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In pregnant women, the diabetic condition results in a three- to fivefold increased risk for fetal cardiac malformations as a result of elevated glucose concentrations and the resultant osmotic stress in the developing embryo and fetus. Heart development before septation in the chick embryo was studied under two hyperglycemic conditions. Pulsed hyperglycemia induced by daily administration of glucose during 3 days of development caused daily spikes in plasma glucose concentration. In a second model, sustained hyperglycemia was induced with a single injection of glucose into the yolk on day 0. The sustained model raised the average plasma glucose concentration from 70 mg/dL to 180 mg/dL and led to decreased gene expression of glucose transporter GLUT1. Both models of hyperglycemia reduced embryo size, increased mortality, and delayed development. Within the heart outflow tract, reduced proliferation of myocardial and endocardial cells resulted from the sustained hyperglycemia and hyperosmolarity. The cell cycle inhibitor p21 was significantly increased, whereas cyclin D1, a cell cycle promoter, decreased in sustained hyperglycemia compared with controls. The evidence suggests that hyperglycemia-induced developmental delays are associated with slowed cell cycle progression, leading to reduced cellular proliferation. The suppression of critical developmental steps may underlie the cardiac defects observed during late gestation under hyperglycemic conditions. Diabetes 62:234-242, 2013, Structural malformations of the heart affect 1% of newborn infants in the U.S. and are the leading cause of noninfectious death among children. Maternal diabetes is associated with a three- [...]

Estrogen and hypertension appear to have opposite effects on the heart. Researchers used female sheep who were either given estrogen or made hypertensive by obstructing the aorta. After three weeks, the sheep were given the opposite treatment. Estrogen caused the heart to increase in size and heart function dropped when these sheep were then made hypertensive. However, the sheep who were made hypertensive first had no heart changes even when they received estrogen.

Congenital cystic adenomatoid malformation (CCAM) is a regional overgrowth of bronchioles with suppression of alveolar development in fetal and newborn lung. Twelve patients with CCAM were treated. Six premature infants had acute respiratory distress. Prenatal ultrasound was performed only five patients and was abnormal in all five. Five premature neonates also had patent ductus arteriosus complicating their courses. Six older children presented with recurrent pneumonitis. Radiographs showed asymmetry of the chest and radiolucent masses in all 12 patients. Seven had type I lesions, two had type 11 lesions, and three had type Ill lesions. Hydramnios and hydrops were present in three, and hydrops alone was present in one of the six neonates. These four patients died. One other neonate died of respiratory failure and persistent fetal circulation. Seven patients survived for an extended period. Ultrasound makes the prenatal diagnosis of hydramnios and hydrops possible. It is in this group that fetal interventions can be considered. For the remaining patients, surgical intervention is indicated at the time of diagnosis.

Objective: Increased infant birth weight and adiposity are associated with an altered risk of adult chronic diseases. The objective was to investigate the association between maternal dietary fat intake during pregnancy and newborn adiposity. Study design: The study included 79 singleton pregnancies. Associations between maternal dietary fat intake during each trimester and infant adiposity at birth were assessed. Result: Average total grams of maternal total dietary fat and unsaturated fat intake during pregnancy correlated with infant percent body fat after adjusting for potential confounding variables (r= 0.23, p= 0.045; r= 0.24, p= 0.037). Maternal average daily intake of total fat, saturated fat, and unsaturated fat during the second trimester of pregnancy were each associated with infant percent body fat (r= 0.25, p= 0.029; r= 0.23, p= 0.046; r= 0.25, p= 0.031; respectively). Conclusions: The second trimester of pregnancy is a key time period for fetal adipose tissue metabolic programming and therefore a target for nutritional intervention.

Objective:Women with overweight/obesity have significantly lower rates of exclusive breastfeeding (EBF) at 6 weeks postpartum compared with women of normal weight. We sought to determine whether differences in Baby-Friendly Hospital Initiative (BFHI) adherence, obstetric practices, or social support explain these weight-related EBF disparities.Methods:One hundred forty-two healthy women who intended EBF (61 normal weight, 50 overweight, and 31 obese by preconception body mass index [BMI]) were enrolled in a cross-sectional study. Obstetric data were collected and participants completed modified Infant Feeding Practices Study II surveys at 6 weeks postpartum.Results:Women with obesity were significantly less likely to undergo spontaneous labor and more likely to receive synthetic oxytocin and epidural anesthesia compared with women with overweight or normal weight. Women who were overweight were less likely to report extended family support for breastfeeding compared with women with obesity or normal weight; however, BFHI components and composite BFHI score did not differ by maternal BMI. Furthermore, regardless of BMI, women with greater adherence to BFHI practices were more likely to be EBF at 6 weeks postpartum (p-value <0.001). Nonetheless, at 6 weeks postpartum, women with obesity were expressing milk more frequently and less likely to have met their own breastfeeding goals compared with women with overweight and normal weight.Conclusions:Differences in EBF rates by BMI were not explained by BFHI adherence or obstetric practices. These data suggest physiological differences, rather than intrapartum practices and support services, may explain differences in EBF rates by maternal overweight/obesity.

