Barbra de Vrijer

Altered placental and fetal expression of IGFS and IGF-binding proteins associated with intrauterine growth restriction in fetal sheep during early and mid-pregnancy

The insulin-like growth factors (IGFs) are postulated to be altered in association with the development of intrauterine growth restriction (IUGR). The present studies examined placental and fetal hepatic mRNA concentration of components of the IGF system at two time points (55 and 90 d gestational age, dGA; Term 147 dGA) in a hyperthermia (HT)-induced sheep model of placental insufficiency-IUGR. Maternal plasma insulin and IGF-I were constant at 55 and 90 dGA and were unaffected by treatment. Umbilical vein insulin concentrations tended to be reduced at 90 dGA following HT exposure. Caruncle IGF-I mRNA was increased at 90 dGA in HT placentae (p < 0.05), while cotyledon concentrations were constant over gestation and unaltered by treatment. In control cotyledons, IGF-II mRNA concentration increased (p < 0.01) and IGFBP-3 decreased between 55 and 90 dGA (p < 0.01). Cotyledon IGF-II and caruncle IGFBP-4 mRNA were elevated at 55 dGA in HT placentae compared with control (p < 0.01 and p < 0.05 respectively). Fetal hepatic IGF-I, IGFBP-2, -3 and -4 concentrations rose over gestation (p < 0.05), but there were no treatment effects. These data suggest that changes in placental IGF expression in early and mid gestation may predispose the pregnancy to placental insufficiency, resulting in inadequate substrate supply to the developing fetus later in gestation.

Umbilical uptakes and transplacental concentration ratios of amino acids in severe fetal growth restriction.

Background:This study examines the relationship between placental amino acid (AA) transport and fetal AA demand in an ovine fetal growth restriction (FGR) model in which placental underdevelopment induces fetal hypoxemia and hypoglycemia.Methods:Umbilical uptakes of AA, oxygen, glucose, and lactate were measured near term in eight experimental ewes (FGR group) and in eight controls (C group).Results:The FGR group demonstrated significantly reduced umbilical uptakes of oxygen, glucose, lactate, and 11 AAs per kg fetus. The combined uptake of glucose, lactate, and AAs, expressed as nutrient/oxygen quotients, was reduced almost to 1.00 (FGR: 1.05 vs. C: 1.32, P ≤ 0.02). In contrast to a decrease in umbilical glucose concentration, all but one of the AAs that were transported from placenta to fetus demonstrated normal or elevated fetal concentrations, and five of the essential AAs were transported against a significantly higher feto/maternal (F/M) concentration ratio. This ratio peaked at the lowest fetal oxygen levels.Conclusion:We conclude that, in the hypoxic FGR fetus, the reduction in AA uptake is not due to a disproportionally small placental AA transport capacity. It is the consequence of decreased fetal oxidative metabolism and growth rate, which together reduce fetal AA demand.

Non-Invasive Prenatal Testing: Ethics and Policy Considerations

New technologies analyzing fetal DNA in maternal blood have led to the wide commercial availability of non-invasive prenatal testing (NIPT). We present here for clinicians the ethical and policy issues related to an emerging practice option. Although NIPT presents opportunities for pregnant women, particularly women who are at increased risk of having a baby with an abnormality or who are otherwise likely to access invasive prenatal testing, NIPT brings significant ethics and policy challenges. The ethical issues include multiple aspects of informed decision-making, such as access to counselling about the possible results of the test in advance of making a decision about participation in NIPT. Policy considerations include issues related to offering and promoting a privately available medical strategy in publicly funded institutions. Ethics and policy considerations merge in NIPT with regard to sex selection and support for persons living with disabilities.

Maternal, umbilical arterial and umbilical venous 25‐hydroxyvitamin D and adipocytokine concentrations in pregnancies with and without gestational diabetes

Gestational diabetes mellitus (GDM) has been associated with inflammation as well as Vitamin D insufficiency. While Vitamin D has anti‐inflammatory properties, relationships between Vitamin D and inflammatory markers remain unexplored in GDM. Therefore, this case‐–control study investigated adipocytokine and Vitamin D [25(OH)D] concentrations and correlations in GDM and control women, as well as their neonates.

Male gender promotes an increased inflammatory response to lipopolysaccharide in umbilical vein blood

Objectives: To establish gender-specific differences in maternal and fetal immune response in healthy human fetuses at term. Methods: Forty-five women with elective caesarean sections for uncomplicated singleton pregnancies were recruited for two studies. Using a multiplex biomarker immunoassay system, unstimulated maternal and fetal plasma concentrations of interleukin (IL)-1β, IL-1ra, IL-6, IL-8, macrophage inflammatory protein (MIP)-1α, and tumor necrosis factor (TNF)-α were measured from one study population. Lipopolysaccharide (LPS)-stimulated cytokine response was measured in a second study. Results: There were no significant gender differences in either maternal or fetal unstimulated plasma cytokine concentrations, but concentrations of the proinflammatory cytokines IL-1β and IL-6 were significantly greater in male fetal LPS-stimulated samples than in female fetal samples. Conclusions: Blood of male fetuses mounts a larger pro-inflammatory response to lipopolysaccharide (LPS). This heightened response could be a critical pathway in promoting premature rupture of membranes (PPROM) and may be associated with life long differential gender response to infection.

