The impact of maternal diabetes on birth to placental weight ratio and umbilical cord oxygen values with implications for fetal-placental development.

Introduction: We determined the impact of gestational diabetes (GDM) and pre-existing diabetes (DM) on birth/placental weight and cord oxygen values with implications for placental efficiency and fetal-placental growth and development.

Methods: A hospital database was used to obtain birth/placental weight, cord PO and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA >34 weeks (N = 69,854). Oxygen saturation was calculated from the cord PO and pH data, while fetal O extraction was calculated from the oxygen saturation data.

Fetal sex impacts birth to placental weight ratio and umbilical cord oxygen values with implications for regulatory mechanisms.

Background: We determined the effect of fetal sex on birth/placental weight and umbilical vein and artery oxygen values with implications for placental efficiency and regulatory mechanisms underlying fetal-placental growth differences.

Methods: A hospital database was used to obtain birth/placental weight, cord PO and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 weeks (N = 69,836). Oxygen saturation was calculated from the cord PO and pH data, while fractional O extraction was calculated from the oxygen saturation data.

Differential and Synergistic Effects of Low Birth Weight and Western Diet on Skeletal Muscle Vasculature, Mitochondrial Lipid Metabolism and Insulin Signaling in Male Guinea Pigs.

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar "Western" diet (WD) modulates these changes.

Gestational age impacts birth to placental weight ratio and umbilical cord oxygen values with implications for the fetal oxygen margin of safety.

Background: We determined the impact of gestational age (GA) from near term to term to post-term on birth/placental weight ratio and cord oxygen values with implications for placental transport efficiency for oxygen, fetal O consumption relative to delivery or fractional O extraction, and oxygen margin of safety.

Materials And Methods: A hospital database was used to obtain birth/placental weight ratios, cord PO and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 completed weeks (N = 69,852). Oxygen saturation was calculated from the cord PO and pH data, while fractional O extraction was calculated from the oxygen saturation data.

Maternal Undernourishment in Guinea Pigs Leads to Fetal Growth Restriction with Increased Hypoxic Cells and Oxidative Stress in the Brain.

Background: We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for brain hypoxia and oxidative stress.

Methods: Guinea pigs were fed ad libitum (control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1) was injected into pregnant sows.

Fetal Growth Restriction Is Associated With Decreased Number of Ovarian Follicles and Impaired Follicle Growth in Young Adult Guinea Pig Offspring.

Background: The mechanisms mediating the impacts of fetal growth restriction (FGR) on follicular development are commonly studied in mouse/rat models, where ovarian development occurs largely during the early postnatal period. These models have shown that FGR is associated with premature follicle loss, early pubertal onset, and accelerated ovarian aging. Whether the same occurs in precocious species is unknown.

Maternal nutrient restriction in guinea pigs leads to fetal growth restriction with increased brain apoptosis.

Background: We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts cell death in the brain with implications for neurodevelopmental adversity.

Methods: Guinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Fetuses were necropsied near term and brain tissues processed for necrosis (H&E), apoptosis (TUNEL), and pro- (Bax) and anti- (Bcl-2 and Grp78) apoptotic protein immunoreactivity.

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic.

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health.

A Doubly Stochastic Change Point Detection Algorithm for Noisy Biological Signals.

Experimentally and clinically collected time series data are often contaminated with significant confounding noise, creating short, noisy time series. This noise, due to natural variability and measurement error, poses a challenge to conventional change point detection methods. We propose a novel and robust statistical method for change point detection for noisy biological time sequences.

Maternal nutrient restriction in guinea pigs as an animal model for studying growth-restricted offspring with postnatal catch-up growth.

We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs with fetal growth restriction (FGR) on offspring body and organ weights, hypothesizing that FGR-MNR animals will show catch-up growth but with organ-specific differences. Guinea pig sows were fed ad libitum (Control) or 70% of the control diet from 4 weeks preconception, switching to 90% at midpregnancy (MNR). Control newborns >95 g [appropriate for gestational age (AGA); n = 37] and MNR newborns <85 g (FGR; n = 37) were monitored until neonatal (~25 days) or adult (~110 days) necropsy.