Birthweight is a well-known predictor of adult-onset chronic disease. The placenta plays a necessary role in regulating fetal growth and determining birth size. Maternal stressors that affect placental function and prenatal growth include maternal overnutrition and undernutrition, toxic social stress, and exposure to toxic chemicals. These stressors lead to increased vulnerability to disease within any population. This vulnerability arises from placental and fetal exposure to stressors during fetal life. The biological drivers linking various social determinants of health to compromised placental function and fetal development have been little studied.

AbstractObjective:Higher body–mass index (BMI) and lower birth weight (BW) are associated with elevated risk of diabetes in adulthood, but the extent to which they compose two distinct pathways is unclear.Methods:We used data from the National Longitudinal Study of Adolescent to Adult Health, a cohort of adolescents (1994–1995) followed for 14 years over four waves into adulthood (n= 13,413). Sex-stratified path analysis was used to examine pathways from BW [kg; linear (BW) and quadratic (BW2)] to latent trajectories in BMI from adolescence to adulthood to prevalent diabetes or prediabetes (pre/diabetes) in adulthood, adjusting for sociodemographic characteristics.Results:Two pathways from BW to pre/diabetes were characterized: one from higher BW to elevated BMI and pre/diabetes and a second from lower BW, independent of BMI. In the BMI-independent pathway, greater BW was associated with marginally lower odds of pre/diabetes in women, but not men. Girls born at lower and higher BW exhibited elevated BMI in adolescence [coeff (95% CI): BW: −2.1 (−4.1, −0.05); BW2: 0.43 (0.09, 0.76)]; higher BW predicted marginally faster BMI gain and higher adolescent BMI and faster BMI gain were associated with pre/diabetes [coeff (95% CI): BMI intercept: 0.09 (0.06, 0.11); BMI slope: 0.11 (0.07, 0.15)]. In boys, BW was weakly associated with BMI intercept and slope; BMI slope, but not BMI intercept, was positively associated with pre/diabetes [coeff (95% CI): 0.29 (0.19, 0.39)].Conclusions:Findings suggest that in girls, slowing BMI gain is critical for diabetes prevention, yet it may not address distinct pathology stemming from early life.

ObjectiveTo compare long-term cardiovascular outcomes in survivors of fetal anaemia and intrauterine transfusion with those of non-anaemic siblings.DesignRetrospective cohort study.SettingAuckland, New Zealand.ParticipantsAdults who received intrauterine transfusion for anaemia due to rhesus disease (exposed) and their unexposed sibling(s).ExposureFetal anaemia requiring intrauterine transfusion.Main outcome measuresAnthropometry, blood pressure, lipids, heart rate variability and cardiac MRI, including myocardial perfusion.ResultsExposed participants (n=95) were younger than unexposed (n=92, mean±SD 33.7±9.3 vs 40.1±10.9 years) and born at earlier gestation (34.3±1.7 vs 39.5±2.1 weeks). Exposed participants had smaller left ventricular volumes (end-diastolic volume/body surface area, difference between adjusted means −6.1, 95% CI −9.7 to −2.4 mL/m2), increased relative left ventricular wall thickness (difference between adjusted means 0.007, 95% CI 0.001 to 0.012 mm.m2/mL) and decreased myocardial perfusion at rest (ratio of geometric means 0.86, 95% CI 0.80 to 0.94). Exposed participants also had increased low frequency-to-high frequency ratio on assessment of heart rate variability (ratio of geometric means 1.53, 95% CI 1.04 to 2.25) and reduced high-density lipoprotein concentration (difference between adjusted means −0.12, 95% CI −0.24 to 0.00 mmol/L).ConclusionsThis study provides the first evidence in humans that cardiovascular development is altered following exposure to fetal anaemia and intrauterine transfusion, with persistence of these changes into adulthood potentially indicating increased risk of cardiovascular disease. These findings are relevant to the long-term health of intrauterine transfusion recipients, and may potentially also have implications for adults born preterm who were exposed to anaemia at a similar postconceptual age.

