Maternal serum IGF-I, IGFBP-1 and IGFBP-3 at 11-13 weeks in trisomy 21 and trisomy 18 pregnancies

Objective

To investigate the possible value of maternal serum concentration of insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1) and IGFBP-3 in first-trimester screening for fetal aneuploidies.

Study design

Maternal serum concentrations of IGF-I, IGFBP-1 and IGFBP-3 at 11-13 weeks of gestation were measured and compared in 30 trisomy 21, 30 trisomy 18 and 120 euploid pregnancies.

Results

The median multiple of the normal median (MoM) values of maternal serum IGF-I, IGFBP-1 and IGFBP-3 in trisomy 21, trisomy 18 and euploid pregnancies were not significantly different (IGF-I: 1.10, 1.14 and 1.0 MoM, respectively; IGFBP-1: 1.10, 1.01 and 1.0 MoM; IGFBP-3: 0.90, 1.16 and 0.98 MoM).

Conclusion

Measurement of maternal serum IGF-I, IGFBP-1 and IGFBP-3 at 11-13 weeks of gestation is unlikely to be useful in screening for trisomies 21 and 18.     

Maternal serum insulin-like growth factor (IGF-I) and binding proteins IGFBP-1 and IGFBP-3 at 11-13 weeks' gestation in pregnancies delivering small for gestational age neonates

Objective

To investigate the possible value of maternal serum concentration of insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1) and IGFBP-3 at 11–13 weeks’ gestation in the prediction of small-for-gestational age (SGA) neonates.

Study design

Maternal serum concentrations of IGF-I, IGFBP-1 and IGFBP-3 at 11–13 weeks were measured in 60 cases that subsequently delivered SGA neonates in the absence of pre-eclampsia, and compared to 120 non-SGA controls.

Results

In the SGA group, compared to the non-SGA group, there was significantly lower median IGF-I (61.8, IQR 43.4–93.4 ng/mL vs 94.9, IQR 56.7–131.2 ng/mL, p = 0.002) and IGFBP-1 (58.2, IGR 39.8–84.9 ng/mL vs 81.4, IGR 57.3–105.5 ng/mL, p = 0.002) but not IGFBP-3 (54.5, IGR 45.6–61.5 ng/mL vs 55.4, IGR 47.4–64.9 ng/mL, p = 0.402). However, after multiple regression analysis and adjustment for maternal characteristics, these biomarkers were not useful in predicting SGA.

Conclusion

Maternal serum IGF-I, IGFBP-1 and IGFBP-3 at 11–13 weeks are unlikely to be useful biochemical markers for early prediction of SGA.     

Periconceptional alcohol consumption causes fetal growth restriction and increases glycogen accumulation in the late gestation rat placenta

Introduction

Alcohol consumption is a common social practice among women of childbearing age. With 50% of pregnancies being unplanned, many embryos are exposed to alcohol prior to pregnancy recognition and formation of the placenta. The effects of periconceptional (PC) alcohol exposure on the placenta are unknown.

Methods

Sprague-Dawley rats were exposed to alcohol (12.5% v/v ad libitum) from 4 days prior to 4 days after conception and effects on placental growth, morphology and gene/protein expression examined at embryonic day (E) 20.

Results

PC ethanol (EtOH)-exposed fetuses were growth restricted and their placental/body weight ratio and placental cross-sectional area were increased. This was associated with an increase in cross-sectional area of the junctional zone and glycogen cells, especially in PC EtOH-exposed placentas from female fetuses. Junctional Glut1 and Igf2 mRNA levels were increased. Labyrinth Igf1 mRNA levels were decreased in placentas from both sexes, but protein IGF1R levels were decreased in placentas from male fetuses only. Labyrinth mRNA levels of Slc38a2 were decreased and Vegfa were increased in placentas following PC EtOH-exposure but only placentas from female fetuses exhibited increased Kdr expression. Augmented expression of the protective enzyme 11βHsd2 was found in PC EtOH-exposed labyrinth.

Discussion

These observations are consistent with a stress response, apparent well beyond the period of EtOH-exposure and demonstrate that PC EtOH alters placental development in a sex specific manner.

