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The Role of Placenta in the Fetal Programming Associated to Gestational DiabetesCarlos Escudero1, Marcelo Gonzalez2, Jesenia Acurio1, Francisco Valenzuela1 and Luis Sobrevia3[1] Vascular Physiology Laboratory, Group of Investigation in Tumor Angiogenesis (GIANT), Department of Basic Sciences, University of Bio-Bio, Chillan, Chile[2] Vascular Physiology Laboratory, Department of Physiology, University of Concepcion, Concepcion, Chile[3] Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile1. Preexisting diabetes is a well known risk factor for congenital anomalies since maternal hyperglycemia during time of embryogenesis has a teratogenic effect of the development of the embryo. Disturbance of fetal development causing these disorders must occur during the first 8 weeks of pregnancy. Our study aimed to determine the incidence of congenital anomalies in women with hyperglycemia diagnosed first in pregnancy and to identify clinical predictors for an increased risk for anomalies. The majority of our study population belonged to the ethnic group of Mexican-American who are characterized by a high degree of glucose intolerance due to insulin resistance.
In pregnancies with type 1 diabetes there is a predominance of organ systems which are frequently affected by congenital anomalies.
The overall rate of major anomalies was slightly higher than in non-diabetic women of our population. The diagnosis of GDM is based on the glucose values obtained by an oral glucose tolerance test. All used definitions were derived from the original criteria from O’ Sullivan and Mahan from 1964. 39 For termination of thresholds for increased morbidity an untreated population of women with glucose intolerance in pregnancy would be needed. The aim of the present study was to determine the impact of borderline glucose intolerance on diabetic fetopathy indicated by neonatal obesity, fetal hyperinsulinism and placenta immaturity. Women with one abnormal value had significantly higher rates of LGA infants and infants with central obesity, of hyperinsulinism and neonatal hyperglycemia compared to women with normal oGTT with a rate similar to women with GDM. Neonatal glucose testing is routine part of neonatal care in infants of mothers with known diabetes.
There was no clinical useful predictor for hypoglycemia unless glucose values of an oGTT in pregnancy were available.
Several groups have been shown that women with glucose intolerance below the existing thresholds for gestational diabetes have a higher rate of macrosomia, cesarean delivery and preeclampsia. The hypothesis of Pedersen proposed that glucose from the maternal circulation is a major regulator for fetal growth.
Existing studies are limited to the investigation of the influence of maternal glycemia and LGA at time of birth.
The complexity of fetal growth occurs at several levels determined by the mother, the placenta and the fetus. In summary, our GDM management that was focused on tight glucose control could not lower the macrosomia rate in obese women.
As demonstrated above, the reliability of maternal glycemic values to predict diabetic morbidity in the newborn is limited.
Existing data demonstrate the tight relation of the fetal AC in the third trimester with the LGA status at birth but there is a paucity of data investigating the predictive power of the fetal AC compared to maternal parameters known to influence fetal growth. The fetal AC measurement is an indirect approach to assess fetal morbidity in pregnancies with diabetes based on a clinical manifestation of fetal hyperinsulinism. Both our studies support the importance of the fetal AC in the management of pregnancies with diabetes.
Fetal growth in pregnancies complicated by diabetes is related to maternal glycemia but it is controversial to what extend hyperglycemia determines morbidity. Both our studies demonstrated that a management based on relaxed glycemic criteria combined with fetal AC measurements is a safe approach for mother and child independent on the ethnic background of the study population. Detroit birth injury attorney answers an FAQ: Can jaundice cause brain damage, cerebral palsy and seizures? The yellow-orange skin tone characteristic of jaundice is caused by excessive bilirubin in the blood. Indeed, some babies have characteristics that cause their bodies to have excessive amounts of bilirubin in their blood, called hyperbilirubinemia. Testing for hyperbilirubinemia involves placing a light meter on the baby’s head, which is called transcutaneous monitoring. Factors that make it harder for a baby’s body to remove bilirubin can also cause severe hyperbilirubinemia. Newborns who have problems nursing or whose mother’s milk is slow to come in may develop breastfeeding jaundice, also called breastfeeding failure jaundice. Breastfeeding failure jaundice typically occurs within the first week of life, as lactation failure leads to poor feeding by the baby, causing the baby to lose a lot of weight and fluid. Regular and frequent feeding of a newborn can greatly reduce the chance of her having high bilirubin levels. Refraining from use of forceps or vacuum extractors during delivery can help prevent brain bleeds (cephalohematomas) that cause hyperbilirubinemia. If the physician does not believe the accuracy of a test and wants to confirm it, treatment should be started while waiting for confirmation.
Phototherapy should not be postponed or interrupted for just because the baby is having tests done.  Most tests can be done under the lights, or the lights can be moved with the baby if she needs an outside test. HOW DO JAUNDICE & HYPERBILIRUBINEMIA CAUSE BRAIN DAMAGE, KERNICTERUS, ENCEPHALOPATHY, CEREBRAL PALSY & SEIZURES? If high bilirubin level are not promptly decreased, ABE quickly progresses to chronic (long-term) bilirubin encephalopathy (CBE). Chronic bilirubin encephalopathy (CBE) is when there are severe lesions (abnormal tissue) in the brain caused by bilirubin.
These medical problems are associated with lesions in parts of the brain stem and basal ganglia. When a baby has hyperbilirubinemia, the only way to prevent brain damage, encephalopathy and kernicterus is to lower serum bilirubin levels either by phototherapy or exchange transfusion. Physicians must remember that when signs of bilirubin induced brain damage first appear, it is usually not too late to treat the baby.
If your child was diagnosed with a permanent disability, such as kernicterus, cerebral palsy, a seizure disorder, or hypoxic ischemic encephalopathy (HIE), the award winning lawyers at ABC Law Centers can help. Role of feto-placental endothelial function in fetal growth during normal pregnancy and gestational diabetes. 23-28 Data from animal and clinical studies have demonstrated a correlation of the degree of maternal hyperglycemia during early pregnancy and the occurrence of malformations in the embryo.
Thus, GDM is not considered as risk factor for congenital malformations because it typically develops not before the late second trimester coincident with the decreasing insulin sensitivity at this time. To exclude that our results were valid only for women with presumably undiagnosed preexisting type 2 diabetes, we repeat the analysis in a subgroup of women with normal oGTT (n= 1600) 1- 4 month postpartum.
Maternal historical (age, prepregnancy BMI, prior pregnancy with macrosomia, stillbirth or anomalies) and clinical parameter (gestational age at first prenatal visit, first trimester exposure to sulfonylurea agents) and value of the initial fasting glucose and HbA1c were investigated regarding their relation to anomalies. There was no predominance seen of any organ system affected with increasing fasting glucose values (figure 4). Additionally, we saw the same predominance of anomalies affecting the heart, skeleton and central nervous system in a mixed population of women with GDM and known type 2 diabetes as reported from pregnancies with type 1 diabetes. Our women with GDM had an unusual wide range of the degree of glucose intolerance partly due to the high level of insulin resistance in the Mexican-American population in Los Angeles. There is an ungoing discussion for three decade about the thresholds for defining maternal glucose intolerance in pregnancy which resulted in a great variation of glucose values used for the definition of GDM (table 2).
