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1.  Placental Insufficiency and Fetal Growth Restriction 
Objectives
Fetal growth restriction is defined as a pathologic decrease in the rate of fetal growth. The most frequent etiology for late onset fetal growth restriction is uteroplacental dysfunction which is due to inadequate supply of nutrients and oxygen to support normal aerobic growth of the fetus. However, for symmetrical IUGR, fetal chromosomal anomalies, structural anomalies and fetal infections should be carefully excluded. Consequent to the uteroplacental vascular maladaptation of endovascular trophoblastic invasion, there is increased vascular resistance and decreased blood flow to the placenta in the choriodecidual compartment.
Conclusions
This under perfusion of the placenta causes villous damage; that is, total tertiary villous capillary bed is reduced leading to increased placental resistance. These changes can be diagnosed by Doppler and characteristic changes are seen in the uterine, umbilical, middle cerebral arteries and ductus venosus vessels. In severe cases, delivery of the fetus with optimum intrapartum surveillance, or caesarean section, is essential.
doi:10.1007/s13224-011-0092-x
PMCID: PMC3257343  PMID: 23024517
IUGR; Placental insufficiency; Colour doppler; Low birth weight
2.  Human fetal cardiac function during the first trimester of pregnancy 
Heart  2005;91(3):334-338.
Objective: To investigate first trimester human fetal cardiac function in relation to cardiac volume blood flow, and peripheral arterial and venous blood flow patterns.
Methods: Transvaginal Doppler ultrasonography was performed in 16 uncomplicated pregnancies at 6+, 7+, 8+, 9+, and 10+ gestational weeks. The shape of the inflow waveform and the presence of atrioventricular valve regurgitation (AVVR) were noted. The outflow mean velocity (Vmean) was calculated. The proportions of the isovolumetric relaxation (IRT%) and contraction times (ICT%) of the cardiac cycle were defined. Ductus venosus and umbilical artery pulsatility indices (PI) were obtained.
Results: Every inflow waveform was monophasic before 9+ weeks. At 9+ weeks 11 of 16 and at 10+ weeks all waveforms were biphasic. At 7+ and 8+ weeks AVVR was documented in one case. At 9+ and 10+ weeks AVVR was present in four and seven fetuses, respectively. Mean (SD) outflow Vmean increased between 6+ and 8+ weeks from 3.6 (1.5) to 8.4 (3.0) cm/s (p < 0.05). IRT% decreased significantly from 6+ to 7+ weeks (39.8 (2.6) to 19.2 (6.2), p < 0.001). ICT% decreased between 8+ and 9+ weeks from 13.2 (4.0) to 8.5 (2.5) (p < 0.05). Ductus venosus PIs were unchanged. Umbilical artery Vmean increased between 7+ and 10+ weeks from 1.59 (0.51) to 5.06 (1.06) cm/s (p < 0.001) and PIs remained unchanged.
Conclusions: The first trimester of pregnancy is characterised by significant improvements in cardiac diastolic and systolic function with a concomitant increase in cardiac volume blood flow. At 10+ weeks AVVR is a common finding. Placental volume blood flow increases significantly with no change in the placental vascular impedance.
doi:10.1136/hrt.2003.029736
PMCID: PMC1768783  PMID: 15710713
fetus; early pregnancy; Doppler; ventricular function; physiology
3.  Significant correlations between the flow volume of patent ductus venosus and early neonatal liver function: possible involvement of patent ductus venosus in postnatal liver function 
Background
The biochemical features of portosystemic venous shunt with high flow volume are hypergalactosaemia, hyperammonaemia, prolonged blood coagulation time, and raised serum bile acid concentration. The ductus venosus remains open with shunt flow in most neonates for a certain period after birth. However, the effects of blood flow through the ductus venosus on neonatal liver function remain unclear.
Objective
To elucidate the effect of patency of the ductus venosus on liver function in early neonates.
Methods
Subjects were divided into three groups by gestational age (group I, 29–32 weeks; group II, 33–36 weeks; group III, 37–41 weeks). The shunt flow volume through the ductus venosus was examined serially using ultrasonography, and correlations between flow volume and liver function in the respective groups were calculated during the first week after birth.
Results
Group I had a higher flow volume and later functional closure than the other two groups. Plasma ammonia and serum total bile acid concentrations correlated with flow volume in groups I and II, and blood galactose and galactose 1‐phosphate concentrations correlated significantly with flow volume in group III. Percentage hepaplastin also correlated significantly with flow volume in all groups, but plasma vitamin K concentration did not in any group.
Conclusions
Patent ductus venosus has a considerable effect on crucial liver functions such as ammonia detoxification, blood coagulation, and regulation of serum total bile acid concentration in early neonates.
doi:10.1136/adc.2005.079822
PMCID: PMC2672699  PMID: 16449256
gestational age; liver function; patent ductus venosus; portosystemic venous shunt
4.  Iodine Deficiency in Pregnancy: The Effect on Neurodevelopment in the Child 
Nutrients  2011;3(2):265-273.
