Placental abnormalities differ between small for gestational age fetuses in dichorionic twin and singleton pregnancies

ObjectiveTwin fetuses grow slower during the third trimester compared with singletons. However, the extent to which the relative smallness of twins is the result of placenta-mediated factors similar to those associated with fetal growth restriction in singletons remains unclear. Our aim was to address this question by comparing placental findings between small for gestational age (SGA) twins and SGA singletons.MethodsRetrospective cohort study of all SGA non-anomalous newborns from singleton and dichorionic twin pregnancies in a single tertiary referral center between 2002 and 2015. SGA was defined as birth weight <10th percentile for gestational age according to sex-specific national reference charts. Placental findings were compared between SGA twins and SGA singletons and were classified into lesions associated with maternal vascular malperfusion, fetal vascular malperfusion, placental hemorrhage and chronic villitis.ResultsA total of 532 SGA twins and 954 SGA singletons met the inclusion criteria. SGA twins had a higher mean placental weight (371 ± 103 g vs. 319 ± 107, p < 0.001) and a lower fetal-placental ratio (6.0 ± 2.5 vs. 6.7 ± 3.2, p < 0.001) compared with SGA singletons. Compared with SGA singletons, SGA twins were less likely to have any placental pathology (aOR 0.37, 95%-CI 0.29–0.46), hypercoiled cord (aOR 0.45, 95%-CI 0.33–0.61), placental weight<10th% (aOR 0.13, 95%-CI 0.08–0.20), maternal vascular malperfusion pathology (aOR 0.24, 95%-CI 0.18–0.30) and fetal vascular malperfusion pathology (aOR 0.62, 95%-CI 0.48–0.82). By contrast, SGA twins had higher odds of a marginal or velamentous cord insertion compared with SGA singletons (aOR 13.82, 95%-CI 10.44–18.30). Similar significant associations were observed in subgroups of SGA fetuses with a birth weight below the 5th and 3rd percentile for gestational age.ConclusionsOur findings illustrate that the mechanisms underlying reduced fetal growth in dichorionic twins differ from those involved in singletons, and may provide support to the hypothesis that smallness in dichorionic twins may be more benign than in singletons.     

Impact of early- and late-onset preeclampsia on features of placental and newborn vascular health

IntroductionOffspring exposed to preeclampsia (PE) show an increased risk of cardiovascular disease in adulthood. We hypothesize that this is mediated by a disturbed vascular development of the placenta, umbilical cord and fetus. Therefore, we investigated associations between early-onset PE (EOPE), late-onset PE (LOPE) and features of placental and newborn vascular health.MethodsWe performed a nested case-control study in The Rotterdam Periconceptional Cohort, including 30 PE pregnancies (15 EOPE, 15 LOPE) and 218 control pregnancies (164 uncomplicated controls, 54 complicated controls including 28 fetal growth restriction, 26 preterm birth) and assessed macroscopic and histomorphometric outcomes of the placenta and umbilical cord.ResultsA significant association was observed between PE and a smaller umbilical vein area and wall thickness, independent of gestational age and birth weight. In EOPE we observed significant associations with a lower weight, length and width of the placenta, length of the umbilical cord, and thickness and wall area of the umbilical vein and artery. These associations attenuated after gestational age and birth weight adjustment. In LOPE a significant association with a larger placental width and smaller umbilical vein wall thickness was shown, independent of gestational age and birth weight.DiscussionOur study suggests that PE is associated with a smaller umbilical cord vein area and wall thickness, independent of gestational age and birth weight, which may serve as a proxy of disturbed cardiovascular development in the newborn. Follow-up studies are needed to ultimately predict and lower the risk of cardiovascular disease in offspring exposed to PE.     