Decorin over-expression by decidual cells in preeclampsia: a potential blood biomarker

BACKGROUNDnDecorin, a leucine-rich proteoglycan that is produced by decidual cells, limits invasion and endovascular differentiation of extravillous trophoblast cells during early placentation by binding to multiple tyrosine kinase receptors, in particular, vascular endothelial growth factor receptor-2.nnnOBJECTIVEnBecause many studies have reported an association between poor trophoblast invasion and endovascular differentiation with preeclampsia, the studies reported here tested (1) whether decorin over-expression in the chorionic villi and/or basal decidua is associated with preeclampsia and, if so, (2) whether this association results in a hypoinvasive placenta, and (3) whether elevated plasma decorin concentration in the second trimester is a predictive biomarker for preeclampsia.nnnSTUDY DESIGNnDecorin messenger RNA expression was measured with quantitative polymerase chain reaction at the tissue level and with in situ hybridization at the cellular level using (35)S-labeled antisense complimentary RNA probe in placentas from healthy control subjects and subjects with preeclampsia (14 each, 23-40 weeks of gestation). Tissue sections of the same placentas were also immunostained for decorin protein. A decorin over-expressing human endometrial stromal cell line was tested for invasion-regulatory effects on an invasive first-trimester extravillous trophoblast cell line HTR-8/SVneo plated in cocultures that were separated by a semipermeable membrane. Furthermore, we conducted retrospective measurements of plasma decorin levels during the second trimester (15-18 weeks of gestation) in a cohort of 28 body mass index-matched pairs of control subjects and subjects with preeclampsia before the onset of clinical disease.nnnRESULTSnFirst, decorin messenger RNA expression at the cellular level measured with in situ hybridization exhibited profoundly higher expression levels in basal plate decidual cells within the placentas from preeclamptic subjects than those from control subjects at all gestational ages, whereas no difference between the 2 subject groups was noted in villus mesenchymal cells. Similarly decorin messenger RNA expression at the tissue level in chorionic villi (primarily resulting from fetally derived mesenchymal cells) did not differ significantly between control and preeclampsia placentas. These findings were validated with immunostaining for decorin protein. Second, knocking down decorin gene in a decorin over-expressing endometrial cell line (used as an inxa0vitro surrogate of decorin over-expressing decidual cells) in cocultures with extravillous trophoblast cells abrogated its invasion-restraining actions on trophoblast cells, which indicated paracrine contribution of decorin over-expressing decidua to the poor trophoblast invasiveness in situ. Finally, retrospective measurement of plasma decorin levels during the second trimester in 28 body mass index-matched pairs of control subjects and subjects with preeclampsia revealed elevated plasma decorin levels in all subjects with preeclampsia in all body mass index groups. A receiver operating characteristic curve analysis revealed strong diagnostic performance of plasma decorin in the prediction of preeclampsia status. Although there was no significant gestational age-related change in decorin levels during the second trimester in control or subjects with preeclampsia, we found that plasma decorin had a significant inverse relationship with body mass index or bodyweight.nnnCONCLUSIONnWe conclude that decorin over-expression by basal decidual cells is associated with hypoinvasive phenotype and poor endovascular differentiation of trophoblast cells in preeclampsia and that elevated plasma decorin concentration is a potential predictive biomarker for preeclampsia before the onset of clinical signs.

Hyperpolarized (1- 13 C)Pyruvate MRI for Noninvasive Examination of Placental Metabolism and Nutrient Transport: A Feasibility Study in Pregnant Guinea Pigs

To test the feasibility of hyperpolarized [1‐13C]pyruvate magnetic resonance imaging (MRI) for noninvasive examination of guinea pig fetoplacental metabolism and nutrient transport.

Understanding Fetoplacental Growth Through Transgenic IGF Models

A review of: Crossey PA, Pillai CC, Miell JP 2002 Altered placental development and intrauterine growth restriction in IGF binding protein-1 transgenic mice. J Clin Invest 110:411–418

Socioeconomic status and adverse birth outcomes: A population-based canadian Sample

This study assessed the strength of the association between socioeconomic status (SES) and low birth weight (LBW) and preterm birth (PTB) in Southwestern Ontario. Utilizing perinatal and neonatal databases at the London Health Science Centre, maternal postal codes were entered into a Geographic Information System to determine home neighbourhoods. Neighbourhoods were defined by dissemination areas (DAs). Median household income for each DA was extracted from the latest Canadian Census and linked to each mother. All singleton infants born between February 2009 and February 2014 were included. Of 26,654 live singleton births, 6.4% were LBW and 9.7% were PTB. Top risk factors for LBW were: maternal amphetamine use, chronic hypertension and maternal marijuana use (OR respectively: 17.51, 3.18, 2.72); previously diagnosed diabetes, maternal narcotic use and insulin-controlled gestational diabetes predicted PTB (OR respectively: 17.95, 2.69, 2.42). Overall, SES had little impact on adverse birth outcomes, although low maternal education increased the likelihood of a LBW neonate (OR: 1.01).

Comparison of modified two-point dixon and chemical shift encoded MRI water-fat separation methods for fetal fat quantification: Compare Water-Fat Methods for Fetal Fat

Fetal fat is indicative of the energy balance within the fetus, which may be disrupted in pregnancy complications such as fetal growth restriction, macrosomia, and gestational diabetes. Water‐fat separated MRI is a technique sensitive to tissue lipid content, measured as fat fraction (FF), and can be used to accurately measure fat volumes. Modified two‐point Dixon and chemical shift encoded MRI (CSE‐MRI) are water‐fat separated MRI techniques that could be applied to imaging of fetal fat. Modified two‐point Dixon has biases present that are corrected in CSE‐MRI which may contribute to differences in the fat measurements.