Iodine is an integral part of the thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), necessary for normal growth and development. An adequate supply of cerebral T3, generated in the fetal brain from maternal free T4 (fT4), is needed by the fetus for thyroid hormone dependent neurodevelopment, which begins in the second half of the first trimester of pregnancy. Around the beginning of the second trimester the fetal thyroid also begins to produce hormones but the reserves of the fetal gland are low, thus maternal thyroid hormones contribute to total fetal thyroid hormone concentrations until birth. In order for pregnant women to produce enough thyroid hormones to meet both her own and her baby’s requirements, a 50% increase in iodine intake is recommended. A lack of iodine in the diet may result in the mother becoming iodine deficient, and subsequently the fetus. In iodine deficiency, hypothyroxinemia (i.e., low maternal fT4) results in damage to the developing brain, which is further aggravated by hypothyroidism in the fetus. The most serious consequence of iodine deficiency is cretinism, characterised by profound mental retardation. There is unequivocal evidence that severe iodine deficiency in pregnancy impairs brain development in the child. However, only two intervention trials have assessed neurodevelopment in children of moderately iodine deficient mothers finding improved neurodevelopment in children of mothers supplemented earlier rather than later in pregnancy; both studies were not randomised and were uncontrolled. Thus, there is a need for well-designed trials to determine the effect of iodine supplementation in moderate to mildly iodine deficient pregnant women on neurodevelopment in the child.
doi:10.3390/nu3020265
PMCID: PMC3257674  PMID: 22254096
iodine; pregnancy; child; cretinism; neurodevelopment
5.  Inherited liver shunts in dogs elucidate pathways regulating embryonic development and clinical disorders of the portal vein 
Mammalian Genome  2011;23(1-2):76-84.
Congenital disorders of the hepatic portal vasculature are rare in man but occur frequently in certain dog breeds. In dogs, there are two main subtypes: intrahepatic portosystemic shunts, which are considered to stem from defective closure of the embryonic ductus venosus, and extrahepatic shunts, which connect the splanchnic vascular system with the vena cava or vena azygos. Both subtypes result in nearly complete bypass of the liver by the portal blood flow. In both subtypes the development of the smaller branches of the portal vein tree in the liver is impaired and terminal branches delivering portal blood to the liver lobules are often lacking. The clinical signs are due to poor liver growth, development, and function. Patency of the ductus venosus seems to be a digenic trait in Irish wolfhounds, whereas Cairn terriers with extrahepatic portosystemic shunts display a more complex inheritance. The genes involved in these disorders cannot be identified with the sporadic human cases, but in dogs, the genome-wide study of the extrahepatic form is at an advanced stage. The canine disease may lead to the identification of novel genes and pathways cooperating in growth and development of the hepatic portal vein tree. The same pathways likely regulate the development of the vascular system of regenerating livers during liver diseases such as hepatitis and cirrhosis. Therefore, the identification of these molecular pathways may provide a basis for future proregenerative intervention.
doi:10.1007/s00335-011-9364-0
PMCID: PMC3275728  PMID: 22052005
6.  Adiponectin Enhances Mouse Fetal Fat Deposition 
Diabetes  2012;61(12):3199-3207.
Maternal obesity increases offspring birth weight and susceptibility to obesity. Adiponectin is an adipocyte-secreted hormone with a prominent function in maintaining energy homeostasis. In contrast to adults, neonatal blood adiponectin levels are positively correlated with anthropometric parameters of adiposity. This study was designed to investigate the role of adiponectin in maternal obesityenhanced fetal fat deposition. By using high-fat diet–induced obese mouse models, our study showed that maternal obesity increased fetal fat tissue mass, with a significant elevation in fetal blood adiponectin. However, adiponectin gene knockout (Adipoq−/−) attenuated maternal obesity-induced high fetal fat tissue mass. We further studied the effects of fetal adiponectin on fetal fat deposition by using a cross breeding approach to create Adipoq−/+ and Adipoq−/− offspring, whereas maternal adiponectin was null. Adipoq−/+ offspring had more fat tissue mass at both birth and adulthood. Significantly high levels of lipogenic genes, such as sterol regulatory element–binding protein 1c and fatty acid synthase, were detected in the livers of Adipoq−/+ fetuses. In addition, expression of genes for placental fatty acid transport was significantly increased in Adipoq−/+ fetuses. Together, our study indicates that adiponectin enhances fetal fat deposition and plays an important role in maternal obesity-induced high birth weight.
doi:10.2337/db12-0055
PMCID: PMC3501876  PMID: 22872236
7.  Effects of congenital heart disease on brain development 
Brain and heart development occurs simultaneously in the fetus with congenital heart disease. Early morphogenetic programs in each organ share common genetic pathways. Brain development occurs across a more protracted time-course with striking brain growth and activity-dependent formation and refinement of connections in the third trimester. This development is associated with increased metabolic activity and the brain is dependent upon the heart for oxygen and nutrient delivery. Congenital heart disease leads to derangements of fetal blood flow that result in impaired brain growth and development that can be measured with advanced magnetic resonance imaging. Delayed development results in a unique vulnerability to cerebral white matter injury in newborns with congenital heart disease. Delayed brain development and acquired white matter injury may underlay mild but pervasive neurodevelopmental impairment commonly observed in children following neonatal congenital heart surgery.
doi:10.1016/j.ppedcard.2010.06.011
PMCID: PMC2927012  PMID: 20802830
Congenital heart defects; Brain development; White matter injury; Periventricular leukomalacia; Infant heart surgery; Fetal circulation
8.  Intrahepatic and intramyocellular lipids are determinants of insulin resistance in prepubertal children 
Diabetologia  2010;54(4):869-875.