21 But these were based on the subsequent maternal risk for diabetes and did not investigate the risk for fetal or neonatal morbidity.
Our study was performed between 1992 and 1993 at the Department for Obstetrics at the Vivantes Medical Center Neukoelln in Berlin. Central obesity and hyperinsulinism with consecutive neonatal hypoglycemia was even more frequent than in pregnancies with GDM. Additionally, neonatal glucose testing is recommended in all LGA infants (birth weight> 90th percentile) independently of the diabetic status of the mother. In the subgroup of infants of mothers with oGTT the 1 hour-glucose value was an excellent discriminator between infants at low, intermediate or high risk for hypoglycemia.
14 A large body of clinical and experimental studies supported that maternal hyperglycemia enhances fetal growth by an excessive glucose supply to the fetus at a time when the fetal pancreas is able to respond by increasing its production of insulin. Our study aimed to examine the correlation of maternal glucose values and fetal growth at different gestational weeks of pregnancies in normal and overweight women with GDM.
Both of our presented studies revealed the strong influence of maternal obesity on the risk for accelerated growth. Maternal hyperglycemia leads via fetal hyperinsulinism to an increase of the insulin sensitive tissue, like the adipose tissue.
Considering the strong influence of non-glucose related parameters, a modified approach in obese women might be more effective to lower the high rate of LGA infants in these women.
Normalization of maternal hyperglycemia could lower the rate of adverse outcome in pregnancies with GDM but the rate of macrosomia and neonatal morbidity is still elevated compared to the normal obstetrical population. 7) measured in the early third trimester revealed to be a good predictor for a LGA newborn. 65-68 The level of fetal insulin is supposed to correspond to the level of insulin in the amniotic fluid secondary to the urinary excretion.
But since fetal growth is influenced by many other factors beside the fetal insulin levels there is still a concern of over- or under-treatment when insulin therapy is administered solely depending on the fetal AC. The percentiles of the fetal AC corresponded to the level of the fetal insulin indirectely determined by the AF insulin. 1 In agreement with other groups, we could show that the relation of neonatal morbidity and maternal glucose values seems to behave in a continuous fashion. Both institutions take care of a multiethnic population with a rate of approximately 40% women from Turkey, Arabian countries or East Europe. The measurement of the fetal AC with ultrasound reliably identified fetuses at low risk for accelerated growth.
If a baby’s bilirubin level gets too high, the bilirubin can enter the brain tissue and cause permanent brain damage, such as kernicterus, cerebral palsy and encephalopathy. This should not be a problem, however, because testing for and treating high bilirubin levels is very easy. Severe hyperbilirubinemia can occur when a newborn has a disorder or condition that increases the number of red blood cells being broken down. This can cause the baby’s blood volume and blood pressure to drop, which can cause hyperbilirubinemia. There are no downsides to treating a baby with phototherapy, increasing feeding and hydration, and ordering a type and cross match of blood in the event that an exchange transfusion is necessary. A bilirubin level in a baby who is a day old may be normal or dangerously high, depending on whether the baby is closer to 24 hours of age or 47 hours of age. When bilirubin levels get too high, bilirubin can pass through the blood brain barrier and enter brain tissue. Bilirubin then builds up in the gray matter, which contains most of the brain’s neuronal cell bodies. A child with SBE will have neurological, movement and learning disorders, and some hearing problems are also likely to occur.
This is because when a baby is jaundiced and signs are present, damage is continuing to occur. We have helped children throughout the country obtain compensation for lifelong treatment, therapy and a secure future, and we give personal attention to each child and family we represent. Estimation of the epidemiological impact of GDM has indicated that at least 1 out of 10 pregnant woman is being affected by GDM worldwide.
29-31 Preconceptional care and optimizing of maternal glucose control can reduce the rate of anomalies to the level of the normal population.
Furthermore there is more and more evidence that the relationship between maternal glycemia during pregnancy and neonatal morbidity behaves more like a continuum, with no precise threshold to discriminate between high and low risk fetus. They investigated the outcome either in women with positive glucose challange test but negative oGTT or in women with only one pathologic value in the oGTT.
We involved 325 women with risk factors for GDM who were tested for glucose intolerance by a 75 g oGTT.
Severe placental immaturity was seen most frequently in GDM pregnancies but again the rate in IGT was significantly higher compared to normal pregnancies. Excessive growth is the major clinical sign of fetal hyperinsulinism due to maternal hyperglycemia in pregnancy. They could demonstrate a graded increase in adverse maternal-fetal outcome with increasing maternal carbohydrate intolerance. 43-45 Although the stimulation of insulin secretion starts with 11-15 weeks of gestation 46 , accelerated growth due to maternal diabetes occurs at around 28 weeks, presumable because of the fetal capacity to store triglycerides at that time. We use the above described population to determine independent predictors for fetal macrosomia at different periods of pregnancies and at birth. At no time in pregnancy, a higher rate of fetal macrosomia was associated with higher maternal glucose values but with obesity. 1 In studies with very strict control the macrosomia rate had been lowered to 10% but this management required intensive insulin therapy in 66-100% of the women. Secondly, we aimed to create a score of the discriminatory parameters and quantitated the predictive power by receiver operator characteristics (ROC) curves analysis.
Thus, we investigated the correlation between amniotic fluid insulin (AF insulin) and fetal AC percentiles at time of amniocentesis performed in the third trimester in 121 diabetic women.
The fetal AC ≥ 90th percentile was the strongest predictor for an LGA infant within a wide selection of tested parameters. 38, 42, 73-76Thus, the glucose targets that we aim to achieve during pregnancies are arbitrary and consensus based. In the experimental group insulin therapy was limited to pregnancies with a fetal AC > 70th percentile at entry or in one of the subsequent monthly ultrasound examinations.
The baby may also have seizures, intellectual disabilities, developmental delays, and hearing and sight problems. When a baby has hyperbilirubinemia, she can be placed under special lights to reduce her bilirubin levels. This will show the total serum bilirubin level, which is a more accurate assessment of bilirubin in the blood. One reason hyperbilirubinemia occurs in this scenario is because when blood pressure drops, the body doesn’t get rid of bilirubin as fast. Even if a newborn does not have risk factors for hyperbilirubinemia, she should have her bilirubin levels frequently checked.  If a newborn goes home shortly after birth, a follow up visit with the physician should be scheduled within the first seven days after birth. Gray matter plays a major role in muscle control, seeing, hearing, memory, emotions, decision-making, speech and self-control. The sooner the bilirubin is reduced, the better, and the less severe the brain damage will be, in most cases. News and World Report 2014, which also recognized ABC Law Centers as one of the best medical malpractice law firms in the nation. These transport mechanisms are in a perfect equilibrium between demand and consumption, and they are highly dependent on the appropriated endothelial function in the placental vascular bed. In addition, GDM causes not only short-term complication in both mother and fetus, but also is associated with elevated risk for long-term complication such as cardiovascular disease, obesity and diabetes. 27, 32, 33 In women with preexisting diabetes, a great body of data is available to assess the risk for diabetes based on the level of maternal glucose values. It can be speculated that women with severe hyperglycemia at time of diagnosis of GDM might have had hyperglycemia in early pregnancy high enough to impart a risk for malformation to their children. Study subjects were again retrieved from our database of diabetic women attending the Diabetes Clinic of the Los Angeles County women’s hospital.