Placental histology in spontaneous and indicated preterm birth: A case control study

IntroductionPlacental pathology is an important contributor in preterm birth, both spontaneous and indicated. The aim of this study was to describe and compare placental histological features of spontaneous preterm birth versus indicated preterm birth.MethodsA case control study was performed at the University Medical Center Utrecht. Women with spontaneous or indicated preterm birth (17–37 weeks of gestation) delivered in 2009 were included. Women with a pregnancy complicated by congenital and/or chromosomal abnormalities were excluded. Placentas were systematically examined by an expert pathologist blinded for pregnancy outcome, except for gestational age. Placental histological abnormalities were classified into infectious inflammatory lesions and maternal vascular malperfusion lesions and compared between spontaneous and indicated preterm birth. Analysis was stratified for immature (17–23⁺⁶ weeks), extremely (24–27⁺⁶ weeks), very (28–31⁺⁶ weeks) and moderate/late (32–36⁺⁶ weeks) preterm birth.ResultsWe included 233 women, 121 women with spontaneous preterm birth and 112 women with indicated preterm birth. Among women with spontaneous extremely preterm birth, higher rates of severe chorioamnionitis were found (56.0% vs. 0%). Furthermore, a shift from infectious-inflammatory lesions to maternal vascular malperfusion lesions was seen after 28 weeks; in women with spontaneous very and moderate/late preterm birth, maternal vascular malperfusion lesions were the main finding (46.8% and 47.7% respectively). In women with indicated preterm birth, maternal vascular malperfusion lesions were most often contributing through all gestational age categories.ConclusionMaternal vascular malperfusion lesions are most frequent in both spontaneous and indicated very and moderate/late preterm birth. In spontaneous extreme preterm birth chorioamnionitis is the main finding.     

Villitis of unknown etiology – prevalence and clinical associations

Objectives: We aimed to determine the association of villitis of unknown etiology (VUE) in complicated and uncomplicated pregnancies.

Methods: Placentas from term pregnancies (≥37 weeks) were sent to histopathology evaluation. Maternal and labor characteristics and pathological reports were compared between placentas with VUE (VUE group) and without VUE (controls). Immunohistochemical studies were performed to identify T-cells infiltration in foci of VUE. Placentas were analyzed for concomitant lesions consistent with maternal malperfusion, fetal vascular supply and inflammatory lesions. Small for gestational age (SGA) was defined as birth weight below the 10th %.

Results: A total of 1203 placentas were obtained, in which VUE was diagnosed in 5% (n?=?60). Compared to controls ((n?=?1143), the VUE group was characterized by lower birth weights, p?<?0.001, higher rate of SGA, p?=?0.009 and lower placental weight, p?<?0.001. By logistic regression analysis, after controlling for gestational age, nulliparity, pregnancy complications, obesity, smoking and SGA, only SGA was found to be independently associated with VUE, aOR: 2.3, 95% CI: 1.2–4.4, p?=?0.012. Additionally, VUA and maternal malperfusion lesions were found to be independent risk factors for the development SGA.

Conclusions: VUE is associated with lower birth weights, SGA and lower placental weight. Both VUE and maternal malperfusion lesions are risk factors for the development of SGA.     

Maternal and placental responses before preterm birth: adaptations to increase fetal thyroid hormone availability?

Background: During pregnancy, maternal thyroid hormone supply is crucial for fetal development. Preterm infants often present with hypothyroxinemia. Preterm birth, either spontaneous or medically indicated, is always the result of a complicated pregnancy. We hypothesized that in preterm birth, the maternal transplacental thyroid hormone supply is influenced by the pregnancy complication and we questioned whether maternal and placental compensatory mechanisms are activated to increase thyroid hormone transfer.

Methods: Observational case-control study in mother–infant-dyads with complicated pregnancies ending in spontaneous preterm birth (n?=?31) or indicated preterm birth due to vascular complications (n?=?45) and normal pregnancies (healthy term controls; n?=?41). At delivery, maternal and cord blood and placenta samples were collected. Cord and maternal plasma concentrations of thyroid stimulating hormone (TSH), total T4, fT4/FTI, total T3, and T4 binding globulin (TBG), and maternal serum concentrations of thyroid peroxidase (TPO)-antibodies were measured. Placental maturity was evaluated histologically and mRNA and/or protein levels of thyroid hormone deiodinases (DiO) 1, 2 and 3, and transporters (MCT8, MCT10, and OATP1c1) were quantified.

Results: In indicated and spontaneous preterm births, cord plasma T4 concentrations were lower than in healthy term controls (p?≤?.001), whereas T3 was only decreased in spontaneous preterm birth (p?≤?.001). Compared with spontaneous preterm births and healthy term controls, indicated preterm birth was characterized by higher maternal plasma TSH (p?≤?.05), earlier placental maturation, higher placental DiO2 gene and MCT10 protein levels and lower DiO3 gene levels (all p?≤?.01).