Aims/hypothesis
We hypothesised that ectopic fat deposition is present in liver and skeletal muscle before puberty and that both are potentially important factors in the early pathogenesis of insulin resistance.
Methods
Proton magnetic resonance spectroscopy was used to evaluate intramyocellular and intrahepatic lipids in 50 male and 42 female multi-ethnic, prepubertal (Tanner<2) children (8.1±0.8 years; 35.4±10.7 kg; 27.9±8.3% body fat; means ± SD). Intramyocellular lipid was measured in soleus muscle and intrahepatic lipid in the middle right lobe. Abdominal fat was measured by magnetic resonance imaging, body fat by dual energy X-ray absorptiometry, and insulin resistance using homeostatic model assessment.
Results
Intrahepatic lipid ranged from 0.11% to 4.6% relative to the liver water signal (mean 0.79±0.79%) whereas intramyocellular lipid ranged from 0.13% to 1.86% relative to the muscle water signal (mean 0.51±0.28%). Intramyocellular and intrahepatic lipids were significantly correlated with total adiposity (r=0.49 and 0.59), abdominal adiposity (r=0.44 and 0.54), and each other (r=0.39, p<0.05, Spearman). Both intramyocellular and intrahepatic lipid were positively correlated with fasting insulin (r=0.37 and 0.38 respectively) and insulin resistance (r=0.37 and 0.37; p<0.01). After adjustment for race and sex, the relations between ectopic fat and insulin resistance remained, whereas both disappeared when further adjusted for body fat or BMI z scores.
Conclusions/Interpretations
These results suggest that typical relations between body composition, ectopic fat and insulin resistance are present in children before puberty. Thus, interventions aimed at reducing adiposity have the potential to decrease ectopic fat accumulation, delay the onset of insulin resistance and decrease the risk for development of type 2 diabetes in children.
doi:10.1007/s00125-010-2022-3
PMCID: PMC3053439  PMID: 21181394
Diabetes in childhood; Human; Insulin sensitivity and resistance; Metabolic syndrome; Pathophysiology/metabolism; Prediction and prevention of type 2 diabetes
9.  Comparison of the configuration of the posterior bifurcation of the posterior communicating artery between fetal and adult brains: A study of a Sri Lankan population 
Objective:
The purpose of this study was to examine the degree of contribution from the vertebrobasilar and carotid systems to the origin of the PCA in fetal autopsy brains of last trimester of pregnancy and to compare with published data on the configuration of adult and fetal brains in a population of Sri Lankan origin.
Materials and Methods:
The external diameter of the PcomA, pre-communicating part (P1), and the post-communicating part (P2) of posterior cerebral artery (PCA) of 34 fetal brain in the last trimester of pregnancy (30 to 40 weeks of gestation) was measured using a stereomicroscope equipped with a micrometer calibrator.
Results:
The blood supply to the occipital lobe mainly via the PCA was seen in 25 (59%) of fetal brains as compared to that in the literature 220 (93%) in adults brains and the blood supply to the occipital lobe mainly via the internal carotid artery (ICA) was seen in 16 (34%) of fetal brains as compared to 25 (7%) of adults brains (P < 0.0001), transitional configuration where the PcomA is equal in diameter to P1 segment of the PCA was seen in 5 (7.4%) of fetal brains and 8 (2%) of adults brains.
Conclusions:
The present study reveals that from the newborn to the adult there is shift from carotid system to the vertebrobasilar system, this justifies further studies on different racial and geographic regions which may give a clearer picture about the cerebral hemodynamics from childhood to adult.
doi:10.4103/0972-2327.70886
PMCID: PMC2981758  PMID: 21085531
Configuration; fetal brain; posterior cerebral artery; vertebrobasilar
10.  First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study 
Objective To examine whether first trimester fetal growth restriction correlates with cardiovascular outcomes in childhood.
Design Population based prospective cohort study.
Setting City of Rotterdam, the Netherlands.
Participants 1184 children with first trimester fetal crown to rump length measurements, whose mothers had a reliable first day of their last menstrual period and a regular menstrual cycle.
Main outcomes measures Body mass index, total and abdominal fat distribution, blood pressure, and blood concentrations of cholesterol, triglycerides, insulin, and C peptide at the median age of 6.0 (90% range 5.7-6.8) years. Clustering of cardiovascular risk factors was defined as having three or more of: high android fat mass; high systolic or diastolic blood pressure; low high density lipoprotein cholesterol or high triglycerides concentrations; and high insulin concentrations.