Conclusion

Public awareness should be increased to educate women about how excessive drinking even before falling pregnant may impact on placental development and fetal health.     

Gene expression patterns of insulin-like growth factor 1, 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in human placenta from preterm deliveries: influence of additional factors

Objective

To compare patterns of human placental gene expression of IGF from pregnancies that ended with preterm delivery vs. full term pregnancies as controls.

Study design

Real-time PCR was used to assess gene expression of IGF in human placental samples from 104 preterm and 140 full term pregnancies.

Results

In the preterm delivery group, the proportion of smokers was significantly higher than in the control group. A history of preterm delivery was more common in the preterm delivery group compared to the control group. In the preterm delivery group, placental samples showed an underexpression of the IGF-1 gene compared to controls. In cases of male fetal gender an overexpression of both the IGF-2 and the IGFBP-3 genes was observed.

Conclusion

Among environmental factors influencing preterm delivery, smoking was the most significant in our study. In the majority of cases, preterm delivery was induced by intrauterine infection leading to a decreased activity of the IGF system. This mechanism may also play a role in the development of neurological sequelae and in decreased tolerance to fetal distress. The overexpression of the IGF-2 gene observed in the placenta with male fetal gender can be explained by its physiological role in the development of the male phenotype.     

LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation

Introduction

During pregnancy, maternal infection at different stages of gestation increases the risk of developing several psychiatric and neurological disorders later in life for affected offspring. As placental health is intrinsically linked to neurodevelopmental outcome, maternal infection may adversely affect the placenta at or before the gestational stages it affects fetal neurodevelopment. Here we examined this premise.

Methods

Pregnant-Sprague Dawley rats were administered saline or lipopolysaccharide by intraperitoneal injection on embryonic days 12–18. We then examined a number of key placental inflammatory and endocrine mediators, along with fetal, birth and neuronal characteristics at different stages of development.

Results

Maternal exposure to lipopolysaccharide at later gestational ages significantly increased pro-inflammatory IL-1β expression and reduced placental HSD11B2 expression. This was accompanied by a reduction in placental weight and embryo number without an effect on embryo weight or crown-rump length. In utero lipopolysaccharide exposure at later gestational ages also impaired the growth of neurons from affected offspring.

Discussion

These data show that maternal infection at later gestational ages modifies placental inflammatory and endocrine mediators that may adversely affect the growth of developing neurons in affected offspring.     

Recapitulation of characteristics of human placental vascular insufficiency in a novel mouse model

Objective

We tested the effects of selective reduction of placental blood flow by mesenteric uterine artery branch ligation (MUAL) resulting in fetal growth restriction (FGR).

Methods

Timed mated C57BL/6J Day(D) 18 dams were divided into two groups: MUAL (n = 18); and control-sham (n = 18). Pups were delivered on D20, cross-fostered to surrogate CD-1 mothers for 4 weeks, and followed for 8 weeks. Outcome data included birth and placental weight, postnatal growth, placental volume determined by stereology, quantification of placental insulin-like growth factors-1(IGF-1) and IGF-2 and IGF binding proteins(IGFBP 2 and 6) by ELISA and gene expression by qPCR and GeneChip microarray analysis.

Results

Compared with control, MUAL had an 11% reduction in mean birth weight (1.06 ± 0.13 g vs. 0.94 ± 0.13 g, p < 0.001) but no difference in placental weight. At 4 weeks of age, mean body weights of MUAL pups were significantly lower than sham. By 8 weeks, males but not females MUAL mice achieved equivalent mean body weight to control. Placental labyrinth depth, volume, and placental gene expression of IGF-1 and 2 were significantly reduced by MUAL. In contrast, placental protein level of IGFBP-2 and 6 were significantly elevated in the MUAL. Genomic expression analysis demonstrated that MUAL pups significantly up-regulated genes that were associated with apoptosis and growth pathways.

Conclusion

This novel mouse animal model of FGR using selective ligation recapitulates multiple characteristics of placental vascular insufficiency (PI) in humans. This is the first non-genetic mouse model of PI which offers its application in transgenic mice to better study the underlying mechanisms in PI.

