Maternal taurine supplementation in the late pregnant rat stimulates postnatal growth and induces obesity and insulin resistance in adult offspring

An adequate supply of taurine during fetal life is important for normal beta-cell development and insulin action. An altered availability of taurine may programme glucose metabolism in utero and result in type 2 diabetes in adult age. We examined whether maternal taurine supplementation in late pregnant rats affects postnatal growth, adult body composition, insulin sensitivity and endogenous insulin secretion in intrauterine growth restricted (IUGR) and normal offspring. Uterine artery ligation or sham operations were performed on gestational day (GD) 19. Taurine supplementation was given to half of the dams from GD 18 until term, resulting in four groups of offspring: sham ( n = 22), sham/taurine ( n = 22), IUGR ( n = 22) and IUGR/taurine ( n = 24). The offspring were studied at 12 weeks of age. In offspring with normal birth weight, fetal taurine supplementation markedly stimulated postnatal growth. In sham/taurine females, fat depots, plasma free fatty acid and leptin concentrations were increased, and insulin sensitivity was reduced. Insulin sensitivity was unaltered in IUGR and IUGR/taurine offspring. However, whereas IUGR offspring showed little catch-up growth, 50% of IUGR/taurine animals displayed complete catch-up at 12 weeks of age, and these animals had increased fat depots and reduced insulin sensitivity. In conclusion, taurine supplementation in late gestation resulted in accelerated postnatal growth, which was associated with adult obesity and insulin resistance in both IUGR and normal offspring. This effect was particularly evident in females. These data suggest that fetal taurine availability is an important determinant for postnatal growth, insulin sensitivity and fat accumulation.     

Developmental origins of type 2 diabetes: Focus on epigenetics

Traditionally, genetics and lifestyle are considered as main determinants of aging-associated pathological conditions. Accumulating evidence, however, suggests that risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. Type 2 diabetes (T2D), an age-related disease generally manifested after the age of 40, is among such disorders. Since several age-related conditions, such as pro-inflammatory states, are characteristic of both T2D and aging, this disease is conceptualized by many authors as a kind of premature or accelerated aging. There is substantial evidence that intrauterine growth restriction (IUGR), induced by poor or unbalanced nutrient intake, exposure to xenobiotics, maternal substance abuse etc., may impair fetal development, thereby causing the fetal adipose tissue and pancreatic beta cell dysfunction. Consequently, persisting adaptive changes may occur in the glucose–insulin metabolism, including reduced capacity for insulin secretion and insulin resistance. These changes can lead to an improved ability to store fat, thus predisposing to T2D development in later life. The modulation of epigenetic regulation of gene expression likely plays a central role in linking the adverse environmental conditions early in life to the risk of T2D in adulthood. In animal models of IUGR, long-term persistent changes in both DNA methylation and expression of genes implicated in metabolic processes have been repeatedly reported. Findings from human studies confirming the role of epigenetic mechanisms in linking early-life adverse experiences to the risk for T2D in adult life are scarce compared to data from animal studies, mainly because of limited access to suitable biological samples. It is, however, convincing evidence that these mechanisms may also operate in human beings. In this review, theoretical models and research findings evidencing the role of developmental epigenetic variation in the pathogenesis of T2D are summarized and discussed.     

Recent observations on the regulation of fetal metabolism by glucose

Glucose is the principal energy substrate for the the fetus and is essential for normal fetal metabolism and growth. Fetal glucose metabolism is directly dependent on the fetal plasma glucose concentration. Fetal glucose utilization is augmented by insulin produced by the developing fetal pancreas in increasing amounts as gestation proceeds, which enhances glucose utilization among the insulin-sensitive tissues (skeletal muscle, liver, heart, adipose tissue) that increase in mass and thus glucose need during late gestation. Glucose-stimulated insulin secretion increases over gestation. Both insulin secretion and insulin action are affected by prevailing glucose concentrations and the amount and activity of tissue glucose transporters. In cases of intrauterine growth restriction (IUGR), fetal weight-specific tissue glucose uptake rates and glucose transporters are maintained or increased, while synthesis of amino acids into protein and corresponding insulin–IGF signal transduction proteins are decreased. These observations demonstrate the mixed phenotype of the IUGR fetus that includes enhanced glucose utilization capacity, but diminished protein synthesis and growth. Thus, the fetus has considerable capacity to adapt to changes in glucose supply by relatively common and understandable mechanisms that regulate fetal metabolism and growth and could underlie certain later life metabolic disorders such as insulin resistance, obesity and diabetes mellitus.     