Results One standard deviation score greater first trimester fetal crown to rump length was associated with a lower total fat mass (−0.30%, 95% confidence interval −0.57% to −0.03%), android fat mass (−0.07%, −0.12% to −0.02%), android/gynoid fat mass ratio (−0.53, −0.89 to −0.17), diastolic blood pressure (−0.43, −0.84 to −0.01, mm Hg), total cholesterol (−0.05, −0.10 to 0, mmol/L), low density lipoprotein cholesterol (−0.04, −0.09 to 0, mmol/L), and risk of clustering of cardiovascular risk factors (relative risk 0.81, 0.66 to 1.00) in childhood. Additional adjustment for gestational age and weight at birth changed these effect estimates only slightly. Childhood body mass index fully explained the associations of first trimester fetal crown to rump length with childhood total fat mass. First trimester fetal growth was not associated with other cardiovascular outcomes. Longitudinal growth analyses showed that compared with school age children without clustering of cardiovascular risk factors, those with clustering had a smaller first trimester fetal crown to rump length and lower second and third trimester estimated fetal weight but higher weight growth from the age of 6 months onwards.
Conclusions Impaired first trimester fetal growth is associated with an adverse cardiovascular risk profile in school age children. Early fetal life might be a critical period for cardiovascular health in later life.
doi:10.1136/bmj.g14
PMCID: PMC3901421  PMID: 24458585
11.  Ethanol exposure during pregnancy persistently attenuates cranially-directed blood flow in the developing fetus: Evidence from ultrasound imaging in a murine second trimester equivalent model 
Background
Ethanol consumption during pregnancy can lead to fetal growth retardation, mental retardation and neurodevelopmental delay. The fetal brain initiates neurogenesis and vasculogenesis during the second trimester, and depends on maternal-fetal circulation for nutrition and growth signals. We used high resolution in vivo ultrasound imaging to test the hypothesis that ethanol interferes with fetal brain-directed blood flow during this critical developmental period.
Methods
Pregnant mice were lightly anesthetized on gestational day 12 with an isoflurane/oxygen mixture. We assessed the effect of single and repeated binge-like maternal ethanol exposures at 3 g/kg, administered by intragastric gavage or intraperitoneal injection, on maternal circulation and fetal umbilical, aortic, internal carotid and middle cerebral arterial circulation.
Results
Binge maternal ethanol exposure, regardless of exposure route, significantly reduced fetal arterial blood acceleration and velocity time integral (VTI), from umbilical to cerebral arteries, without a change in fetal heart rate and resistivity indices. Importantly a single maternal binge ethanol exposure induced persistent suppression of fetal arterial VTI for at least 24 hours. Repeated binge episodes resulted in a continuing and persistent suppression of fetal VTI. Qualitative assessments showed that maternal ethanol exposure induced oscillatory, non-directional blood flow in fetal cerebral arteries. Maternal cardiac and other physiological parameters remained unaltered.
Conclusion
These data show that binge-type maternal ethanol exposure results in rapid and persistent loss of blood flow from the umbilical artery to the fetal brain, potentially compromising nutrition and the maternal/fetal endocrine environment during a critical period for neuron formation and angiogenesis in the maturing brain.
doi:10.1111/j.1530-0277.2011.01676.x
PMCID: PMC3297711  PMID: 22141380
Second trimester; fetal ethanol exposure; high-resolution ultrasound; cerebral blood flow; fetal arterial blood flow
12.  Ultrasonographic study of ductus venosus in healthy neonates 
AIM—To assess ultrasonographically the flow pattern and the time of postnatal closure of ductus venosus related to the other fetal shunts.
METHODS—Fifty healthy, term neonates were studied from day 1 up to day 18 using a VingMed CFM 800A ultrasound scanner.
RESULTS—Ductus arteriosus was closed in 94% of the infants before day 3. Ductus venosus, however, was closed in only 12% at the same time, in 76% before day 7, and in all infants before day 18. A closed ductus venosus or ductus arteriosus did not show signs of reopening. Pulsed and colour Doppler flow could be detected across the foramen ovale in all infants during the sequential investigation. At day 1, when the pulmonary vascular resistance was still high, a reversed Doppler flow velocity signal was seen in ductus venosus in 10 infants (20%) and a bidirectional flow in ductus arteriosus in 26 (52%). Closure of the ductus venosus was not significantly correlated with closure of the ductus arteriosus nor related to sex nor weight loss.
CONCLUSIONS—The time of closure of the ductus venosus evaluated by ultrasonography is much later than that of the ductus arteriosus. The flow pattern in ductus venosus reflects the portocaval pressure gradient and the pressure on the right side of the heart and in the pulmonary arteries. Both the flow pattern in the ductus venosus as well as that in the ductus arteriosus may be an indication of compromised neonatal haemodynamics.

 Keywords: ductus venosus; ductus arteriosus; foramen ovale; Doppler echocardiography
PMCID: PMC1720700  PMID: 9377136
13.  Transplacental transport of lead. 
Neurotoxicity is the major health effect from exposure to lead for infants and young children, and there is current concern regarding possible toxic effects of lead on the child while in utero. There is no placental-fetal barrier to lead transport. Maternal and fetal blood lead levels are nearly identical, so lead passes through the placenta unencumbered. Lead has been measured in the fetal brain as early as the end of the first trimester (13 weeks). There is a similar rate of increase in brain size and lead content throughout pregnancy in the fetus of mothers in the general population, so concentration of lead probably does not differ greatly during gestation unless exposure of the mother changes. Cell-specific sensitivity to the toxic effects of lead, however, may be greater the younger the fetus. Lead toxicity to the nervous system is characterized by edema or swelling of the brain due to altered permeability of capillary endothelial cells. Experimental studies suggest that immature endothelial cells forming the capillaries of the developing brain are less resistant to the effects of lead, permitting fluid and cations including lead to reach newly formed components of the brain, particularly astrocytes and neurons. Also, the ability of astrocytes and neurons to sequester lead in the form of lead protein complexes occurs only in the later stages of fetal development, permitting lead in maturing brain cells to interact with vital subcellular organelles, particularly mitochondria, which are the major cellular energy source. Intracellular lead also affects binding sites for calcium which, in turn, may affect numerous cell functions including neurotransmitter release.