Macrosomic newborns are at increased risk for neonatal hypoglycemia when after delivery the insulin secretion has to be adapted to the sudden drop in glucose supply.
38 In addition to other studies which were limited to clinical complications known to be increased in diabetes, we could confirmed the influence of borderline glucose intolerance on very specific parameters for diabetic fetopathy.
47 Thus, it is obvious that maternal hypergylcemia is a risk factor for macrosomia, however the regulation of fetal growth is far more complex and is influenced by many factors.
A fetal abdominal circumference > 90th percentile according to gestational age 48 was defined as fetal macrosomia. We included maternal historical (prior pregnancy with LGA or GDM, prepregnancy BMI and parity) and glycemic parameters at entry (oGTT, HbA1c and mean fasting and postprandial glucose values of the daily profile) and the glucose values of the profiles at the different periods of pregnancy.
Obesity is often associated with elevated lipids and proteins and peripheral hyperinsulinism which had been shown to be related to the risk for macrosomia.
57-59 Furthermore, in gestational diabetes aggressive lowering of the maternal glucose levels may lead to an increased rate of intrauterine growth retardation and an adverse perinatal outcome for small-for-gestational-age newborns.
Although this approach offers a direct estimation of the fetal reaction on maternal glycemia, it is not widely accepted because it requires an amniocentesis as an invasive procedure to obtain amniotic fluid. In a second step, we aimed to find a threshold for fetal AC measurements that identifies low vs high risk levels of AF insulin without performing an amniocentesis.
In contrast, as we expected from our previous studies, the maternal glycemic values in this treated population were not predictive. Interestingly, the AC threshold of the 75th percentile found by our study to identify severe hyperinsulinism was identical to the AC threshold which has been recommended for initiating insulin therapy in GDM. 47, 55, 56 In GDM managed by a fetal-growth based approach the neonatal outcome was similar to pregnancies guided solely by maternal glycemia even in selected women with hyperglycemia from a population of Mexican-Americans that is known to have a high rate of severe glucose intolerance.
Everybody experiences red blood cell breakdown, but in newborns, the breakdown is at a higher rate.

All newborn babies should have their bilirubin levels checked every 9 – 12 hours in the first 2 days of life, at a minimum.
The lawyers at ABC Law Centers have won numerous awards for their advocacy of children and are members of the Birth Trauma Litigation Group (BTLG) and the Michigan Association for Justice (MAJ).
In the images is presented only HUVEC that were seeded at 30 x 103 and hPMEC that were seeded at 10 x 103. Preliminary results in our laboratory suggest that gestational diabetes mellitus (GDM) is associated with elevation of adenosine extracellular levels and high activation and expression of A2A adenosine receptor characterized by high (?) eNOS activation, NO formation and Y-nitration whose are associated to enhancement of cell proliferation and migration and finally it would be occasioned elevated placental angiogenesis characteristic of this disease.7. Congenital anomalies typical for diabetes affect primarily the heart, central nervous system, kidneys and the axial skeleton. So far, there had been very few data to quantify the risk of malformations in these heterogeneous population of women with GDM. There was no difference in maternal historical or glycemic parameters between mothers of pregnancies with normal infants and infants with minor anomalies thus we combined them for the further analysis.
Diagnosed major congenital malformations were categorized by the number and type of affected organ systems. 35 A second analysis in a subgroup of women with normal postpartum oGTT and therefor little chance of having preexisting diabetes confirmed that women who develop severe glucose intolerance first in pregnancy are also at risk for an infant with congenital anomalies.
Diabetes care consisting of diet education and frequent glucose profiles was limited to women with GDM, defined as usual by two pathologic values in the oGTT. Universal testing in all LGA newborns implicates unnecessary diagnostic in infants at low or no risk for hypoglycemia since only a minority of macrosomia is caused by diabetes. Beside macrosomia and hypoglycemia also hyperinsulinism, trunk obesity and placenta immaturity were significantly more frequent in untreated women with IGT than in normal women. The clinical experience indicates that despite of tight glucose control neonatal macrosomia occurs.
Glucose values at diagnosis - oGTT , entry glucose profile and HbA1c – and the glucose values of the profiles performed at 5 different categories of gestational weeks were compared between pregnancies with and without fetal macrosomia diagnosed at correspondent gestational ages. We found different parameters univariately associated with accelerated growth at different times of pregnancy: LGA in a previous pregnancy, parity, prepregnancy obesity, fasting of the oGTT or fasting glucose at 32GA. 50-52 Lipids and amino acid levels are influenced by the carbohydrate metabolism but there is no linear correlation between the elevation of glucose and non-glucose nutrients. Attainment of strict control in all women with GDM might result in unnecessary treatment in low-risk pregnancies and absorption of limited resources needed for intensive therapy in high-risk pregnancies. We can only speculate if maternal glycemia would be more discriminative in an untreated population with a wider range of glycemic values. 77 The best evidence that the same maternal glucose values may result in different outcome comes from observations in twins. 34 Insulin therapy could be avoided in 38 % of these women and in 43% of Caucasian women with hyperglycemia investigated in Berlin. This is because babies have more red blood cells than adults, which is part of the transition from being in the womb. Damage to gray matter can cause cerebral palsy, seizure disorders, intellectual disabilities and speech, sight and hearing problems.
Those cells were maintained in culture under standard conditions (5% CO2, 37oC) during 0, 1, 2, 3 and 4 hours and cells were photographed. Part of this adaptive response, might also include the elevation in the placental consumption of glucose and enhancement of the feto-placental blood flow, especially in fetus large-for-gestational age (LGA). The study population was divided into women with normal oGTT, women with one abnormal value (IGT= impaired glucose tolerance) and women with GDM and neonatal outcome was compared between the groups.
Therefor we investigated the rate of hypoglycemia in LGA newborns of non-diabetic mothers and whether maternal or neonatal risk factors for hypoglycemia could be identified.
Our second work related to this topic concentrated on macrosomic infants of non-diabetic mothers. Thus, the effect of hyperlipidemia and hyperacidemia on fetal growth cannot be eliminated solely by glucose control.
Therefor some researchers were looking for other predictors besides maternal glycemia to identify pregnancies at high risk for morbidity. 78 Applying the strategy of tight glucose control on all women misses the change to target intervention on pregnancies with high risk for morbidity. According to the protocol, the glucose values during pregnancy were lower in the standard group compared to the experimental group. The US-group was started on insulin if fetal AC exceeded the 75th percentile at entry or at any examination thereafter corresponding to a 4 week examination schedule at 20, 24, 28, 32 weeks of gestation. Fetal red blood cells have a short life span, which leads to a lot of cell breakdown and excess bilirubin in the blood.
Both, vasomotor and angiogenic properties are modulating the fetoplacental blood flow continually by a cross talking between placenta and fetus.
As indicated in the pictures, hPMEC exhibit a more rapid response for tube formation under our culture condition and require lesser quantity of cells than HUVEC, suggesting a differential physiological role of these cells in the fetal circulation. On the other hand, due to lack of innervation in the placenta, the vascular tone is controlled by the regulation of the synthesis and release of vasoactive substances from the endothelium like vasoactive molecules, nitric oxide, adenosine, prostaglandin, among others. The fasting glucose is an easy accessible clinical parameter since it is part of the diagnostic procedure. Thus, we could only speculated about the degree of hyperglycemia during embryogenesis which is required to cause anomalies.
