选择早产儿35例,分为胎龄32周以下和33～36周两组,并选择足月新生儿23例作为对照组。在新生儿出生后取脐静脉血进行体外实验,分别以金黄色葡萄球菌和大肠杆菌刺激诱导呼吸爆发后用超氧阴离子特异性探针氢化溴乙非锭进行细胞内染色,通过流式细胞仪检测中性粒细胞超氧阴离子阳性细胞比率和产生水平;同时对两组不同胎龄早产儿细菌感染实际发生情况进行比较。结果：胎龄32周以下早产儿超氧阴离子阳性中性粒细胞比率与胎龄32周以上早产儿和足月新生儿相比差异有显著性,呈明显低下状态［金黄色葡萄球菌:（79.4±8.6）% vs （89±6.1）% vs （91.3±3.8）%,F＝18.05,P＜0.01;大肠杆菌: （78.2±7.8）% vs （89.3±5.3）% vs （92±4.1）%,F＝28.3, P＜0.01)］;而且阳性率和早产儿胎龄大小密切相关(y＝2.66 x ,P＜0.01);但3组不同胎龄的新生儿活性氧代谢阳性细胞超氧阴离子产生水平之间的差异无显著性。临床观察发现小胎龄早产儿组全身性细菌感染实际发生率高于大胎龄组早产儿。结论：新生儿中性粒细胞细菌诱导活性氧代谢的总体能力直接和新生儿成熟度相关,在胎龄小于32周早产儿中处于明显低下状态,并随着胎龄的增加逐渐成熟。早产儿中性粒细胞活性氧代谢水平的总体低下是导致早产儿细菌感染高易感性的重要原因之一。［中国当代儿科杂志,2007,9（4）：355-357］     

Fetal malnutrition and its impacts on neonatal outcome in preterm infants

Fetal malnutrition is an important risk factor for both early and late neonatal outcome and adult diseases. In this study, we aimed to investigate the incidence and characteristics of fetal malnutrition and its impacts on early neonatal morbidity and mortality in preterm infants by using the clinical assessment of nutritional status score (CANSCORE). Preterm infants whose gestational ages were between 28-34 weeks were included in the study. Detailed prenatal and natal history, anthropometric measurements, and intrauterine growth status were defined, and CANSCORE was applied to all infants. Infants were separated into two groups according to total score as malnourished (total score < 25) and well nourished (total score > or = 25). Early and late neonatal morbidities, which were observed during the clinical progress, were noted in all infants. A total of 93 preterm infants were enrolled in the study. The incidence of fetal malnutrition was 54.8% (n = 51) in all infants. The incidences of maternal hypertension and preeclampsia, oligohydramnios and disturbed umbilical artery Doppler flow in the prenatal period and the incidences of neonatal hypoglycemia, polycythemia, feeding intolerance, and necrotizing enterocolitis in the postnatal period were significantly higher in preterm infants with fetal malnutrition. Fetal malnutrition contributes significantly to many early and late neonatal morbidities in preterm infants, and it should be identified in every preterm infant in the first days of life for predicting neonatal outcome, even though they are appropriately grown.     

Control of vitamin D metabolism in preterm infants: feto-maternal relationships.

To assess the relationship between maternal and fetal mineral homeostasis, serum calcium, magnesium, inorganic phosphate, parathyroid hormone, and vitamin D metabolite concentrations in venous cord sera from 15 preterm singletons and 3 twin pairs were compared with the levels found in maternal sera. Cord calcium, magnesium, and phosphorus levels were significantly higher than the respective levels in maternal samples. There was a significant relationship between the two compartments for all three analyses. Cord serum 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D levels were significantly lower than those observed for the mothers. Association of the cord concentration with that of the mothers was observed only for the first two metabolites. There was no relationship between the maternal 1,25-dihydroxyvitamin D levels and gestational age, calcium, magnesium, inorganic phosphate, or 25-hydroxyvitamin D. Cord 1,25-dihydroxyvitamin D correlated significantly only with cord calcium levels. Immunoreactive parathyroid hormone levels were within normal limits both in cord and maternal samples. Our data suggest that after 31 weeks of gestation: (1) calcium, magnesium, and inorganic phosphate cross the placental barrier against a concentration gradient; (2) the fetus depends on the maternal supply for 25-hydroxyvitamin D and 24,25 dihydroxyvitamin D; (3) the feto-placental unit synthesizes 1,25-dihydroxyvitamin D according to fetal needs.     

Vitamin D metabolism in preterm infants: effect of a calcium load

Decrease in serum calcium level leading to hypocalcemia during the first week of life is a frequent finding in premature neonates. Eight premature neonates presenting with such an episode of hypocalcemia in the course of their first 4 days of life were studied. They were fed with a phosphate-enriched human milk and given vitamin D3 (2,100 IU/day per os). We have evaluated the effect of a 24-hour pharmacologic calcium infusion on the circulating levels of calcium, inorganic phosphate, magnesium, 25-hydroxycalciferol (25-OHD), 1 alpha,25-dihydroxycalciferol [1,25(OH)2D] and immunoreactive parathyroid hormone (iPTH). After the infusion, circulating iPTH and Pi levels dropped significantly (p less than 0.025 and p less than 0.005 respectively) whereas serum Ca and 25-OHD (p less than 0.005) increased. Mg and 1,25(OH)2D serum levels remained unchanged. Our data show that an increased calcium supply sustained for 24 h induces an appropriate response in iPTH secretion. Effects on circulating levels of 1,25(OH)2D were variable and probably reflected individual differences in half life of 1,25(OH)2D or in set points in the feedback mechanisms involved in the control of 1,25(OH)2D synthesis.     

Morphine metabolism in acutely ill preterm newborn infants.

To examine the manner in which morphine is metabolized in acutely ill premature infants, we measured the levels of morphine, morphine-3- and -6-glucuronides, and codeine in timed urine specimens and paired plasma specimens at 4 hours and 24 hours after a single dose of morphine in 16 preterm infants (less than 32 weeks of gestational age). A large amount of unmetabolized morphine was found in the urine in 13 (81.2%) of the 16 infants at 4 hours; in 12 of them, morphine was excreted even at 24 hours. Urinary morphine levels varied greatly; the coefficient of variation was 130% at 4 hours and 118% at 24 hours. Codeine was not found in any of the infants. In 10 (62.5%) of the 16 infants, at least one metabolite was found in either plasma or urine. Plasma and urinary levels of morphine conjugates also varied greatly among these 10 infants (coefficient of variation: 109% to 317%). All six infants (37.5%) who had no metabolites excreted large amounts of unmetabolized morphine in the urine for up to 24 hours. Birth weight, gestational age, postnatal age, systemic blood pressure, and other clinical or physiologic variables did not differ significantly between the 10 infants who had morphine conjugates and the six who did not. We conclude that (1) nearly two thirds of acutely ill preterm infants born at less than 32 weeks of gestational age conjugate morphine; (2) irrespective of their ability to produce morphine conjugates, preterm infants excrete large amounts of morphine unmetabolized, as late as 24 hours after a single dose; (3) morphine handling patterns are highly variable among premature infants, and no obvious factors account for the variability; and (4) such variability in morphine handling in general, and the production of the highly potent morphine-6-glucuronide in particular, could explain the variance in morphine pharmacokinetic measures and in the clinical responses to morphine during the newborn period.