Maternal body mass index impacts fetal-placental size at birth and umbilical cord oxygen values with implications for regulatory mechanisms.

Background: Maternal under- and over-nutrition are known to effect fetal growth with altered placental development and nutrient transport, but whether fetal oxygenation is also altered remains unknown.

Aims: To examine linkages between maternal BMI and birth weights, placental weights, and umbilical vein and artery PO with implications for signaling mechanisms.

Study Design: Population-based cohort study.

Maternal nutrient restriction in guinea pigs leads to fetal growth restriction with evidence for chronic hypoxia.

BackgroundWe determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for tissue hypoxia, implicating a mechanistic role for chronic hypoxia.MethodsGuinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows.

Brain Injury and Inflammatory Response to Umbilical Cord Occlusions Is Limited With Worsening Acidosis in the Near-Term Ovine Fetus.

We hypothesized that repetitive umbilical cord occlusions (UCOs) with worsening fetal acidemia will lead to an inflammatory response within the brain and thereby brain injury which will be exacerbated by chronic hypoxemia and low-grade infection. Chronically instrumented fetal sheep served as controls (N = 10) or underwent repeated UCOs for up to 4 hours or until arterial pH was <7.00.

Accelerated acidosis in response to variable fetal heart rate decelerations in chronically hypoxic ovine fetuses.

Background: Due to limitations of technology, clinicians are typically unable to determine if human fetuses are normoxic or moderately, chronically hypoxic. Risk factors for chronic hypoxia include fetal growth restriction, which is associated with an increased incidence of oligohydramnios and thus a risk for umbilical cord occlusion (UCO) and variable fetal heart rate (FHR) decelerations. At delivery, fetal growth restriction infants (<3rd percentile) have nearly twice the incidence of low Apgar scores and umbilical pH <7.

Apoptosis in the Ovine Fetal Brain Following Placental Embolization and Intermittent Umbilical Cord Occlusion.

The purpose of this study was to compare the regional distribution of apoptotic cells in the near term ovine fetal brain caused by prolonged moderate hypoxia, as seen in placental insufficiency, and intermittent severe hypoxia, as seen in umbilical cord compression, which may then contribute to adverse neurodevelopment in the postnatal life. We hypothesized that apoptosis in the fetal brain will be increased in response to both prolonged moderate hypoxia and intermittent severe hypoxia. Twenty-one near term (126-127 days) sheep were divided into 3 groups: control (CON; n = 7), placental embolization (EMB; n = 7), and umbilical cord occlusion (UCO; n = 8).

Maternal Nutrient Restriction in Guinea Pigs as an Animal Model for Inducing Fetal Growth Restriction.

We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs on pregnancy outcomes, maternal/fetal growth parameters, and blood analytes to further characterize the utility of this model for inducing fetal growth restriction (FGR). Thirty guinea pig sows were fed ad libitum (Control) or 70% of the control diet prepregnant switching to 90% at midpregnancy (MNR). Animals were necropsied near term with weights obtained on all sows, fetuses, and placenta.

Adaptive shut-down of EEG activity predicts critical acidemia in the near-term ovine fetus.

In fetal sheep, the electrocorticogram (ECOG) recorded directly from the cortex during repetitive heart rate (FHR) decelerations induced by umbilical cord occlusions (UCO) predictably correlates with worsening hypoxic-acidemia. In human fetal monitoring during labor, the equivalent electroencephalogram (EEG) can be recorded noninvasively from the scalp. We tested the hypothesis that combined fetal EEG - FHR monitoring allows for early detection of worsening hypoxic-acidemia similar to that shown for ECOG-FHR monitoring.

The Ovine Fetal and Placental Inflammatory Response to Umbilical Cord Occlusions With Worsening Acidosis.