In 887 LGA infants, we observed hypoglycemia within the first day of life in 16% of the infants with a steep decrease of the incidence after the first two hours.
We could show that the risk of neonatal hypoglycemia in these infants is tightly related to the 1-hour oGTT value of the mother.
49 There was no difference in glucose values either at entry or during pregnancy between pregnancies with or without fetal macrosomia either in lean nor in obese women. When we looked for other maternal predictors in the second analysis, we found independent predictors that represent the three major determinants of fetal growth. One approach is based on fetal growth 60-62 and limits intensive insulin therapy to pregnancies with accelerated growth of the fetal abdominal circumference (AC). Easy obtainable historical data by itself seem to provide enough information for clinicians to antenatally estimate the risk for an LGA newborn.
In a pilot study limited to women with normoglycemia it was demonstrated that a single measurement at entry to therapy could identify a fetus at risk for macrosomia.
The overall rate of insulin use was slightly higher in the US-group compared to the standard approach.
In fact, if the transcutaneous level is high, treatment may be given while waiting for the blood test results. On the other hand, there is an increase in the glucose level in the maternal circulation in gestational diabetes mellitus (GDM), which is transported to the feto-placental circulation generating and stated of hyperglycemia, hyperinsulinemia and insulin resistance.
Neonatal obesity was defined according percentile rankings obtained by skinfold measurements that had been previously performed in 250 consecutively born infants. Interestingly, the identified threshold corresponds to the threshold for an abnormal 1-hour value according to the Carpenter and Coustan criteria for GDM. In contrast, the fetal macrosomia rate was significantly higher in obese compared to lean women at each category of gestational age and at birth. A history of a prior LGA infant representing the genetic influence, maternal obesity reflecting genetic and non-glucose fuels and the fasting hyperglycemia indicating an increased glucose supply to the fetus. Diabetes associated macrosomia is characterized by an asymmetric growth of the fetal abdomen versus head and long bones due to the stimulation of the insulin sensitive fat tissue by fetal hyperinsulinism (fig.1 ).
All predictors in a single or combined fashion are superior in identifying an infant at low risk for excessive growth (NPV) while the sensitivity and specificity did not exceed 77% or 53%, respectively.
Intensive insulin therapy could lower the macrosomia rate by 3 fold in this high risk population compared to those who were treated with diet only. The two groups were similar regarding historical data, glycemic data and the rate of fetal AC at entry.
This reflectes the mild degree of glucose intolerance when diagnosis of GDM is based on the low diagnostic criteria for GDM of O’Sullivan. In the womb, the placenta removes the bilirubin, but after birth, the baby’s liver begins removing the bilirubin and this can sometimes take a while.
In turn this high glucose uptake may generate elevated oxygen consumption due to high metabolism. In this regard, several studies have shown that placenta from GDM is characterized by hypervascularization and elevation in the pro-angiogenic signals including the secretion and activity of the vascular endothelial growth factor (VEGF). 31 Regardless the final classification of diabetes after pregnancy, our data provide a useful tool to counsel women with hyperglycemia diagnosed first in pregnancy about their risk for major anomalies based on their fasting glucose levels at time of diagnosis.
20 Thus, all mothers of the infants at greatest risk for hypoglycemia had IGT that was not treated because the oGTT did not fulfill the criteria for GDM. In the early pregnancy the influence of genetic factors predominates; about 15% of the variation in birth weight is due to genetic predisposition. The overall macrosomia rate of the study population was reduced without applying insulin to the majority of the women. Delivery by Cesarean section was performed more frequently in the experimental group but this could not be explained by complications related to diabetes.
21 When we excluded women who did not fulfill the Carpenter and Coustan criteria that require higher post challenge glucose values, the insulin use in both study arms was similar. This elevation in the glucose metabolism in the placenta would generate an endothelial dysfunction characterized by elevation in RNS, ROS, prostaglandin and purine concentration in the feto-placental circulation, which consequently affects the tone regulation in the placenta. In addition, hyperglycemia also generates a status of oxidative stress, where free radicals derived from oxygen (ROS) induces changes in the endothelial cell membranes producing an elevation in the cell permeability.
Secondly, our data support the clinical importance of a general screening for GDM since without available oGTT values a risk assessment for hypoglycemia in LGA newborns seems not be possible. 53 It could be shown that an early symmetric accelerated growth is not associated with fetal hyperinsulinism.
For moderately elevated insulin levels the fetal AC offers no reliable tool for risk assessment.
Our subsequent studies which will be presented in the following aimed (1) to extend this approach to women with hyperglycemia and (2) to proof the applicability of this strategy in a population with a different ethnic background and without prior stratification according to the maternal glycemia status. Despite intensive insulin therapy the LGA rate in women with fetal AC > 70th percentile at entry was higher than in women with normal fetal growth. When we looked at the women who were treated differently in the US-group compared to the standard group we realized a better outcome in the US-group: a tendency toward a lower SGA rate in women with hyperglycemia but normal fetal growth and a lower LGA rate in women with euglycemia but accelerated growth. Moreover, relative hypoxic condition in GDM, may trigger an pro-angiogenic response generating a condition of hypervascularization in the placenta and therefore creating a vicious circle.
Additionally, the high chance for anomalies involving multiple organ systems have to be considered since increasing glucose levels had been associated with a higher number of affected organ systems in the infants of our population.
54 In the early third trimester maternal obesity became a strong predictor coincident with the time of fetal adipocyte proliferation and lipid storage. When we analyzed a subgroup of women with GDM according to Carpenter and Coustan criteria (n=161) the results were identical with the exception of a higher rate of insulin use in the standard group. In this chapter, we will review the available literature focus on the role of feto-placental endothelial dysfunction as the possible main factor in the generation of short-term complication during GDM and speculate how it may program the response of the sibling exposed to GDM.2. Further prospective studies are needed to develop strategies to identify preconceptionally women without overt diabetes but glucose intolerance sufficient to cause congenital anomalies. Kainer et al, the only group so far that investigated the relation of amniotic fluid insulin and the fetal AC also found the AC measurement to be useful only in identifying high levels of insulin.
In a secondary analysis in women with euglycemia and AC >75th percentile (n=34) the rate of LGA, C-section and neonatal hypoglycemia was lower in the insulin treated US-group compared to corresponding women in the standard-group. Finally, this high input of nutrients and elevated circulation will be responsible for macrosomia in GDM.
Gestational diabetes: Definition and epidemiologyPregnancy is a physiological state where occurs a series of complex anatomical and functional adaptation in the mother to facilitate the development of fetus. A minority of the women would have qualified for routine diabetes testing which is limited to women with age > 45 or other risk factors like prior GDM.
70 Our finding corresponds to the data of Weiss et al who had demonstrated that neonatal morbidity was mostly limited to AF insulin levels which were increased 2 - 3 fold above normal.
