The Role of the Kynurenine Pathway in the (Patho) physiology of Maternal Pregnancy and Fetal Outcomes: A Systematic Review

Abstract

Introduction: Tryptophan is the precursor of kynurenine pathway (KP) metabolites which regulate immune tolerance, energy metabolism, and vascular tone. Since these processes are important during pregnancy, changes in KP metabolite concentrations may play a role in the pathophysiology of pregnancy complications. We hypothesize that KP metabolites can serve as novel biomarkers and preventive therapeutic targets. This review aimed to provide more insight into associations between KP metabolite concentrations in maternal and fetal blood, and in the placenta, and adverse maternal pregnancy and fetal outcomes. Methods: A systematic search was performed on 18 February 2022 comprising all KP metabolites, and keywords related to maternal pregnancy and fetal outcomes. English-written human studies measuring KP metabolite(s) in maternal or fetal blood or in the placenta in relation to pregnancy complications, were included. Methodological quality was assessed using the ErasmusAGE quality score (QS) (range: 0-10). A meta-analysis of the mean maternal tryptophan and kynurenine concentrations in uncomplicated pregnancies was conducted. Results: Of the 6262 unique records, 37 were included (median QS = 5). Tryptophan was investigated in most studies, followed by kynurenine, predominantly in maternal blood (n = 28/37), and in the second and third trimester of pregnancy (n = 29/37). Compared to uncomplicated pregnancies, decreased tryptophan in maternal blood was associated with an increased prevalence of depression, gestational diabetes mellitus, fetal growth restriction, spontaneous abortion, and preterm birth. Elevated tryptophan was only observed in women with pregnancy-induced hypertension compared to normotensive pregnant women. In women with preeclampsia, only kynurenic acid was altered; elevated in the first trimester of pregnancy, and positively associated with proteinuria in the third trimester of pregnancy. Conclusions: KP metabolite concentrations were altered in a variety of maternal pregnancy and fetal complications. This review implies that physiological pregnancy requires a tight balance of KP metabolites, and that disturbances in either direction are associated with adverse maternal pregnancy and fetal outcomes.

Maternal Tryptophan Catabolites and Insulin Resistance Parameters in Preeclampsia

“…Furthermore, placental TRP concentration was found to be elevated in early-onset preeclampsia while reduced in late-onset PE [47]. The concentration of placental TRP was found to be elevated in cases of early-onset preeclampsia, whereas it was observed to be reduced in cases of late-onset preeclampsia [47]. These results may explain some controversy in the findings of TRP in PE women.…”

“…A comparative analysis of the placentas revealed dysregulation of TRP metabolism in the placentas of women with PE, compared to the controls [43]. Furthermore, placental TRP concentration was found to be elevated in early-onset preeclampsia while reduced in late-onset PE [47]. The concentration of placental TRP was found to be elevated in cases of early-onset preeclampsia, whereas it was observed to be reduced in cases of late-onset preeclampsia [47].…”

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder

“…KP metabolite levels in the fetal brain are higher during the perinatal period [ 127 ], decrease in the immediate postnatal period, and remain lower in adulthood under physiological conditions [ 128 ]. A recent systematic review also indicated that physiological pregnancy requires a tight balance of KP metabolites [ 129 ]. A major source of these KP metabolites is provided from the mother to the fetus via transplacental transfer and Trp degradation in the placenta [ 128 ].…”

“…Additionally, Carpita et al investigated the changes in KP metabolites in ASD adults, and they found significantly lower levels of Trp and QUIN and no changes in Kyn and Kyna [ 2 ]. Recently, a meta-analysis comprising all KP metabolites and keywords related to maternal pregnancy and the fetal outcome showed that an altered KP metabolite concentration is significantly related to a high risk of preeclampsia, fetal growth restriction, and preterm birth [ 129 ]. These are all considered risk factors for ASD [ 204 , 205 , 206 ].…”

LC-MS/MS-based Quantification of Tryptophan, Kynurenine, and Kynurenic Acid in Human Placental, Fetal Membranes, and Umbilical Cord Samples

“…Furthermore, the kynurenine pathway is involved in many physiological processes, playing an important role in pregnancy, regulating the placental vascular and immune tolerance, and providing neuroprotection during pregnancy 1,2,18,19 . For instance, the functional role of IDO in the maintenance of pregnancy in the mammalian placenta was demonstrated in vivo, where inhibition of IDO resulted in pregnancy loss in mice 20 .…”