Images
PMCID: PMC1567784  PMID: 2088735
14.  Tobramycin: Maternal-Fetal Pharmacology 
To investigate the maternal-fetal transfer of tobramycin (TBM) and its distribution in the fetus, a single dose of 2 mg/kg was administered intramuscularly to 35 pregnant patients (13 first trimester, 22 second trimester) 0.5 to 34 h before hysterectomy. TBM concentration was assayed microbiologically in maternal serum, fetal tissues (placenta, brain, lung, liver, and kidney), and fluids (amniotic, cerebrospinal fluid [CSF], urine, and serum). Mean maternal serum half-life (1.54 h) and mean peak serum concentration of TBM were within ranges reported for nonpregnant adults. In fetal serum, half-life was 5.2 h, and TBM levels did not exceed 0.58 μg/ml. For intervals up to 34 h, the mean TBM concentration in placental tissues was 1.4 μg/g. Concentration differences related to fetal maturation were found for fetal CSF, amniotic fluid, and fetal kidney. No antimicrobial activity was found in the fetal CSF of >16 weeks' gestation. TBM was present predominantly in the second trimester amniotic fluid specimens. Fetal kidney concentrations reached 7.2 μg/g at 34 h after maternal drug administration. Higher TBM concentrations were related to advanced maturation of the fetal kidney. Second trimester fetal urine concentrations for TBM ranged from 0.1 to 3.4 μg/ml, and the fetal urinary half-life was 3.7 h. Knowledge of fetal pharmacology is essential for weighing the fetal benefits or risks of antimicrobial therapy for the infected gravid patient.
PMCID: PMC352051  PMID: 856021
15.  Antenatal Steroids and the IUGR Fetus: Are Exposure and Physiological Effects on the Lung and Cardiovascular System the Same as in Normally Grown Fetuses? 
Journal of Pregnancy  2012;2012:839656.
Glucocorticoids are administered to pregnant women at risk of preterm labour to promote fetal lung surfactant maturation. Intrauterine growth restriction (IUGR) is associated with an increased risk of preterm labour. Hence, IUGR babies may be exposed to antenatal glucocorticoids. The ability of the placenta or blood brain barrier to remove glucocorticoids from the fetal compartment or the brain is compromised in the IUGR fetus, which may have implications for lung, brain, and heart development. There is conflicting evidence on the effect of exogenous glucocorticoids on surfactant protein expression in different animal models of IUGR. Furthermore, the IUGR fetus undergoes significant cardiovascular adaptations, including altered blood pressure regulation, which is in conflict with glucocorticoid-induced alterations in blood pressure and flow. Hence, antenatal glucocorticoid therapy in the IUGR fetus may compromise regulation of cardiovascular development. The role of cortisol in cardiomyocyte development is not clear with conflicting evidence in different species and models of IUGR. Further studies are required to study the effects of antenatal glucocorticoids on lung, brain, and heart development in the IUGR fetus. Of specific interest are the aetiology of IUGR and the resultant degree, duration, and severity of hypoxemia.
doi:10.1155/2012/839656
PMCID: PMC3512319  PMID: 23227338
16.  Humans at high altitude: hypoxia and fetal growth 
High-altitude studies offer insight into the evolutionary processes and physiological mechanisms affecting the early phases of the human lifespan. Chronic hypoxia slows fetal growth and reduces the pregnancy-associated rise in uterine artery (UA) blood flow. Multigenerational vs. shorter-term high-altitude residents are protected from the altitude-associated reductions in UA flow and fetal growth. Presently unknown is whether this fetal-growth protection is due to the greater delivery or metabolism of oxygen, glucose or other substrates or to other considerations such as mechanical factors protecting fragile fetal villi, the creation of a reserve protecting against ischemia/reperfusion injury, or improved placental O2 transfer as the result of narrowing the A-V O2 difference and raising uterine PvO2. Placental growth and development appear to be normal or modified at high altitude in ways likely to benefit diffusion. Much remains to be learned concerning the effects of chronic hypoxia on embryonic development. Further research is required for identifying the fetoplacental and maternal mechanisms responsible for transforming the maternal vasculature and regulating UA blood flow and fetal growth. Genomic as well as epigenetic studies are opening new avenues of investigation that can yield insights into the basic pathways and evolutionary processes involved.