In those pregnancies with maternal hyperglycemia but AC< 75th percentile (n=35) there was no adverse outcome in the US-group although insulin was withheld. It can be only speculated about the influence of increased attention and motivation under the conditions of a clinical trial and the frequent demonstration of fetal growth by serial ultrasound examinations. For instance, during the normal pregnancy a “physiological” insulin resistance is necessary to provide glucose to the growing fetus [1]. 36 But even with routine testing the women who appeared to be at risk would not have been detected considering the existing diagnostic criteria for diabetes outside pregnancy at the time of the study.
However, this normal adaptation is no longer occurring in some conditions and generates a clearly pathological state of insulin resistance, which is called Gestational Diabetes Mellitus (GDM).
Therefore, GDM has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [2]. This discrepancy has been extensively discussed in the literature but the general agreement is that adverse perinatal outcomes occur in lesser degrees of hyperglycemia than the recommended as diagnostic criteria by the WHO [4].Prevalence of diabetes for all ages is increasing worldwide, including women in fertile age.
Therefore, it is not surprising that diabetes diagnosis before or during gestation has been defined as a public health problem [5]. Epidemiologically speaking, it has been estimated that near to 90% of the diagnosis of diabetes in pregnancy is actually GDM [5]. Thus, taken into account the origin of the population, it has been described that women from Asian, African American, and Hispanic background exhibit twice the risk for being diagnosed of GDM compared to those of non-Hispanic White origin, a phenomenon observed also in women in the lowest socio-economical quartiles compared to women in the highest quartiles [8,9]. The underling mechanisms responsible for GDM are under investigation; however, likewise to other causes of type 2 diabetes, GDM is characterized by a dysfunction in the pancreatic ? cell, which does not produce enough insulin to meet the increased requirements of late pregnancy. In addition, it has been described that the large majority of the insulin secretory defects present in the third trimester of gestation, are actually manifesting before and soon after pregnancy [10,11]. In this way, considering that a) obesity, is a condition of insulin resistance and a common risk factor to GDM, and b) insulin secretion during pregnancy increases according to gestational age in women with and without GDM [10]; it has been reinforced the concept that chronic deficiency rather than gestational-acquired deficiency of insulin secretion is the underling cause for GDM. Consequently, these evidences have broken the traditional vision of GDM pathogenesis, where the imbalance in glucose level at the third trimester of gestation has been consider exclusively as a defect in the “physiological” insulin resistance present in pregnant women. With regard to insulin, it is well known that it reduces the elevated level of blood glucose; however, insulin is also regulating the metabolism of amino acids and lipids. Indeed, selective damage of ?-cell in animal models generates a severe lipid defects that induce animal death [12,13].
This idea reinforces the general agreement of hyperglycemia is not the unique feature that may be taken into account during GDM management. In addition, it has been reported that in general, hyperglycemia is resolved after birth; however, there are epidemiological evidences showing that GDM constitutes a risk factor for development of diabetes mellitus type 2 (DMT2), as well as it constitutes a risk factor for hypertension in both mother and offspring. Thus, it has been estimated that about 10% of women with GDM have diabetes mellitus soon after delivery; whereas the rest will develop diabetes mellitus at rates of 20-60% within 5-10 years after the manifestation of GDM in the absence of specific interventions to reduce their risk [10]. Therefore these evidences have suggested that metabolic defects in GDM, characterized by hyperglycemia, and fundamentally, insulin deficiency (relative in GDM) are maintained after birth being a risk factor for metabolic and cardiovascular diseases in the mother and her sibling. Thus, considering data on the difference in the birth weight between the lowest and the highest glucose categories was about 300g. Therefore, this study suggests that maternal hyperglycemia, even in the “normal” range according with the WHO criteria, is related to clinically important perinatal disorders. When the authors excluded the HAPO study from their meta-analysis, the relative risks for the analyzed perinatal outcomes were minimally altered.
This association between GDM and macrosomia is particularly important for our discussion, since it has been described that fetal growth defects are associated with long-term complication, including obesity and diabetes [15,16].
Nevertheless, another highlight of this meta-analysis is that reduction in the criteria for “hyperglycemia” recommended by the WHO, should be considered for the next generation.Although discrepancies in cut off value of glucose level for diagnosis of GDM, most of the alterations observed in GDM have been related with “hyperglycemia”. For instance, it has been shown that intraperitoneal injections of high glucose in early pregnancy were associated with a modest but significantly increased placental weight and fetal weight [17]. Therefore, authors suggest that increased fetal growth may be explained by a large placenta and delivery of more nutrients to be transferred to the fetus. Since macrosomia is also present in “normo-glycemic” pregnant women, it has been suggested that other factors rather than high glucose by itself may take part in the pathophysiology of maternal and fetal-neonatal complication present in GDM [18]. In this way, other clinical components in GDM, included metabolic alteration such as insulin resistance, as well as high levels of cholesterol, triglycerides, adenosine, nitric oxide, and several other factors may disrupt normal function of maternal, placental and fetal tissues. Specifically, it is well accepted that hyperglycemia in the fetus exposed to GDM, generates a compensatory elevation of insulin; which in turn, is not only affecting glucose level, but also is acting as a growth factor.
In addition, insulin is also regulating the transport of other nutrients such as amino acids or other regulatory elements such as adenosine [19,20,21].
In particular, it has been described that insulin increases the L-arginine uptake in human umbilical vein endothelial cells (HUVEC), a phenomenon associated with generation of vein relaxation and increasing Sp1-activated SLC7A1 (for human cationic amino acid transport type 1, hCAT-1) expression [22]. In addition, it has been described that insulin increases the activity of neutral amino acid through the system A [23]. On the other hand, insulin recovers the reduced adenosine transport mediated by the Equilibrative Nucleside Transport type 1 (ENT-1) in HUVEC, an effect that was associated with increased relaxation of the umbilical vein [24]. In the next section, it will be reviewed some of these evidences and the mechanisms linked with fetal programming in GDM.4.
Programming and GDMProgramming is defined as "the phenomenon whereby a stimulus occurring during a critical window of development, namely the prenatal and early postnatal periods, which can cause lifelong changes in the structure and function of the body” [25]. In this regard, the concept that the intrauterine environment might affect health later life became evident with the surprising observation that low birth weight was associated with increased cardiovascular disease 40 years later [15,16,26]. Numerous epidemiological studies extended these observations to suggest a role for the intrauterine environment as a leading cause of schizophrenia, depression, cardiovascular diseases, stroke, diabetes, cancer, pulmonary hypertension, osteoporosis, polycystic ovarian syndrome, among others in adult life [27,28,29,30].

These observational relationships are supported by animal experiments, which fetal growth manipulation by changing maternal nutrition or reducing blood flow to the placenta resulted in obesity, increased blood pressure and other cardiovascular abnormalities in the offspring later life [31].
In addition, a clear association between maternal diseases (including GDM) and future implication in health in the offspring has been affected by several confounding variables such as genetic factors (a particular phenotype may be genetically transmitted to the offspring), paternal implication (the father genotype may affect the phenotype), gender (hormonal differences may induce a particular gender-linked phenotype), diagnosis criteria used for maternal disease (in the particular case of GDM, the level of glycaemia), retrospective evidences (most of the epidemiological analysis coming from retrospective rather than prospective studies), among others. Despite those confounding factors, most of the available data in the case of GDM supports a predominant role for intrauterine exposition to hyperglycemia as one of the underling mechanisms for future chronic disease in the offspring exposed to this disease [25]. Among the evidences that support this assumption, it has been described that children born after a diabetic pregnancy in Indian Pima women exhibited a high (6-fold) prevalence of type 2 diabetes than those who were born from a non-diabetic pregnancy. Interestingly, this high prevalence persists after a multivariable analysis, taken into account paternal diabetes, age of onset of parental diabetes in father and mother and obesity in the offspring [32].