Conclusions: Low T4 was observed in preterm infants irrespective of the cause of preterm birth, while maternal (TSH) and placental (DiO2, DiO3, and MCT10) compensatory responses were only activated in indicated preterm birth due to vascular complications. This may have mediated the normal fetal T3 availability in preterm infants born after indicated preterm birth but not after spontaneous preterm birth.     

Stillbirth Following Normal Ultrasound Findings and Maternal Placental Growth Factor Levels

BackgroundAttempts to reduce the current rate of antepartum stillbirth in the late third trimester have largely focused on the accurate identification of fetal growth restriction. Universal ultrasound significantly increases detection, especially when combined with maternal angiogenic growth factors, but this screening strategy is not well suited to identify umbilical cord pathology. While this poses unique challenges to pregnancy care, the recurrence risk of cord obstruction is low in comparison with many intrinsic placental diseases.CaseA 30-year-old woman with normal uterine artery Doppler waveforms, fetal growth ultrasounds, and circulating placental growth factor experienced an unexpected third-trimester stillbirth. Placental pathology demonstrated fetal vascular malperfusion and cord hyper-coiling.ConclusionDespite normal placental function, the otherwise healthy fetus is at risk of antepartum stillbirth due to cord-related pathology.     

Placental findings in late-onset SGA births without Doppler signs of placental insufficiency

Objectives

To describe placental pathological findings in late-onset small-for-gestational age (SGA) births for which Doppler signs of placental insufficiency are lacking.

Methods

A series of placentas were evaluated from singleton pregnancies of SGA births (birth weight below the 10th percentile) delivered after 34 weeks with normal umbilical artery Doppler (pulsatility index below the 95th percentile), that were matched by gestational age with adequate-for-gestational age (AGA) controls. Using a hierarchical and standardized system, placental lesions were classified histologically as consequence of maternal underperfusion, fetal underperfusion or inflammation.

Results

A total of 284 placentas were evaluated (142 SGA and 142 AGA). In the SGA group, 54.2% (77/142) of the placentas had weights below the 3rd percentile for GA while it was a 9.9% (14/142) in the AGA group (p < 0.001). Only 21.8% (31/142) of SGA placentas were free of histological abnormalities, while it was 74.6% (106/142) in the AGA group (p < 0.001). In the abnormal SGA placentas (111/142) there were a total of 161 lesions, attributable to MUP in 64% (103/161), FUP in 15.5% (25/161), and inflammation in 20.5% (33/161).

Discussion

In most placentas of term SGA neonates with normal UA Doppler histological abnormalities secondary to maternal underperfusion prevail, reflecting latent insufficiency in uteroplacental blood supply. This is consistent with the higher risk of adverse perinatal outcome reported in this population and underscores a need for new markers of placental disease.

Conclusions

A significant proportion of late-onset SGA births with normal umbilical artery Doppler may still be explained by placental insufficiency.     

Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

ObjectiveA classification model based on preterm birth clinical presentations (phenotypes) was proposed at the International Conference on Prematurity and Stillbirth, with calls for validation. This study sought to determine the distribution of clinical phenotypes of preterm birth among nulliparous women, their corresponding associations with maternal characteristics, and the odds ratios (ORs) of preterm Caesarean section and other adverse outcomes.MethodsA population-based cohort study was performed of all nulliparous women with singleton pregnancies (>20 weeks) who gave birth in a hospital in Ontario between 2012 and 2014. Logistic regression models were used to estimate adjusted ORs (Canadian Task Force Classification II-2).ResultsAmong 113 942 nulliparous women, 6.1% delivered at <37 weeks, at a mean gestational age of 33.9 weeks. Of those women, 34.1% did not meet the criteria for the presence of any clinical phenotype; 42.3% had one maternal, fetal, or placental condition; 22.3% had two clinical conditions; and 1.3% had three clinical conditions. The most common preterm birth phenotypes were worsening of maternal diseases (24.0%), intrauterine growth restriction (23.5%), and fetal distress (23.0%). Compared with preterm births without any significant clinical phenotype, those with maternal, fetal, or placental phenotypes were associated with increased odds of Caesarean section (adjusted ORs 2.70 [95% confidence interval [CI] 2.30–3.17], 1.66 [95% CI 1.36–2.03], and 6.49 [95% CI 4.29–9.80], respectively).ConclusionApproximately two thirds of nulliparous preterm births were grouped into distinct clinical phenotypes. This study demonstrated that outcomes varied across phenotypes, thus providing evidence of benefit for the phenotypic classification model.     