Condensation

A new mouse model of placental vascular insufficiency by selective ligation of mesenteric uterine artery branch recapitulates multiple findings observed in human placental vascular insufficiency.     

Cellular inhibitors of apoptosis (cIAP) 1 and 2 are increased in placenta from obese pregnant women

Introduction

Independent of their role in apoptosis, cellular inhibitors of apoptosis (cIAP) 1 and 2, have emerged as regulators of inflammation. Obesity in pregnancy is characterised by maternal and placental inflammation. Thus, the aim of this study was to determine the effect of maternal obesity and pro-inflammatory mediators on cIAP expression in human placenta.

Methods

The expression of cIAP was assessed in human placenta from lean (n = 15) and obese (n = 14) patients by qRT-PCR and Western blotting. Primary trophoblast cells were used to determine the effect of pro-inflammatory cytokines on cIAP expression, and the effect of cIAP siRNA on pro-inflammatory cytokines.

Results

cIAP1 and cIAP2, gene and protein expression were significantly higher in placenta from women with pre-existing maternal obesity compared to placenta form lean women. Additionally, bacterial endotoxin LPS and the pro-inflammatory cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1β significantly increased the expression of both cIAP1 and cIAP2 in primary trophoblast cells isolated from human term placenta. Knockdown of cIAP1 or cIAP2 in human primary trophoblast cells significantly decreased TNF-α induced expression and secretion of pro-inflammatory cytokines IL-6 and IL-8 and of matrix metalloproteinase (MMP)-9.

Discussion

cIAP1 and cIAP2 expression is increased in placenta from women with pre-existing maternal obesity and in response to treatment with pro-inflammatory cytokines. Functional studies in placental trophoblast cells revealed that cIAPs are involved in TNF-α induced-expression of pro-inflammatory cytokines. Given the central role of pro-inflammatory cytokines in placental nutrient transport, this data suggest that cIAP1 and cIAP2 may play a role in fetal growth and development.     

Placental glucose transporter 3 (GLUT3) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction

Introduction

Transport of glucose from maternal blood across the placental trophoblastic tissue barrier is critical to sustain fetal growth. The mechanism by which GLUTs are regulated in trophoblasts in response to ischemic hypoxia encountered with intrauterine growth restriction (IUGR) has not been suitably investigated.

Objective

To investigate placental expression of GLUT1, GLUT3 and GLUT4 and possible mechanisms of GLUT regulation in idiopathic IUGR.

Methods

We analyzed clinical, biochemical and histological data from placentas collected from women affected by idiopathic full-term IUGR (n = 10) and gestational age-matched healthy controls (n = 10).

Results

We found increased GLUT3 protein expression in the trophoblast (cytotrophoblast greater than syncytiotrophoblast) on the maternal aspect of the placenta in IUGR compared to normal placenta, but no differences in GLUT1 or GLUT4 were found. No differential methylation of the GLUT3 promoter between normal and IUGR placentas was observed. Increased GLUT3 expression was associated with an increased nuclear concentration of HIF-1α, suggesting hypoxia may play a role in the up-regulation of GLUT3.

Discussion

Further studies are needed to elucidate whether increased GLUT3 expression in IUGR is a marker for defective villous maturation or an adaptive response of the trophoblast in response to chronic hypoxia.

Conclusions

Patients with IUGR have increased trophoblast expression of GLUT3, as found under the low-oxygen conditions of the first trimester.     

What factors determine placental glucose transfer kinetics?

Introduction

Transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations even when these are well above the physiological range. This study investigates the relationship between maternal and fetal glucose concentrations and transfer across the placenta.

Methods

Transfer of d-glucose, ³H-3-o-methyl-d-glucose (³H-3MG) and ¹⁴C-l-glucose across the isolated perfused human placental cotyledon was determined for maternal and fetal arterial d-glucose concentrations between 0 and 20 mmol/l.

Results

Clearance of ³H-3MG or ¹⁴C-l-glucose was not affected by maternal or fetal d-glucose concentrations in either circulation.