Developmental origins of health and disease (DOHaD) focuses on the earliest stages of human development, and provides a novel paradigm to complement other strategies for lifelong prevention of common chronic health conditions. The 3rdInternational Congress on DOHaD, held in 2005, retained the most popular features from the first two biannual Congresses, while adding a number of innovations, including increased emphasis on implications of DOHaD for the developing world; programs for trainees and young investigators; and new perspectives, including developmental plasticity, influences of social hierarchies, effects of prematurity, and populations in transition. Emerging areas of science included, first, the controversial role of infant weight gain in predicting adult obesity, diabetes, and cardiovascular disease. Second, in the era of epidemic obesity, paying attention to the over-nourished fetus is as important as investigating the growth retarded one. Third, environmental toxins appear to have abroad range of long-lasting effects on the developing human. Fourth, epigenetic mechanisms could unite several strands of human and animal observations, and explain how genetically identical individuals raised in similar postnatal environments can nonetheless develop widely differing phenotypes. Improving the environment to which an individual is exposed during development may be as important as any other public health effort to enhance population health world wide.

Protein tyrosine phosphatases (PTPs) mediate the dephosphorylation of phosphotyrosine. PTPs are known to be involved in many signal transduction pathways leading to cell growth, differentiation, and oncogenic transformation. We have cloned a new family of novel protein tyrosine phosphatase-like genes, the Ptpl(protein tyrosine phosphatase-like; proline instead of catalytic arginine) gene family. This gene family is composed of at least three members, and we describe here the developmental expression pattern and chromosomal location for one of these genes, Ptpla. In situhybridization studies revealed that Ptplaexpression was first detected at embryonic day 8.5 in muscle progenitors and later in differentiated muscle types: in the developing heart, throughout the liver and lungs, and in a number of neural crest derivatives including the dorsal root and trigeminal ganglia. Postnatally Ptplawas expressed in a number of adult tissues including cardiac and skeletal muscle, liver, testis, and kidney. The early expression pattern of this gene and its persistent expression in adult tissues suggest that it may have an important role in the development, differentiation, and maintenance of a number of different tissue types. The human homologue of Ptpla(PTPLA) was cloned and shown to map to 10p13–p14.

Right and left ventricular function were investigated in 12 fetal lambs (127-140 days gestation) instrumented with electromagnetic flow sensors on the ascending aorta and the main pulmonary artery, and with vascular catheters. Nine fetuses were equipped with a postductal aortic occluder and the trachea was cannulated in eight. Control arterial blood values were pH 7.36 ± 0.02 (SD), PCO249.3 ± 2.3 torr, PO218.4 ± 1.7 torr, and hematoerit 37.3 ± 4.4. Biventricular function curves relating stroke volume to mean right and left atrial pressure were generated by rapid withdrawal and reinfusion of fetal blood. Both function curves were composed of steep ascending and plateau limbs that intersected at a breakpoint. Stroke volumes at the breakpoints were 0.94 ± 0.19 ml kg-1and 0.63 ± 0.15 ml · kg-1for right and left ventricle, respectively (p<0.001). During postductal aortic occlusion, arterial pressure increased by 19.3 ± 7.9 torr while right ventricular stroke volume decreased by ~48 and left ventricular stroke volume decreased by ~9. In uteroventilation increased arterial pressure, heart rate, PO2, and oxygen content. Right atrial pressure increased from 3.9 ± 1.3 to 5.8 ± 2.9 torr (p<0.05); left atrial pressure from 3.5 ± 1.5 to 10.0 ± 4.4 torr (p<0.05). Aortic now nearly doubled (112 ± 29 to 211 ± 3 5 ml·min-1kg-1) (p<0.05), and the left ventricular function curve shifted upward. The right ventricular function curve was shifted downward during ventilation. We conclude that the fetal ventricles differ significantly in their outputs, response to changes in arterial pressure, and to the onset of in utero ventilation.