The association between placental histopathology and autism spectrum disorder

IntroductionResearch suggests that autism spectrum disorder (ASD) has its origins in utero. This study examines the association between evidence of placental histopathology and ASD.MethodsAdministrative claims data and medical records data were used to identify ASD cases (N = 55) and matched controls (N = 199) born at New York Methodist Hospital between 2007 and 2014 and subsequently seen in affiliated pediatrics clinics. Placentas from all births during this time period were reviewed as part of routine care. Data were analyzed using conditional logistic regression to account for the matched (gender, gestational age, and birth weight) design.ResultsAcute placental inflammation, regardless of type was associated with an increased risk of ASD (odds ratio [OR] = 3.14, 95% CI = 1.39, 6.95). Chronic uteroplacental vasculitis (OR = 7.13; 95% CI = 1.17, 43.38), the fetal inflammatory response in the chorionic plate vessels (OR = 5.12; 95% CI = 2.02, 12.96), and maternal vascular malperfusion pathology (OR = 12.29; 95% CI = 1.37, 110.69) were associated with an increased risk of ASD. Placental villous edema was associated with a decreased risk of ASD (OR = 0.05; 95% CI = 0.0005, 0.42). In subanalyses among male placentas acute inflammation overall, fetal inflammatory response in the chorionic plate vessels, and maternal vascular malperfusion pathology remained significantly associated with an increased risk of ASD whereas placental villous edema remained associated with a decreased risk of ASD.DiscussionHistologic evidence of placental inflammation and maternal vascular malperfusion pathology are associated with ASD.     

Association of caesarean delivery for first birth with placenta praevia and placental abruption in second pregnancy

Objective  To quantify the risk of placenta praevia and placental abruption in singleton, second pregnancies after a caesarean delivery of the first pregnancy.
Design  Retrospective cohort study.
Setting  Linked birth and infant mortality database of the USA between 1995 and 2000.
Population  A total of 5 146 742 singleton second pregnancies were available for the final analysis after excluding missing information.
Methods  Multiple logistic regressions were used to describe the relationship between caesarean section at first birth and placenta praevia and placental abruption in second-birth singletons.
Main outcome measures  Placenta praevia and placental abruption.
Results  Placenta praevia was recorded in 4.4 per 1000 second-birth singletons whose first births delivered by caesarean section and 2.7 per 1000 second-birth singletons whose first births delivered vaginally. About 6.8 per 1000 births were complicated with placental abruption in second-birth singletons whose first births delivered by caesarean section and 4.8 per 1000 birth in second-birth singletons whose first births delivered vaginally. The adjusted odds ratio (95% CIs) of previous caesarean section for placenta praevia in following second pregnancies was 1.47 (1.41, 1.52) after controlling for maternal age, race, education, marital status, maternal drinking and smoking during pregnancy, adequacy of prenatal care, and fetal gender. The corresponding figure for placental abruption was 1.40 (1.36, 1.45).
Conclusion  Caesarean section for first live birth is associated with a 47% increased risk of placenta praevia and 40% increased risk of placental abruption in second pregnancy with a singleton.     

Second Trimester Placental Growth Factor Levels and Placental Histopathology in Low-Risk Nulliparous Pregnancies

ObjectivePlacental growth factor (PlGF) levels are lower at delivery in pregnancies with preeclampsia or fetuses small for gestational age (SGA). These obstetrical complications are typically mediated by placental dysfunction, most commonly related to the specific placental phenotype termed placental maternal vascular malperfusion (MVM). The objective of this study was to determine the relationship between PlGF levels in the second trimester and the development of placental diseases that underlie adverse perinatal outcomes.MethodsWe performed a secondary analysis of the prospective Placental Health Study in unselected healthy nulliparous women (n = 773). Maternal demographic data, Doppler ultrasound measurements, and plasma PlGF levels at 15 to 18 weeks gestation were analyzed for association with pregnancy outcomes and placental pathology following delivery.ResultsLow PlGF levels in the second trimester (<10th percentile; <72 pg/mL) was associated with preterm delivery (<37 weeks; 26% vs. 6%, P < 0.001; unadjusted odds ratio (OR) 5.75, 95% CI 3.2–10.5), reduced mean birth weight (2998 vs. 3320 g, P < 0.001), SGA deliveries (25% vs. 11%, P = 0.001; OR 2.6, 95% CI 1.5–4.6), and preeclampsia (7% vs. 2%, P = 0.02; OR 4.3, 95% CI 1.5-12.8) relative to normal PlGF levels (≥10th percentile; ≥72 pg/mL). Low PlGF was associated with lower mean placental weight (447 vs. 471 g, P = 0.01), aberrant cord insertion (25% vs. 12%, P = 0.001) and a pathologic diagnosis of MVM (18% vs. 11%, P = 0.04; OR 1.9, 95% CI 1.01–3.55) but not with other placental pathologies.ConclusionMVM placental pathology and related adverse perinatal outcomes are associated with low PlGF in the early second trimester for healthy nulliparous women.     

