Broekhuizen Michelle, Allenberg Heike, van der Ley Claude P, van Zundert Sofie K M, Cai Zongye, van Faassen Martijn, Merkus Daphne, Danser A H Jan, Lange Anja, Reiss Irwin K M, Heckmann Matthias
Division of Neonatology, Department of Pediatric and Neonatal Intensive Care, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Reprod Biol Endocrinol. 2025 Jul 21;23(1):105. doi: 10.1186/s12958-025-01436-6.
Tryptophan and its kynurenine pathway (KP) metabolites play key roles in modulating the immune system and vasculature, and exhibit both pro- and antioxidant properties, making them crucial for a healthy pregnancy and fetal development. Disruptions in the KP may impact both prenatal and postnatal health, however, data on fetal KP metabolite concentrations and their alterations in pregnancy-related disorders remain scarce. This study aims to investigate the association between pregnancy complications and KP metabolite concentrations in umbilical cord blood.
Pregnancies complicated by preeclampsia (n = 40), fetal growth restriction (FGR, n = 33), pregestational diabetes mellitus (DM, n = 42), gestational diabetes mellitus (GDM, n = 61), and amniotic infection syndrome (AIS, n = 47) were included, along with 410 controls matched in a 1:2 ratio using Mahalanobis nearest-neighbor matching from a prospective birth cohort study. Tryptophan, kynurenine, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid, xanthurenic acid, quinolinic acid, picolinic acid, and nicotinic acid were measured in umbilical cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differences in metabolite concentrations were analyzed using unpaired t-tests and linear regression models to control for potential confounders.
Tryptophan concentrations were decreased in cases of preeclampsia and DM. We identified elevated levels of 3-hydroxykynurenine in preeclampsia, kynurenine in GDM, and nicotinic acid in both FGR and DM. Quinolinic acid levels were also higher in preeclampsia and GDM, although this was not significant after adjusting for confounding variables. We observed no changes in KP metabolites in AIS.
This study identified distinct alterations in umbilical cord blood KP metabolite concentrations in pregnancies with preeclampsia, FGR, DM, and GDM, but not AIS. This suggests differential regulation and activation of the KP depending on the pregnancy disorder. Such changes may influence maternal and infant health and could play a role in fetal programming, with potential long-term effects on child development and health.
色氨酸及其犬尿氨酸途径（KP）代谢产物在调节免疫系统和血管系统中起关键作用，兼具促氧化和抗氧化特性，对健康妊娠和胎儿发育至关重要。然而，KP紊乱可能影响产前和产后健康，关于胎儿KP代谢产物浓度及其在妊娠相关疾病中的变化的数据仍然匮乏。本研究旨在探讨脐带血中妊娠并发症与KP代谢产物浓度之间的关联。
纳入患有子痫前期（n = 40）、胎儿生长受限（FGR，n = 33）、孕前糖尿病（DM，n = 42）、妊娠期糖尿病（GDM，n = 61）和羊膜腔感染综合征（AIS，n = 47）的孕妇，以及来自一项前瞻性出生队列研究中使用马氏距离最近邻匹配以1:2比例匹配的410名对照。采用液相色谱-串联质谱法（LC-MS/MS）测定脐带血中的色氨酸、犬尿氨酸、邻氨基苯甲酸、3-羟基犬尿氨酸、3-羟基邻氨基苯甲酸、犬尿酸、黄尿酸、喹啉酸、吡啶酸和烟酸。使用非配对t检验和线性回归模型分析代谢产物浓度差异，以控制潜在混杂因素。
子痫前期和糖尿病患者的色氨酸浓度降低。我们发现子痫前期患者的3-羟基犬尿氨酸水平升高，妊娠期糖尿病患者的犬尿氨酸水平升高，胎儿生长受限和糖尿病患者的烟酸水平升高。子痫前期和妊娠期糖尿病患者的喹啉酸水平也较高，尽管在调整混杂变量后这一差异不显著。我们观察到羊膜腔感染综合征患者的KP代谢产物无变化。
本研究发现子痫前期、胎儿生长受限、糖尿病和妊娠期糖尿病孕妇的脐带血KP代谢产物浓度有明显变化，但羊膜腔感染综合征患者无此变化。这表明根据妊娠疾病的不同，KP存在差异调节和激活。这些变化可能影响母婴健康，并可能在胎儿编程中起作用，对儿童发育和健康产生潜在的长期影响。