Besides, another study showed that the risk of diabetes was significantly higher (? 4 fold) in siblings born after GDM than those who were born before the mother has been diagnosed with diabetes [33]. Offspring “exposed” to GDM shows a high risk for developing obesity, impaired glucose tolerance, type 2 diabetes, malignant neoplasm and hypertension in adulthood [34,35,36,37,38,39]. For instance, initially, it has been reported that offspring (10-16 years) “exposed” to maternal diabetes showed a higher prevalence (6-fold) of impaired glucose tolerance and body mass index than controls non-exposed [40].
Furthermore, this finding was confirmed in another study including children (1-9 years) who their mothers presented pregestational insulin-dependent diabetes (IDDM) or GDM [41]. Following to this study, prospective data from the Framingham Offspring Study [42], which included a large sample (2.527 subjects), found that offspring (26-82 years) of women with diabetes showed a high risk (?3-fold) to impaired glucose tolerance and type 2 diabetes compared to individuals without parental diabetes.
This risk was almost three times higher in children belong to diabetic mothers <50 years. Moreover, another study also confirms these findings, where offspring “exposed” to GDM exhibited ? 7 folds increase in the prevalence of type 2 diabetes or impaired glucose tolerance compared to offspring from non-diabetic pregnancy [39].
Interestingly, this risk was even higher than offspring of women with type 1 diabetes who presented ? 4 fold risk for being diabetic [39], reinforcing the idea that maternal intrauterine environment generates a particular phenotype which is not explained only by heritage. Nevertheless, Clausen et al (2009) have reported a high risk (? 2 fold) for developing overweight or metabolic syndrome in offspring of women with GDM or type 1 diabetes compared to offspring from non-diabetic pregnancies. It has been also reported that the higher hyperglycemia in the mother [36] or the weight for gestational age in children exposed to GDM [43], the higher risk for metabolic syndrome in the offspring in future life.
Moreover, GDM is also associated with high risk for cardiovascular diseases in the offspring. Thus, in a large cohort study, it has been reported that children exposed to GDM had higher systolic blood pressure (?3 mm Hg) than non-exposed children [44]. Interestingly, a significantly higher risk for those groups of diseases were also observed in children whose mother had type 1 diabetes or pre-gestational type 2 diabetes. Therefore, a hyperglycemic intrauterine environment seems to be part of the pathogenesis of chronic metabolic and cardiovascular disease in the offspring of GDM [36,37,39]. The mechanisms linked with fetal programming during GDM have been associated with hyperglycemia, through the hypothesis of fuel-mediated toxicity (Freinkel’s hypothesis) [46], which indicates that fetus experiences a “tissue culture” environment, in such circumstances, where high availability of nutrients may induce a “fuel-mediated teratogenicity”.
Particularly, we will focus on the alterations observed in the placental vasculature, early in life, that may support the association between elevated risk for cardiovascular disease during adulthood and GDM. Since placental circulatory system form a continuous network with the fetal circulation, it is feasible to propose that changes in the function and regulation of all these vessels early after birth may give clues of the abnormalities that will occur later in life.5. The placenta prevents the passage of macromolecules over 700 Daltons, whereas the smallest particles can cross (for instance melatonin, catecholamines and other hormones) [49,50]; therefore, this tissue exhibits a selective permeability that is known as the placental barrier. In the formation of human placenta, the maternal vessels are invaded by trophoblastic cells, which in turn are in direct contact with maternal blood. In the maternal side, a laminar degenerative process in the junctional zone forms the maternal layer or uterine surface, which in general are formed by maternal vessels where the endothelium has been replaced by placental cells (invasive cytothrophoblast), remnants of endometrial glands and connective tissue.
Moreover, grooves is shown in this structure, which subdivide the surface of placenta in about 10-40 elevated areas similar to lobules named maternal cotyledons, which are in perfect correlation with fetal cotyledon [51].
The fetal component, cotyledon, is formed by several villous trees (1-3 villous trees per fetal cotyledon), which in fact are formed by chorionic villus.
Cytotrophoblast and differentiated syncytiotrophoblast are derived from trophoblastic cells. The syncytiotrophoblast is a multinucleated and continuous layer of epithelial cells, which is formed by the fusion of cytotrophoblasts. In the other hand, syncytiotrophoblast is covering the villous trees and it is in direct contact with maternal blood, therefore, it is the area where direct exchange of oxygen, nutrient and removal of waste products occurs [53].
Moreover, syncytiotrophoblast have an endocrine function characterized by production of human chorionic gonadotrophin (hCG) regulated by progesterone [50]. Besides, those cells also secrete a variant of growth hormone (GH), human placental lactogen (hPL), insulin-like growth factor I (IGF-I) and endothelial growth factor [50,53].
On the other hand, cytotrophoblasts (or Langhans?cells) are continually differentiating into syncytiotrophoblast. There is a trophoblastic basement membrane supporting these two layers, cytotrophoblast and syncythiotrophoblast. This membrane forms the physical separation of those layers with the stromal core villi, a structure formed by connective tissue where the fetal vessels are immersed.
In the placenta, the blood vessels constitute the largest component among the structures creating the cotyledons. In fact, placental vessels constitute a continuous circulatory system with the fetal cardiovascular system. In the placenta, the veins are conducting oxygenated blood toward the fetus, whereas the arteries contain deoxygenated blood toward the placenta. Anatomically, from the umbilical cord to the deep in the placental cotyledons, the umbilical arteries and veins branch themselves to form chorionic arteries and vein, respectively, over fetal surface of the term placenta, and those branches subdivide themselves before entering into the villi.
Likewise other vascular beds, in the placenta the veins are more elastic, exhibit high capacity and a miniscule layer of both smooth muscle cells and adventitia compared to arteries; which in turn are vessels that offer a high resistance. These characteristics, especially those observed in the umbilical cord, have been used for functional non invasive studies, like Doppler, in order to analyze the status of the feto-placental circulation. Finally, and similar to any other tissue, the placenta blood vessels are lined by the endothelium.
The endothelial cells are supported by a basal membrane and pericytes, both of them involved in vessel permeability and integrity, and importantly in the endothelium differentiation [56].In GDM, it has been reported macroscopical and histological alterations in the term placenta. On the other hand, regarding studies, in syncytiotrophoblast from diabetes during pregnancy, have shown functional alteration in this cell type. Thus, it has been described an increase in the number of cytotrophoblast identified by number of nuclei [60], high fibrin deposit over syncytiotrophoblast and hyperplasia of cytotrophoblast [59,61,62], whose in turn may be related with the enhancement of the thickness of syncytial basement membranes in GDM compared to normal pregnancy [63]. Moreover, using functional studies of syncytiotrophoblast microvillous membrane vesicles, Jansson and collages [64] showed non-changes in the glucose transport in samples from GDM. Contrarily, other reports showed reduced glucose uptake and glucose utilization [65], as well as low expression of glucose transporter type 1 (GLUT1) and 3 (GLUT 3) in placentas from GDM compared with non-diabetic controls [66]. Other alterations in the throphoblastic cells from GDM were low expression of serotonin transporter (SERT) and receptors (5-HT2A) [67], as well as high activity of amino acid transporter system A [68]. Nevertheless, it has been reported a high expression of inducible nitric oxide synthase (iNOS) in the whole placenta but mainly in the trophoblastic cells using immunohistochemistry in GDM [69], a phenomena that may be correlated with high nitric oxide synthesis [24] and nitrative stress [70] observed in placentas from GDM.