Placental ratio and risk of velamentous umbilical cord insertion are increased in women with placenta previa

The purpose of this study was to explore the maternal risk profile and obstetric outcome in pregnancies affected by placenta previa. Retrospective case-control study involved all women (93 [0.37%] women with diagnosed placenta previa and 24,857 unaffected controls) who gave birth to singleton infants at Kuopio University Hospital between the years 1989 and 2000. Grand multiparity, infertility problems, and advanced maternal age were independent risk factors of placenta previa, with adjusted relative risks of 5.8, 3.7, and 2.4, respectively. Most women with placenta previa (88.2%) underwent cesarean delivery before term. They also more often had velamentous umbilical cord insertion (7.5%) and higher placental-to-birthweight ratios than the controls. Placenta previa was associated with risks of preterm delivery, low birthweight infants, and need for neonatal intensive care, at odds ratios of 27.7, 7.4, and 3.4, respectively. In conclusion, placenta previa is an infrequent pregnancy complication associated with multiparity, advanced maternal age, infertility problems, elevated placental ratio, and velamentous umbilical cord insertion.     

Associations between the levels of soluble (pro)renin receptor in maternal and umbilical cord blood and hypertensive disorder of pregnancy

IntroductionThe prorenin (PR) receptor [(P)RR] contributes to the regulation of the tissue renin-angiotensin system (RAS) and Wnt signaling, which is involved in embryogenesis and the pathological progression of malignant tumors and diabetes mellitus. Placental (P)RR is significantly upregulated in placental tissues from preeclamptic women. However, because it cannot be examined during pregnancy, the chronological relationship between the acceleration of tissue RAS and the disease state of hypertensive disorder of pregnancy (HDP) has not been reported. In this study, we examined whether chronological changes in placental tissue RAS can be assessed by measuring soluble (P)RR [s(P)RR].MethodsWe obtained maternal and umbilical cord blood samples from 517 pregnant women (441 singleton and 76 twin pregnancies). The concentrations of s(P)RR and prorenin (PR) were measured using enzyme-linked immunosorbent assays.ResultsMultivariate analysis showed that maternal serum s(P)RR levels were significantly higher in patients with HDP or fetal growth restriction (FGR) and were positively correlated with serum PR levels. Furthermore, the maternal s(P)RR level was significantly higher in HDP with severe hypertension and after the onset of HDP. However, maternal s(P)RR levels were not affected by the severity of proteinuria. Serum s(P)RR levels in umbilical cord blood of singleton pregnancies were significantly correlated with gestational week at delivery and PR level.DiscussionMaternal serum s(P)RR concentrations may reflect acceleration of tissue RAS in the placenta and blood pressure severity; however, the umbilical serum s(P)RR concentration was not affected by maternal HDP.     

Pregnancy outcome and placental pathology in small for gestational age neonates in relation to the severity of their growth restriction

Purpose: To investigate neonatal outcome and placental pathology in pregnancies complicated with small for gestational age neonates (SGA), in relation to the severity of growth restriction.

Methods: The medical records and placental histology reports of all neonates with a birth-weight (BW) ≤10th percentile, born between 24–42 weeks, during 2010–2015, were reviewed. Placental lesions were classified into maternal and fetal vascular malperfusion (MVM and FVM) lesions. Results were compared between neonates with BW <5th percentile (severe SGA group), neonates with BW between 5th–10th percentile (mild SGA group) and a control group of appropriate for gestational age (AGA) neonates. Composite neonatal outcome was defined as one or more of early complications.