doi:10.1016/j.resp.2011.04.017
PMCID: PMC3146554  PMID: 21536153
Adaptation; Andean; genetic; pregnancy; Tibetan; uteroplacental blood flow
17.  Venous Doppler in the Evaluation of Fetal Hydrops 
Objective. To examine venous blood flow velocity in different types of fetal hydrops and its value in the prediction of outcome of pregnancies. Methods. Venous Doppler sonography was performed in 100 hydropic fetuses from 15 to 37 weeks of gestation. Blood velocity was recorded in the right hepatic vein (HV), the ductus venosus (DV) and in the intra-abdominal part of the umbilical vein (UV). Blood velocity indices were calculated and pulsations in the umbilical vein noted and grouped into a single, double or triple flow pattern. Blood velocity was related to cause of hydrops. Results. Mortality was noted in 51 cases of which 19 were by termination of pregnancy. Mortality in the 30 with normal venous blood velocity was 35%, but 58% in cases of abnormal Doppler. Abnormal HV and DV blood velocities were recorded in 39 and 34 cases, respectively and were strongly related to mortality (P < .04 and P < .003, resp.). UV pulsations were noted in 49 fetuses and were significantly related to mortality (P < .04). Mortality and abnormal venous velocities were most frequent in the low-output hydrops group (79% and 75%, resp.). Conclusions. Abnormal venous blood velocity is related to mortality in pregnancies complicated by fetal hydrops. Venous Doppler sonography should be a part of the routine work-up of pregnancies complicated by fetal hydrops.
doi:10.1155/2010/430157
PMCID: PMC2864890  PMID: 20454533
18.  The Expression and Function of Fatty Acid Transport Protein-2 and -4 in the Murine Placenta 
PLoS ONE  2011;6(10):e25865.
Background
The uptake and trans-placental trafficking of fatty acids from the maternal blood into the fetal circulation are essential for embryonic development, and involve several families of proteins. Fatty acid transport proteins (FATPs) uniquely transport fatty acids into cells. We surmised that placental FATPs are germane for fetal growth, and are regulated during hypoxic stress, which is associated with reduced fat supply to the fetus.
Methodology/Principal Findings
Using cultured primary term human trophoblasts we found that FATP2, FATP4 and FATP6 were highly expressed in trophoblasts. Hypoxia enhanced the expression of trophoblastic FATP2 and reduced the expression of FATP4, with no change in FATP6. We also found that Fatp2 and Fatp4 are expressed in the mouse amnion and placenta, respectively. Mice deficient in Fatp2 or Fatp4 did not deviate from normal Mendelian distribution, with both embryos and placentas exhibiting normal weight and morphology, triglyceride content, and expression of genes related to fatty acid mobilization.
Conclusions/Significance
We conclude that even though hypoxia regulates the expression of FATP2 and FATP4 in human trophoblasts, mouse Fatp2 and Fatp4 are not essential for intrauterine fetal growth.
doi:10.1371/journal.pone.0025865
PMCID: PMC3197585  PMID: 22028793
19.  Cardiorenal Syndrome is Present in Human Fetuses with Severe, Isolated Urinary Tract Malformations 
PLoS ONE  2013;8(5):e63664.
Objective
We analyzed the association between renal and cardiovascular parameters in fetuses with isolated severe urinary tract malformations.
Methods
39 fetuses at a mean gestational age of 23.6 weeks with nephropathies or urinary tract malformations and markedly impaired or absent renal function were prospectively examined. Fetal echocardiography was performed, and thicknesses of the interventricular septum, and left and right ventricular wall were measured. Blood flow velocity waveforms of the umbilical artery, middle cerebral artery, and ductus venosus were obtained by color Doppler ultrasound. Concentrations of circulating n-terminal pro-B-type natriuretic peptide (nt-proBNP), cystatin C, ß2-microglobulin, and hemoglobin were determined from fetal blood samples.
Results
Malformations included 21 cases of obstructive uropathy, 10 fetuses with bilateral nephropathy, and 8 cases of bilateral renal agenesis. Marked biventricular myocardial hypertrophy was present in all cases. The ratio between measured and gestational age-adjusted normal values was 2.01 (interventricular septum), 1.85, and 1.78 (right and left ventricular wall, respectively). Compared to controls, levels of circulating nt-proBNP were significantly increased (median (IQR) 5035 ng/L (5936 ng/L) vs. 1874 ng/L (1092 ng/L); p<0.001). Cystatin C and ß2-microglobulin concentrations were elevated as follows (mean ± SD) 1.85±0.391 mg/L and 8.44±2.423 mg/L, respectively (normal range 1.66±0.202 mg/L and 4.25±0.734 mg/L, respectively). No correlation was detected between cardiovascular parameters and urinary tract morphology and function. Despite increased levels of nt-proBNP cardiovascular function was preserved, with normal fetal Doppler indices in 90.2% of cases.
Conclusion
Urinary tract malformations resulting in severe renal impairment are associated with biventricular myocardial hypertrophy and elevated concentrations of circulating nt-proBNP during fetal life. Cardiovascular findings do not correlate with kidney function or morphology.
doi:10.1371/journal.pone.0063664
PMCID: PMC3661568  PMID: 23717461
20.  Hepatic manifestations of familial patent ductus venosus in adults 
Gut  1999;45(3):442-445.
BACKGROUND—The ductus venosus connects the umbilical vein to the inferior vena cava during fetal life and subsequently closes rapidly after birth. It is known as patent ductus venosus when it remains patent in adulthood.