The purpose of this study was to investigate atrial myocardial blood flow in the fetus under conditions of acute right ventricular pressure load and adenosine infusion. Late gestation fetal sheep were instrumented for acute right ventricular pressure loading or adenosine infusion, and regional myocardial blood flow was measured at rest and under experimental conditions with radiolabeled microspheres and standard reference sample technique. Resting myocardial blood flow to the atria was less than half of ventricular flow per gram tissue. During the maximum tolerated pulmonary artery pressure load, right atrial peak systolic pressure rose significantly, and atrial blood flow increased 3-fold. The percentage of total myocardial blood flow received by the right atrium during maximal pressure loading increased from 4.3 ± 1.4 to 5.9 ± 1.6, p< 0.05. Adenosine infusion was associated with a 4-fold increase in atrial myocardial blood flow and a 3-fold increase in ventricular and septal blood flow. The percentage of total myocardial blood flow to both atria also increased with adenosine infusion (right atrium, 3.8 ± 0.4 to 5.4 ± 1.3, and left atrium, 4.2 ± 0.8 to 6.9 ± 2.0, p< 0.05). We conclude the following: 1) at rest, fetal atrial myocardial blood flow is less than one half of ventricular myocardial blood flow per gram tissue; 2) fetal atrial blood flow increases more than ventricular blood flow with acute right ventricular pressure load or adenosine infusion; and 3) these data suggest that fetal atrial blood flow is regulated independently from ventricular blood flow and may be influenced by atrial work.

To study the effectiveness of in utero ventilation in altering fetal arterial gas composition, we ventilated 15 near-term fetal lambs with a range of inspired gas mixtures. To accomplish this, double lumen nasogastric tubes were surgically placed in the tracheas of 15 near-term (135 days’ gestation) fetal lambs. After 4 ± 1 SD postoperative days, the fetuses were respired by positive pressure ventilation. 13 of these fetuses were also ventilated with their umbilical cords completely occluded. Ventilation was maintained for an average of 4.5 h (range 2.5–7.5 h). All 15 fetuses were effectively oxygenated on room air when exposed to a small net positive end expiratory pressure. In fetuses with intact umbilical cords, PaO2 could be maintained at levels between 11 and 280 mm Hg and PaCO2 from 36 to 139 mm Hg by altering the inspired O2 and CO2 with a gas mixing device. During umbilical cord occlusion, PaO2 was regulated from 2.2 to 103 mm Hg and PaCO2 from 37 to 187 mm Hg.

Arterial blood pressures in 18 lambs who had been nephrectomized 3–24 days before were not significantly different from those of 26 control fetuses or from those of control fetuses in the literature. Plasma renin activities were below the detection level of our assay. The nephrectomized fetuses continued to grow according to a variety of indices. We concluded that neither the kidney nor the renin angiotensin system are necessary for the long-term regulation of fetal blood pressure, probably because of their inability to affect placental exchange of water and electrolytes.

In the conscious, nonmedicated sheep fetus, blood volume strongly influences placental blood flow, a change of 1% in volume being associated with a change of 1.7 ± 0.1% in flow. This relationship is valid between blood volumes of 80 to 110% of normal, is independent of time over a period of several days and independent of concomitant changes in fetal hemoglobin concentration.We are indebted to Mr. Frederick Arfmann, Dr. J. Metcalfe and Mrs. Alice Fitzgerald for help with this study.

Maternal obesity has been associated with placental inflammation and an increased risk of stillbirth. A study conducted in nonhuman primates found that chronic maternal consumption of a Western-style high-fat diet (HFD) resulted in fetal lipotoxicity; the effect was independent of maternal obesity or insulin resistance. The relationship of maternal diet to the obstetric complications associated with obesity in pregnant women is unclear.

Almost all substances that are passively transferred fall into two classes. Their transfer is either purely “flow limited” or purely “diffusion limited,”with few in between. Diffusion limited transfer (most lipid insoluble materials) is determined by the diffusion permeability of the interhemal membrane. In the epitheliochorial placenta, this permeability declines precipitously with increasing molecular weight and with the presence ofelectric charge. In the various hemochorial placentas, molecular weight is not discriminated, except to the extent that it affects the coefficient of free diffusion in water and electric charge is of little or no consequence. Flow limited transfer applies to those substances (lipid soluble) whose concentrations in maternal and fetal blood equilibrate in a single pass through the placenta. Transfer of oxygen is flow limited or nearly so. The effectiveness of flow limited transfer depends on vascular geometry. The “counter current” labyrinthine placentas of the rabbit and the guinea pig are highly efficient, whereas the villous placentas of sheep, monkey and man, which appear to allow end venous equilibration, are much less so. The price of efficient flow limited transfer may be less reserve when one of the blood flows declines. Maternofetal water flow per unit surface area of the placenta may be much greater in the embryo than in the fetus. If so, ultrafiltration may play more than a negligible role in the embryo in the transfer of lipid insoluble solutes and species differences may be less pronounced than in the fetus. A relation between placental transfer regime and evolutionary pressure is not yet apparent.