We hypothesized that repetitive umbilical cord occlusions (UCOs) leading to severe acidemia will stimulate a placental and thereby fetal inflammatory response which will be exacerbated by chronic hypoxemia and low-grade bacterial infection. Chronically instrumented fetal sheep served as controls or underwent repetitive UCOs for up to 4 hours or until fetal arterial pH was <7.00.

Online detection of fetal acidemia during labour by testing synchronization of EEG and heart rate: a prospective study in fetal sheep.

Severe fetal acidemia during labour can result in life-lasting neurological deficits, but the timely detection of this condition is often not possible. This is because the positive predictive value (PPV) of fetal heart rate (FHR) monitoring, the mainstay of fetal health surveillance during labour, to detect concerning fetal acidemia is around 50%. In fetal sheep model of human labour, we reported that severe fetal acidemia (pH<7.

Acceleration and deceleration capacity of fetal heart rate in an in-vivo sheep model.

Background: Fetal heart rate (FHR) variability is an indirect index of fetal autonomic nervous system (ANS) integrity. FHR variability analysis in labor fails to detect early hypoxia and acidemia. Phase-rectified signal averaging (PRSA) is a new method of complex biological signals analysis that is more resistant to non-stationarities, signal loss and artifacts.

Adaptive brain shut-down counteracts neuroinflammation in the near-term ovine fetus.

Objective: Repetitive umbilical cord occlusions (UCOs) in ovine fetus leading to severe acidemia result in adaptive shut-down of electrocortical activity [electrocorticogram (ECoG)] as well as systemic and brain inflammation. We hypothesized that the fetuses with earlier ECoG shut-down as a neuroprotective mechanism in response to repetitive UCOs will show less brain inflammation and, moreover, that chronic hypoxia will impact this relationship.

Methods: Near-term fetal sheep were chronically instrumented with ECoG leads, vascular catheters, and a cord occluder and then underwent repetitive UCOs for up to 4 h or until fetal arterial pH was <7.

Sampling rate of heart rate variability impacts the ability to detect acidemia in ovine fetuses near-term.

Background: To evaluate the impact of sampling rate on the predictive capability of continuous fetal heart rate (FHR) variability (fHRV) monitoring for detecting fetal acidemia during labor, we tested the performance of the root mean square of successive differences (RMSSD) in R-R intervals from the ECG when acquired with the sampling rate of 4 Hz currently available in FHR monitors, in comparison to the gold standard of 1000 Hz.

Methods: Near-term ovine fetuses (N = 9) were chronically prepared with precordial electrodes for recording ECG, vascular catheters for blood sampling, and an umbilical cord occluder. For 1 min every 2.

Microtubule-associated protein 2 and synaptophysin in the preterm and near-term ovine fetal brain and the effect of intermittent umbilical cord occlusion.

We have determined the change in immunoreactivity (IR) for microtubule-associated protein 2 (MAP-2) and synaptophysin (SYN) as markers for dendritic and presynaptic nerve development, respectively, in the ovine fetal brain with advancing gestation and in response to intermittent umbilical cord occlusion (UCO), which might then contribute to adverse neurodevelopment. Fetal sheep (control and experimental groups preterm at 111-115 and near term at 132-138 days of gestation; term = 145 days) were studied over 4 days with UCOs performed by inflation of an occluder cuff for 90 seconds every 30 minutes for 3 to 5 hours each day. Animals were then euthanized and fetal brains assessed for IR of MAP-2 and SYN.

Cytokines in umbilical cord blood and the impact of labor events in low-risk term pregnancies.

Background: Inflammatory mechanisms involved in the onset and progression of labor at term may affect the fetal compartment impacting neonatal outcomes.

Study Design: Umbilical cord blood collected from umbilical cords after delivery of the fetus and again after delivery of the placenta in low-risk non-laboring and laboring patients was analyzed for blood gases/pH and multiple cytokines.

Results: Umbilical cord levels of IL-6, IL-8 and IL-10 were increased 6, 2 and 1.