PATIENTS—A 43 year old man with a history of panhypopituitarism presented with recurrent bouts of pedal oedema associated with fatigue, hypoalbuminaemia, and elevated prothrombin time. An ultrasound examination of his abdomen with Doppler revealed notable attenuation of the main portal vein with diminished intrahepatic branches; a computed tomography scan with angiography revealed a large collateral vein within the liver consistent with a patent ductus venosus. Sequential liver biopsies showed a considerable reduction in the calibre and number of the portal veins. His younger brother, who was diagnosed with alcohol related cirrhosis, suffered from intermittent bouts of encephalopathy and was found to have the same vascular lesion. A third brother was found to have a patent ductus venosus as well as two large hepatic masses consistent with focal nodular hyperplasia.
CONCLUSION—The syndrome of familial patent ductus venosus has only previously been described in three infant brothers who presented with hepatic encephalopathy and fatty degeneration of the liver. This report documents three brothers with a patent ductus venosus presenting in adulthood with different manifestations of liver disease. The presence of the same vascular anomaly in three brothers is highly suggestive of a recessive genetic trait with an anatomical manifestation of patent ductus venosus.


Keywords: patent ductus venosus; portal vein sclerosis; familial; hepatic synthetic dysfunction; hepatic encephalopathy
PMCID: PMC1727628  PMID: 10446116
21.  Effect of trans fatty acid intake on abdominal and liver fat deposition and blood lipids: a randomized trial in overweight postmenopausal women 
Nutrition & Diabetes  2011;1(1):e4-.
Background:
Intake of industrially produced trans fatty acids (TFAs) is, according to observational studies, associated with an increased risk of cardiovascular disease, but the causal mechanisms have not been fully elucidated. Besides inducing dyslipidemia, TFA intake is suspected to promote abdominal and liver fat deposition.
Objective:
We examined the effect of a high intake of TFA as part of an isocaloric diet on whole-body, abdominal and hepatic fat deposition, and blood lipids in postmenopausal women.
Methods:
In a 16-week double-blind parallel intervention study, 52 healthy overweight postmenopausal women were randomized to receive either partially hydrogenated soybean oil providing 15.7 g day−1 of TFA or a control oil with mainly oleic and palmitic acid. Before and after the intervention, body composition was assessed by dual-energy X-ray absorptiometry, abdominal fat by magnetic resonance (MR) imaging, and liver fat by 1H MR spectroscopy.
Results:
Compared with the control fat, TFA intake decreased plasma high-density lipoprotein (HDL)-cholesterol by 10%, increased low-density lipoprotein (LDL)-cholesterol by 18% and resulted in an increased LDL/HDL-cholesterol ratio (baseline adjusted mean (95% CI) difference between diet groups 0.41 (0.22; 0.60); P<0.001). TFA tended to increase the body fat (0.46 (−0.20; 1.17) kg; P=0.16) and waist circumference (1.1 (−0.1; 2.4) cm; P=0.08) more than the control fat, whereas neither abdominal nor liver fat deposition was affected by TFA.
Conclusion:
The adverse effect of dietary TFA on cardiovascular disease risk involves induction of dyslipidemia, and perhaps body fat, whereas weight gain-independent accumulation of ectopic fat could not be identified as a contributory factor during short-term intake.
doi:10.1038/nutd.2010.4
PMCID: PMC3302130  PMID: 23154296
randomized clinical trial; trans fatty acids; ectopic fat; dietary intervention
22.  Nutrition of the Fetus and Newborn 
Western Journal of Medicine  1987;147(4):435-448.
Both the successful development of healthy, long-term animal models to study fetal nutrition and metabolism and the improved survival of low-birth-weight, preterm infants have focused interest and research on fetal and neonatal nutrition and metabolism. Such a focus is important, given the recent emphasis on promoting neonatal growth in preterm infants at “normal” in utero growth rates. Estimates of nutrient requirements for growth in a human fetus remain ill defined, however. Body composition data appear biased toward thin infants. Animal data suggest that fetal nutrition proceeds according to species-specific growth rates, with variations in fat content largely dependent on placental fat permeability and on maternal nutrient supply as regulated by the placenta.
After birth, neonatal nutrition is affected primarily by food intake and the functional integrity and capacity of the gastrointestinal tract. Additionally, muscle activity, thermoregulation and stresses of various kinds and degrees modify a neonate's nutritional requirements. Functional deficits of the gastrointestinal tract have been circumvented by a more aggressive use of intravenous nutrition. Both intravenous and enteral nutrient mixtures have been substantially improved in the quantity of all nutrients and have been modified qualitatively toward compositions that are closer to those of human milk. These nutrient mixtures now produce plasma nutrient concentrations that approximate those of a healthy, breast-fed infant.
Although such efforts to improve the nutritional balance and growth of preterm infants have been successful, much remains to be learned about the nutritional requirements of sick infants.
PMCID: PMC1025905  PMID: 3318138
23.  Cell Free Expression of hif1α and p21 in Maternal Peripheral Blood as a Marker for Preeclampsia and Fetal Growth Restriction 
PLoS ONE  2012;7(5):e37273.