In addition, it has been reported high level of degenerative lesions such as fibrinoid necrosis and vascular lesions like chorangiosis, as well as elevated signs of villous immaturity and presence of nucleated fetal erithrocytes in placentas from GDM compared to normal pregnancy [58].
Thus, it has been reported in GDM that the elevation of plasma glucose in the umbilical vein is associated with reduced oxygen saturation and oxygen content, as well as a significant increase of lactate concentration compared with normal pregnancy [59]. Interestingly, these changes were not observed in the umbilical artery, suggesting high placental oxygen consumption in GDM, which may generate a compensatory response in the placenta itself.
Therefore, placental alteration in GDM includes changes in the transport of nutrients (such as amino acid), enhanced blood formation and glucose consumption that may generate a “relative hypoxic” status.
Unfortunately, all this findings are described in term placenta; therefore, non-invasive test such as Doppler will offer more clinically relevant information regarding fetal status and feto-placental circulation before delivery. Placental blood flow and GDM One of the non-invasive techniques used widely to estimate the blood flow in the feto-placental circulation is Ultrasound and Doppler. Moreover, the absence of end-diastolic blood flow before 36 weeks gestation is utilized clinically as indicator of fetal distress such hypoxia and acidosis [77] and this indicator is also associated to growth restriction [78]. Wharton’s jelly area is surrounding the two arteries and the vein in the umbilical cord, and this jelly has a protective role for preventing interruption of flow by compression or twisting caused by fetal movement [79]. Wharton’s jelly area can be determined by subtraction of umbilical cord area and total vessels area (arteries and vein), and interestingly it is significant correlated with gestational age and fetal anthropometric parameters [79,80], and also it has been described that alterations in this parameter are associated to hypertensive disorders, fetal distress, gestational diabetes and fetal growth restriction [80]. Doppler studies in umbilical vein from GDM have shown no changes neither in the pulsatile index value in the umbilical artery nor in the mean total umbilical venous flow in fetus exposed to GDM compared to normal pregnancy [81].
Interestingly, large for gestational-age fetus showed an increase in the total umbilical venous flow, suggesting that high placental flow toward the fetus may be associated with macrosomia. Moreover in macrosomic fetus without diabetes, it has shown an increase in the umbilical vein blood flow associated with high systolic velocity in the splenic, superior mesenteric, cerebral and umbilical arteries [82], suggesting an increased fetal perfusion especially in the liver. The underling mechanisms for this redistribution in the blood flow are unclear, but considering that GDM increases the synthesis of nitric oxide in human umbilical vein endothelial cells [83], it is feasible to speculate that a overall vasodilatation in the pre-hepatic and hepatic circulation would be taken part in this process. Taken these evidences into account, it is feasible that elevated feto-placental blood flow and hyperglycemia would be responsible for macrosomia in GDM.
These mechanisms include; maintenance of physiological barrier, regulation of vascular tone and angiogenesis. Importantly, feto-placental endothelium forms an uninterrupted tissue that will be extended until fetal circulation, where it is exposed to the same metabolic and hormonal medium than endothelium of the fetus itself [84].
Moreover, since the lack of innervation of the placenta, the regulation of vascular tone is mainly dependent on endothelial cells-mediated synthesis and release of several vasoactive substances including, nitric oxide (NO), prostacyclin, thromboxane, endothelial derived hyperpolarizing factor (EDHF), adenosine, mono or di or tri monophosphate of adenosine (AMP, ADP, ATP), among others [85,86,87]. These characteristics are summarized in the Figure 1, where it also described some functional alterations observed in GDM. On the other hand, there are emerging evidences showing that endothelial cells are able to dedifferentiate into mesenchymal cells, via a process called endothelial-to-mesenchymal transition (EndMT) [88,89], which in fact is related with the capacity of the endothelium to migrate away from the vessel-lining and colonize other tissues where dedifferentiation may occur in order to recover the particular capacity required by the invaded tissue. Both, dedifferentiation and vessel formation are mechanisms controlled by extracellular signals that are sensed by membrane receptors in the endothelium. Therefore, it is not surprising that endothelium exhibits a specialized function according with its cell localization and mainly according with the extracellular medium where they are seeded [91,92,93]. Figure 1.Role of feto-placental endothelial function in fetal growth during normal pregnancy and gestational diabetes. Finally, this high input of nutrients and elevated circulation will be responsible for macrosomia in GDM.Human placenta is an unique source of endothelial cells for studying functional differences considering vessel distribution. Thus, it has been estimated that >70% of the placental tissue is constituted by blood vessels and length of fetal capillaries would be covering an area of 223 miles [91].
In addition, since autonomic control of the vascular resistance will not be part of the mechanisms for controlling blood distribution, endothelial cells are responsible for supplying this lack. Moreover, in human placenta, several studies have been shown that endothelium exhibits morphological and functional differences according to the vascular bed where they are coming from [84,87,91,92].
For instance and similarly to the pulmonary circulation in the adult, the feto-placental endothelium has a particular distribution. The veins transport oxygen and nutrients whereas the arteries contain de-oxygenated blood coming from the fetus. In terms of endothelial-derived vasomotor response, it has been described that acute hypoxia in the placental microvessels generates constriction [95], whereas this challenge generates augmentation of the umbilical blood flow [96]; this phenomenon is attributed to blood redistribution such occurs in the pulmonary circulation.
In addition, HUVEC (i.e, macrovascular endothelium) showed a reduced synthesis of angiotensin II, thromboxane B2, 6-keto-prostaglandin, and endothelin 1,2 compared to placental microvascular endothelial cells (hPMEC) [91]. Thus, placental microvascular placental cells exposed to VEGF or placental growth factor (PlGF) showed a high mitogen response compared to HUVEC [91], a phenomena associated with high expression of VEGF receptor 1 (VEGFR-1) and 2 (VEGFR-2) [98] in this cell type.
In addition, using feto-placental tissue it has been described that several genes related with angiogenic response are preferentially expressed in microvascular than macrovascular endothelium [86,87,91,92]. As indicated in the pictures, hPMEC exhibit a more rapid response for tube formation under our culture condition and require lesser quantity of cells than HUVEC, suggesting a differential physiological role of these cells in the fetal circulation.Several studies have reported dysfunction of feto-placental endothelium during GDM [18,74,75,84,86,91,93,99]. For instances, it has been described that L-arginine transport- mainly via the cationic aminoacid transport type 1 (CAT-1) - is increased in HUVEC from GDM [87,100,101,102].