Discussion

Based on the arterial glucose concentrations and the reported K_M for GLUT1, the transfer of d-glucose and ³H-3MG would be expected to show signs of saturation as d-glucose concentrations increased but this did not occur. One explanation for this is that incomplete mixing of maternal blood and the rate of diffusion across unstirred layers may lower the effective concentration of glucose at the microvillous membrane and subsequently at the basal membrane. Uncertainties about the affinity of GLUT1 for glucose, both outside and inside the cell, may also contribute to the difference between the predicted and observed kinetics.

Conclusion

These factors may therefore help explain why the observed and predicted kinetics differ and they emphasise the importance of understanding the function of transport proteins in their physiological context. The development of a computational model of glucose transfer may improve our understanding of how the determinants of placental glucose transfer interact and function as a system.     

Oxidative stress and maternal obesity: Feto-placental unit interaction

Objective

To determine oxidative stress markers in maternal obesity during pregnancy and to evaluate feto-placental unit interaction, especially predictors of fetal metabolic alterations.

Patients and methods

40 obese pregnant women (prepregnancy BMI > 30 kg/m²) were compared to 50 control pregnant women. Maternal, cord blood and placenta samples were collected at delivery. Biochemical parameters (total cholesterol and triglycerides) and oxidative stress markers (malondialdehyde, carbonyl proteins, superoxide anion expressed as reduced Nitroblue Tetrazolium, nitric oxide expressed as nitrite, reduced glutathione, catalase, superoxide dismutase) were assayed by biochemical methods.

Results

Maternal, fetal and placental triglyceride levels were increased in obese group compared to control. Maternal malondialdehyde, carbonyl proteins, nitric oxide and superoxide anion levels were high while reduced glutathione concentrations and superoxide dismutase activity were low in obesity. In the placenta and in newborns of these obese mothers, variations of redox balance were also observed indicating high oxidative stress. Maternal and placental interaction constituted a strong predictor of fetal redox variations in obese pregnancies.

Discussion

Maternal obesity compromised placental metabolism and antioxidant status which strongly impacted fetal redox balance. Oxidative stress may be one of the key downstream mediators that initiate programming of the offspring.

Conclusion

Maternal obesity is associated with metabolic alterations and dysregulation of redox balance in the mother-placenta – fetus unit. These perturbations could lead to maternal and fetal complications and should be carefully considered.     

The risk of placental abruption and placenta previa in pregnant women with chronic hepatitis B viral infection: A systematic review and meta-analysis

Introduction

Several epidemiological studies have found a positive association between chronic hepatitis B virus (CHB) infection and the risk of placental abruption and placenta previa, but various studies have reported conflicting findings. The objective was to systematically review the literature to determine a possible association between CHB infection and these two placental complications.

Methods

We conducted a computerized search in electronic database through March 1, 2014, supplemented with a manual search of reference lists, to identify original published research on placental abruption and placenta previa rates in women with CHB infection. Data were independently extracted, and relative risks were calculated. The meta-analysis was performed using Stata version 10.0 software.

Results

Five studies involving 9088 placenta previa cases were identified. No significant association between CHB infection and placenta previa was identified (OR = 0.98, 95% CI = 0.60–1.62). Five studies involving 15571 placental abruption cases were identified. No significant association between CHB infection and placental abruption was identified (OR = 1.42, 95% CI, 0.93–2.15).

Discussion

The immune response against the virus represents a key factor in determining infection outcomes. No observation of significant increased risk of the placental complications could be partially explained by the complex immune response during CHB infection.

Conclusions

Our meta-analysis found no evidence of significant associations between CHB infection and increased risk of placental abruption as well as placenta previa. Further well-designed studies were warranted to assess any potential association between CHB infection and increased risk of placental abruption as well as placenta previa.     

Partitioning of glutamine synthesised by the isolated perfused human placenta between the maternal and fetal circulations

Introduction

Placental glutamine synthesis has been demonstrated in animals and is thought to increase the availability of this metabolically important amino acid to the fetus. Glutamine is of fundamental importance for cellular replication, cellular function and inter-organ nitrogen transfer. The objective of this study was to investigate the role of glutamate/glutamine metabolism by the isolated perfused human placenta in the provision of glutamine to the fetus.