Results: Overall, 753 neonates were included, 238 in the severe SGA group, 266 in the mild SGA group, and 249 in the control group. The severe SGA group had higher rates of composite adverse neonatal outcome as compared with the mild SGA and control groups (37.2 versus 17.6%, versus 24.5%, respectively, p?p?Conclusions: Worse neonatal outcome and more placental MVM and FVM lesions correlate with the severity of neonatal growth restriction in a “dose-dependent” manner.     

Placental location and newborn weight

ObjectivePrevious studies suggest that placental location may affect fetal growth and the risks of preterm birth and preeclampsia. We studied the association between placental location and newborn weight.MethodsWe conducted a retrospective cohort study of 796 consecutive singleton births in women who delivered at ≥ 37 weeks’ gestation between July and October 2009. We evaluated placental location at the time of the second trimester prenatal ultrasound at 16 to 24 weeks’ gestation. Placental location was classified as lateral or central/fundal. We assessed the difference in newborn weight according to placental location and the incidence of small for gestational age birth weight < 10th percentile and pregnancy-induced hypertension. Using logistic regression analysis, odds ratios were adjusted for maternal age, world region of birth, gravidity, parity, maternal weight, history of hypertension or diabetes, current smoking or illicit drug use, and infant sex.ResultsAmong women with lateral versus central/fundal placentas, the respective mean (SD) birth weights were 3298 (550) g and 3352 (579) g (mean difference 54 g, 95% CI 53 to 161; P = 0.32). Relative to central/fundal location, laterally located placentas had an adjusted OR of 0.81 (95% CI 0.42 to 1.54) for SGA and 0.62 (95% CI 0.18 to 2.10) for preeclampsia/gestational hypertension.ConclusionPlacental location was not associated with differences in newborn weight or other perinatal outcomes.     

Risk factors for antepartum fetal death

OBJECTIVE: To determine the demographic, maternal, pregnancy-related and fetal risk factors for antepartum fetal death (APFD). STUDY DESIGN: From our perinatal database between the years 1990 and 1997, 68,870 singleton birth files were analyzed. Fetuses weighing < 1,000 g at birth and those with structural malformations and/or known chromosomal anomalies were excluded from the study. In order to determine independent factors contributing to APFD, a multiple logistic regression model was constructed. RESULTS: During the study period there were 246 cases of APFD (3.6 per 1,000 births). The following obstetric factors significantly correlated with APFD in a multiple logistic regression model: preterm deliveries: small size for gestational age (SGA), multiparity (> 5 deliveries), oligohydramnios, placental abruption, umbilical cord complications (cord around the neck and true knot of cord), pathologic presentations (nonvertex) and meconium-stained amniotic fluid. APFD was not significantly associated with advanced maternal age. CONCLUSION: APFD was significantly associated with several risk factors. Placental and umbilical cord pathologies might be the direct cause of death. Grand multiparity, oligohydramnios, meconium-stained amniotic fluid, pathologic presentations and suspected SGA should be carefully evaluated during pregnancy in order to decrease the incidence of APFD.     

Altered placental tryptophan metabolic pathway in human fetal growth restriction

IntroductionTryptophan is a substrate for kynurenine pathway metabolism in the placenta. We investigated if kynurenine metabolites change over gestation, if they are different between pregnancies with normal and fetal growth restriction (FGR), and if the oxygen environment modulated kynurenine pathway activity in the human placenta.MethodsTryptophan, kynurenine, and downstream kynurenine metabolites were determined in maternal venous blood, umbilical cord blood, and placental samples obtained in 1st and 3rd trimester pregnancies including FGR, and in the media of placental explants incubated with 20% or 5–8% O₂ for 24, 48 or 72 h.ResultsAll the major kynurenine metabolites were present in cord blood, and in general were higher than in maternal blood. IDO and TDO mRNA and protein expression, responsible for kynurenine production from tryptophan, were significantly lower in placentas from FGR pregnancies compared with control. Explants prepared from 1st and 3rd trimester placentas actively produced all the major kynurenine pathway metabolites which, together with expression of IDO, TDO, KYN-OHase and 3HAO mRNAs, were significantly lower after 24 h exposure to 5–8% O₂ compared to 20% O₂ConclusionsExpression and activity of the kynurenine pathway is present in the placenta from early gestation, and is down-regulated by hypoxia and in FGR pregnancies.