Preeclampsia, a severe unpredictable complication of pregnancy, occurs in 6% of pregnancies, usually in the second or third trimester. The specific etiology of preeclampsia remains unclear, although the pathophysiological hallmark of this condition appears to be an inadequate blood supply to the placenta. As a result of the impaired placental blood flow, intrauterine growth restriction (IUGR) and consequential fetal oxidative stress may occur. Consistent with this view, pregnancies complicated by preeclampsia and IUGR are characterized by up-regulation of key transcriptional regulators of the hypoxic response including, hif1α and as well as p53 and its target genes. Recently, the presence of circulating cell-free fetal RNA has been documented in maternal plasma. We speculated that pregnancies complicated by preeclampsia and IUGR, will be associated with an abnormal expression of p53 and/or hif1α related genes in the maternal plasma. Maternal plasma from 113 singleton pregnancies (72 normal and 41 complicated pregnancies) and 19 twins (9 normal and 10 complicated pregnancies) were collected and cell free RNA was extracted. The expression of 18 genes was measured by one step real-time RT-PCR and was analyzed for prevalence of positive/negative expression levels. Results indicate that, among the genes examined, cell free plasma expressions of p21 and hif1α were more prevalent in pregnancies complicated by hypoxia and/or IUGR (p<0.001). To conclude, we present in this manuscript data to support the association between two possible surrogate markers of hypoxia and common complications of pregnancy. More work is needed in order to implement these findings in clinical practice.
doi:10.1371/journal.pone.0037273
PMCID: PMC3353943  PMID: 22615960
24.  Troponin T and Pro–B-Type Natriuretic Peptide in Fetuses of Type 1 Diabetic Mothers 
Diabetes Care  2009;32(11):2050-2055.
OBJECTIVE
Cardiomyopathy is noted in up to 40% of infants of diabetic mothers, and the exact mechanisms are unknown. The aim of this study was to determine whether fetal serum markers of cardiac function differ between normal and type 1 diabetic pregnancies and to examine the relationship between these markers and fetal cardiac structure and function.
RESEARCH DESIGN AND METHODS
This was a prospective observational study of 45 type 1 diabetic pregnancies and 39 normal pregnancies. All participants had concentrations of fetal pro–B-type natriuretic peptide (proBNP) and troponin-T (TnT) measured at the time of delivery. All patients with type 1 diabetes had Doppler evaluation of the umbilical artery, middle cerebral artery, and ductus venosus in the third trimester, and a subset (n = 21) had detailed fetal echocardiograms performed in each trimester.
RESULTS
Fetal proBNP and TnT concentrations were higher in the diabetic cohort than in the normal cohort (P < 0.05). ProBNP correlated positively with interventricular septum thickness (P < 0.05) but not with cardiac function indexes in the third trimester. In patients with poor glycemic control, there was a significant positive correlation (P < 0.05) between fetal TnT and the third trimester umbilical artery pulsatility index. There were also increased levels of fetal TnT in infants with poor perinatal outcome (P < 0.05).
CONCLUSIONS
Biochemical markers of cardiac dysfunction are elevated in infants of diabetic mothers, especially those with cardiomyopathy or poor perinatal outcome. Hyperglycemia in early pregnancy may affect myocardial and placental development, thus contributing to the susceptibility to hypoxia seen in these infants.
doi:10.2337/dc09-0552
PMCID: PMC2768225  PMID: 19690080
25.  Fetal Cells in the Pregnant Mouse Are Diverse and Express a Variety of Progenitor and Differentiated Cell Markers1 
Biology of Reproduction  2009;81(1):26-32.
To better understand fetomaternal cell trafficking during pregnancy, we used a mouse model to determine the cell surface markers expressed on fetal cells, based on the hypothesis that fetal progenitor cells have the capacity to repair maternal organs, whereas more differentiated cells might initiate graft versus host disease. Wild-type females were mated to either homozygous or hemizygous transgenic males and euthanized in the peripartum period. Using dual color flow cytometry, we analyzed fetal transgene positive cells for the presence of nine markers (ITGAM, ITGB1, PECAM, CD34, CD44, PTPRC, ENG, SLAMF1, and CXCR4) to begin to identify the phenotype and degree of differentiation of fetal cells in nine maternal organs (lung, liver, spleen, blood, bone marrow, kidney, heart, thymus, and brain). Fetal cells were found in all maternal organs following either type of mating, albeit always at a higher frequency following mating with homozygous males. Some organs (e.g., lung and liver) had a wide variety of fetal cell markers present, while other organs (e.g., bone marrow and spleen) had a skewed distribution of fetal cell markers. Fetal cells in the murine pregnant female are diverse. Our results suggest that the fetal cells comprise a mixed population of progenitor and differentiated cells, with different relative proportions in different maternal organs. Future studies will address whether fetal cells cross the placental barrier in a differentiated state or as a homogenous population and subsequently differentiate in target maternal organs.
Fetal cells in the pregnant mouse comprise a mixed population of progenitor and differentiated cells, with different relative proportions in different maternal organs.
doi:10.1095/biolreprod.108.074468
PMCID: PMC3093984  PMID: 19279322
differentiation; fetal cell microchimerism; phenotype; pregnancy; trafficking

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