Methods

Glutamate metabolism was investigated in the isolated dually perfused human placental cotyledon. U–¹³C-glutamate was used to investigate the movement of carbon and ¹⁵N-leucine to study movement of amino-nitrogen. Labelled amino acids were perfused via maternal or fetal arteries at defined flow rates. The enrichment and concentration of amino acids in the maternal and fetal veins were measured following 5 h of perfusion.

Results

Glutamate taken up from the maternal and fetal circulations was primarily converted into glutamine the majority of which was released into the maternal circulation. The glutamine transporter SNAT5 was localised to the maternal-facing membrane of the syncytiotrophoblast. Enrichment of ¹³C or ¹⁵N glutamine in placental tissue was lower than in either the maternal or fetal circulation, suggesting metabolic compartmentalisation within the syncytiotrophoblast.

Discussion

Placental glutamine synthesis may help ensure the placenta's ability to supply this amino acid to the fetus does not become limiting to fetal growth. Glutamine synthesis may also influence placental transport of other amino acids, metabolism, nitrogen flux and cellular regulation.

Conclusions

Placental glutamine synthesis may therefore be a central mechanism in ensuring that the human fetus receives adequate nutrition and is able to maintain growth.     

Doppler evaluation of the effects of propofol,etomidate and alphaxalone on fetoplacental circulation hemodynamics in the pregnant ewe

Introduction

Umbilical artery (UA) hemodynamics reflect blood flow and vascular resistance in the placental circulation. We examined non-invasively the hemodynamic effects of propofol, etomidate, and alphaxalone on the placental circulation of a sheep model by means of UA Doppler ultrasonography.

Methods

Eleven sheep fetuses were examined at 90–109 days of gestation. UA Doppler ultrasound was performed before and after administration of a single intravenous bolus of propofol, etomidate, or alphaxalone. UA Doppler velocities (peak systolic velocity, end diastolic velocity, and mean velocity), vascular indices (pulsatility index, resistance index, and S/D ratio), blood flow, and fetal heart rate were recorded during the experimental period and UA Doppler waveforms were characterized.

Results

A laminar, parabolic, low resistance flow was observed in the UA of the sheep fetuses. No statistically significant changes were observed in the UA Doppler waveforms or in the UA Doppler hemodynamics after anesthesia induction.

Discussion

Changes in placental vascular resistance may alter the corresponding UA Doppler waveforms. When resistance in the fetal placenta increases, blood flow in the UA becomes more pulsatile. In the present study, umbilical arteries showed a parabolic flow with low resistance in all cases, as it occurs in normal human pregnancy. The administration of these anesthetics did not cause abnormalities in the normal UA Doppler pattern, inducing no changes in the resistance of the placenta in any case.

Conclusion

These results suggest that intravenous anesthetic induction with propofol, etomidate, or alphaxalone does not cause significant detrimental effects on the placental circulation of the pregnant ewe.     

Fetal sex specific differences in human placentation: A prospective cohort study

Introduction

Our objective was to assess fetal sex specific differences in first trimester placental biomarkers of both physiological and pathological pregnancies and their interaction with environmental influences. This study is embedded in the Generation R Study, a prospective cohort study.

Methods

Only live singleton births were included. Linear regression was performed to assess the effect of sex on first trimester placental biomarkers. Interaction analyses were performed to assess interaction of fetal sex with environmental influences. First trimester soluble fms-like tyrosine kinase (s-Flt1), placental growth factor (PLGF), plasminogen activator inhibitor (PAI-2) and homocysteine levels were assessed.

Results

Significant fetal sex specific differences in placental biomarkers were observed. S-Flt1, PAI-2 and PLGF log transformated concentrations were 0.08 ng/mL (95% CI 0.05; 0.11), 0.07 ng/mL (95% CI 0.06; 0.09) and 0.04 pg/mL (95% CI 0.01; 0.06) higher in case of female as compared to male placentas. In pregnancies complicated by pre-eclampsia (PE), preterm birth (PTB) or a newborn being small for gestational age (SGA) no fetal sex specific differences were observed. Interaction analyses suggest that concentrations of s-Flt1, PLGF and PAI-2 decrease in male placentas in the case of hyperhomocysteinemia but remain equal in female placentas.