Besides this alteration, it has been described high expression and activity of endothelial nitric oxide synthase (eNOS) [24,103] as well as iNOS [69] in both umbilical and placental endothelium from GDM. This enhancement would produce a high synthesis and release of NO [20,24], which in turn has been related with a nitrative status in the placenta and umbilical cord from this disease [104,105]. In addition, NO reduces the expression of adenosine transport via hENT-1 [83] and may generate augmentation in the extracellular level of adenosine in umbilical blood [106]. In turn, adenosine activates adenosine receptors (AR) spreading the vascular effects of NO in the feto-placental circulation in both vascular tone regulation [87,100,102] and promoting angiogenesis (see below). Therefore, it is feasible to speculate that the elevation in NO synthesis during GDM may explain the augmented umbilical flow observed in macrosomic fetuses [82]. GD and oxidative stress in the placentaAs detailed above, GDM has been associated with impaired placental development characterized by high placental weights and low ratios between fetal and placental weights [107]. Remarkably, one of the cellular mechanisms associated with the etiology of these changes is the oxidative stress, which is related with an imbalance between the synthesis of reactive oxygen and nitrogen species (ROS and RNS, respectively) and the activity of antioxidant enzymes. The most relevant free radicals are superoxide (O2•-) in the ROS group; and nitric oxide (NO) and peroxinitrite (ONOO-) in the RNS group.
In addition, considering the diffusion distance, NO can diffuse from endothelial cells to smooth muscle cells, whereas O2•- and ONOO- would have actions within the cells where they were synthesized [70]. In fact, it has been described that the elevation in the normal metabolic rate of feto-placental tissues increases the oxidative stress in the placental [109].
Moreover, in placental tissue from early pregnancy has been determined a higher activity of NADPH oxidase; therefore, the synthesis of O2•- is more marked at the end of the first trimester than the activity in term placental tissue [110].
On the other hand, studies using samples obtained from patients with GDM showed that there is an increased activity of xanthine oxidase (XO) and a decreased activity of catalase in maternal plasma, umbilical cord plasma and placental tissue [111].
These findings showed that there is an impairment of antioxidant defenses in the placenta and blood from mother and newborn, which might be related with the high mortality and morbidity in both mother and newborn observed during GDM pregnancies. In addition, placental tissues from GDM exhibited a decreased response to oxidative stress induced by hypoxanthine plus XO, as was reflected by a reduced levels of catalase and glutathione peroxidase (GPx) after exposition to the pro-oxidative challenge, suggesting that placental tissues from GDM would be exposed to damage in an oxidative environment [112]. The hallmark of diabetes is hyperglycemia whose condition has been associated with increases of synthesis of ROS and RNS in tissues and cell cultures from umbilical cord and placenta.
There is an increase of ROS levels in HUVEC exposed to high extracellular concentration of D-glucose mediated by activity of NADPH oxidase in a mechanism that involved a decrease of NO bioavailability and increases of vascular reactivity in umbilical veins [21,113].
In HUVEC, it has been described that the higher increase in the NADPH oxidase-mediated ROS induced by high concentration of D-glucose, the higher NO synthesis mediated by eNOS [21,113]. Considering the reaction rate between O2•- and NO, it is highly probable that the hyperglycemic condition induces the synthesis of ONOO-; therefore, it contributes to the development of endothelial dysfunction in umbilical cord and placenta. Long-term incubation (7-14 days) of HUVEC with high concentration of high D-glucose increases the expression of regulatory subunits of NADPH oxidase p67phox and p47phox [114], whereas 24 hours incubation of the same cell type with high D-glucose increases the expression of the catalytic subunits NOX2 and NOX4 [113]. Thus, an increased expression and activity of NADPH oxidase would be a hallmark of HUVEC exposed to hyperglycemic, suggesting that the same phenomenon would be present in GDM.On the other hand, recently data has been shown that in trophoblastic cells ACH-3P, incubated at 21 % oxygen and under normoglycemic condition, increases ROS levels after 3 days. Interestingly, ACH-3P cells treated (3 days) with high extracellular concentration of D-glucose increases the ROS levels only in cells exposed to lower percentage of oxygen (2.5 %). Therefore, this study is showing that ROS production in normoglycemia is oxygen-dependent but oxygen-independent in hyperglycemia. In summary, there is an imbalance in the control of redox cellular status in pathological conditions related with increases blood concentrations of molecules that induce oxidative stress, like GDM and hyperglycemia, probably due to a higher expression of oxidant enzymes like NADPH oxidase, XO and deregulation of metabolic pathways of NO.Placental angiogenesis and GDM Angiogenesis is a general term that involves the physiological process leading to growth of new blood vessels from a pre-formed one.
This is a vital process involved in embryological growth, tissue development, would healing of damaged tissues and in the context of this chapter is a crucial process for placental development and fetal growth during normal and GDM.
In this regard, as it has been remarked before, macrosomia, present in GDM, has been associated to increased nutrient delivery toward the fetus, a phenomenon that may be related with increased blood flow due to vasodilatation of placental vessels [100].
Thus, placentas from GDM exhibits elevated number of redundant capillary connections per villi, compared to normal pregnancy, suggesting a more intense capillary branching [120]. Moreover, there are increased placental capillary length, branching and surface area that have been reported in women with type 1 [121], pre-gestational and gestational diabetes [18,74], as well as elevated number of terminal villi and capillaries in women with hyperglycemia [73].
In addition, it has been reported that glycemic control was significant correlated with capillary surface area and capillary volume in women with pre-gestational diabetes [117]. Moreover, it is well known that diabetes is associated with increased angiogenic response in some specific tissues such as eye, where hyperglycemia can lead to retinopathy [122].
Nevertheless, it has been shown that GDM is associated to reduction in the circulating endothelial progenitor cells (EPC), in mother and fetus [123,124] a phenomenon that was linking with reduced capacity for recovering endothelial dysfunction in GDM.Associated mechanism behind increased placental angiogenesis in GDM may be related to the pro-angiogenic effect of hyperglycemia [125], which in turn triggers an enhancement in the placental synthesis and release of VEGF, as well as the expression of VEGF receptors (VEGFR) and nitric oxide production [18]. Thus, it has been shown that the placentas from women with hyperglycemia exhibited high levels of VEGF and VEGF receptor 2 (VEGFR-2) but reduced expression of VEGF receptor 1 (VEGFR-1) [73]. Furthermore, it has been reported elevated placental levels of VEGFR-1 mainly in vascular and throphoblastic cells in women with GDM [73,126].
Also, alteration in VEGF-VEGFRs expression has been described in women with type 1 diabetes [18,61,75,127].
Thus, the increased secretion and activity of VEGF may explain hypervascularization observed in placentas from DGM [58,71] On the other hand, increased placental angiogenic response may also be related with hyperinsulinemia present in GDM.
In this regard, it has been described that insulin activates at least two types of insulin receptors (IR), type A (IR-A, associated with a mitogenic phenotype) and type B (IR-B, associated with a metabolic phenotype), which are elevated in both HUVEC [24] and hPMEC [106], respectively. Another potential pathway, involved in the increase of placental angiogenesis during GDM, may be the ALANO pathway described before [100]. In this regard, we have previously proposed that a dysfunction in this pathway is taken part in the physiopathology of reduced placental angiogenesis in pre-eclampsia [129].

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  1. 15.04.2014 at 11:15:32

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  2. 15.04.2014 at 16:42:19

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  3. 15.04.2014 at 14:56:40

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