Discussion

Fetal sex affects early placentation processes with discrepancies regarding pregnancies complicated by PE, PTB or a newborn being SGA. This suggests that other mechanisms causing these complications may dominate the fetal sex effect. The differences concerning homocysteine suggest that fetal sex dependent placental gene–environment interactions exist.

Conclusion

Fetal sex specific differences in placental biomarkers exist.     

Proliferative responses in the placenta after endotoxin exposure in preterm fetal sheep

Objectives

Antenatal infections are associated with an increased risk of perinatal morbidity and mortality. Systemic application of endotoxins to the fetus results in an increase in placental vascular resistance and chronic reduction in umbilical blood flow. We studied morphological alterations of the placenta in response to fetal inflammation in the preterm sheep.

Study design

Therefore, 14 fetal sheep were chronically instrumented at a mean gestational age of 107 ± 1 days (term is 147 days). Four days after surgery fetuses received 100 ng lipopolysaccharide (LPS; n = 8) or saline (control; n = 6) intravenously. Fetal heart rate and arterial blood pressure were monitored continuously while blood gases and acid–base balance were measured at time points 0, +1, +3, +6, +12, +24, +48 and +72 h. Three days after LPS application placental cotyledons were analyzed by immunohistochemistry and morphometry. Different primary antibodies like AE 1 and AE 3 against cytokeratins were used. Secondary antibodies were visualized with 3-amino-9-ethylcarbazole (AEC) or using the Vectastain kit (Vector Laboratories, Burlingame, CA). Double staining was carried out first by utilizing Vectastain kit (black), followed by AEC staining (red). Counterstaining was performed with haematoxylin.

Results

Fetal tachycardia and hypertension were induced transiently during the first 12 h after LPS application. Fetuses suffered from mild hypoxaemia while acidemia was absent. Morphometry revealed a non-significant shift in the relation of maternal and fetal placental compartments towards the maternal parts in response to LPS treatment. Endotoxin induced an increased proliferation in both compartments of the placenta with a 3.2-fold increase on the maternal and a 1.8-fold increase on the fetal side.

Conclusions

Systemic endotoxin exposure of the preterm fetal sheep leads to a change in the gross organization of the placenta and changes in the proliferation patterns in both placental compartments. These rearrangements inside the placenta may disturb its organ function and subsequently lead to fetal morbidity associated with the fetal inflammatory response syndrome and chronic placental dysfunction, respectively.     

The effect of maternal prenatal smoking and alcohol consumption on the placenta-to-birth weight ratio

Background

Maternal influence on fetal growth is mediated through the placenta and this influence may have an implication for the offspring's long-term health. The placenta-to-birth weight ratio has been regarded as an indicator of placental function. However, few studies have examined the effect of maternal lifestyle exposures on the placenta-to-birth weight ratio. This study aims to examine the associations of maternal prenatal smoking and alcohol consumption with the placenta-to-birth weight ratio.

Methods

Data for 7945 term singletons, gestation≥37 weeks, were selected from the Tasmanian Infant Health Survey; a 1988–1995 Australian cohort study. Placenta and birth weight were extracted from birth notification records.

Results

Maternal smoking during pregnancy was strongly associated with a 6.77 g/kg higher (95% CI 4.83–8.71) placenta-to-birth weight ratio when compared to non-smoking mothers. Maternal prenatal smoking was associated with lower placental (β = −15.37 g; 95% CI −23.43 to −7.31) and birth weights (β = −205.49 g; 95% CI −232.91 to −178.08). Mothers who consumed alcohol during pregnancy had a lower placenta–to-birth weight ratio (β = −2.07 g/kg; 95% CI −4.01 to −0.12) than mothers who did not consume alcohol. The associations of maternal alcohol consumption during pregnancy with placental and birth weight did not reach statistical significance.

Discussion

Maternal prenatal smoking and alcohol consumption may influence fetal growth by either directly or indirectly altering the function of the placenta.

Conclusions

The alteration of the in utero environment induced by smoking and alcohol consumption appears to affect placental and fetal growth in differing ways. Further studies are needed to elucidate the mechanism.