Restriction of placental growth in sheep impairs insulin secretion but not sensitivity before birth

Restricted growth before birth is associated with impaired insulin secretion but with initially enhanced insulin sensitivity in early postnatal life, which then progresses to insulin resistance and impaired glucose homeostasis by adulthood. This suggests that prenatal restraint impairs insulin secretion, but increases insulin sensitivity, before birth. Poor placental growth and function are major causes of restricted fetal growth in humans. We have therefore investigated the effects of restricted placental growth and function on plasma glucose, α-amino nitrogen and insulin concentrations and glucose- and arginine-stimulated insulin secretion in the fetal sheep at 120 and 140 days gestational age, and on insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp, at 130 days gestational age. Placental restriction decreased fetal blood pH and oxygen content, and weight in late gestation by ∼20%. Reduced fetal and placental weights and indices of poor placental function, in particular fetal hypoxia and hypoglycaemia, were associated with impaired glucose- and arginine-stimulated insulin secretion, but not with changes in insulin sensitivity in the fetal sheep. We conclude that the impaired insulin secretion capacity reported in children and adults after intrauterine growth restriction, and in the neonatal and young adult sheep which is small at birth, is present in utero and persists. Whether this reflects the actions of the adverse intrauterine environment or changes to intrinsic capacity is unclear, but in utero interventions may be necessary to improve postnatal insulin secretion in the infant who is growth-restricted before birth.     

Intracellular magnesium and insulin resistance.

Magnesium, the second most abundant intracellular divalent cation, is a cofactor of many enzymes involved in glucose metabolism. Magnesium has an important role in insulin action, and insulin stimulates magnesium uptake in insulin-sensitive tissues. Impaired biological responses to insulin is referred to as insulin resistance. This review was designed to reach a better understanding of the mechanism involved in the correlation between magnesium and insulin resistance. Intracellular magnesium concentration is low in type 2 diabetes mellitus and in hypertensive patients. In patients with type 2 diabetes an inverse association exists between the plasma magnesium and insulin resistance due to intracellular changes. The suppressed intracellular magnesium concentration may result in defective tyrosine kinase activity and modify insulin sensitivity by influencing receptor activity after binding or by influencing intracellular signaling and processing. Intracellular magnesium deficiency may affect the development of insulin resistance and alter the glucose entry into the cell. CONCLUSIONS: Magnesium is required for both proper glucose utilization and insulin signaling. Metabolic alterations in cellular magnesium, which may play the role of a second messenger for insulin action, contribute to insulin resistance.     

Lifetime consequences of abnormal fetal pancreatic development

There is ample evidence that an adverse intrauterine environment has harmful consequences for health in later life. Maternal diabetes and experimentally induced hyperglycaemia result in asymmetric overgrowth, which is associated with an increased insulin secretion and hyperplasia of the insulin-producing B-cells in the fetuses. In adult life, a reduced insulin secretion is found. In contrast, intrauterine growth restriction is associated with low insulin secretion and a delayed development of the insulin-producing B-cells. These perinatal alterations may induce a deficient adaptation of the endocrine pancreas and insulin resistance in later life. Intrauterine growth restriction in human pregnancy is mainly due to a reduced uteroplacental blood flow or to maternal undernutrition or malnutrition. However, intrauterine growth restriction can be present in severe diabetes complicated by vasculopathy and nephropathy. In animal models, intrauterine growth retardation can be obtained through pharmacological (streptozotocin), dietary (semi-starvation, low protein diet) or surgical (intrauterine artery ligation) manipulation of the maternal animal. The endocrine pancreas and more specifically the insulin-producing B-cells play an important role in the adaptation to an adverse intrauterine milieu and the consequences in later life. The long-term consequences of an unfavourable intrauterine environment are of major importance worldwide. Concerted efforts are needed to explore how these long-term effects can be prevented. This review will consist of two parts. In the first part, we discuss the long-term consequences in relation to the development of the fetal endocrine pancreas and fetal growth in the human; in the second part, we focus on animal models with disturbed fetal and pancreatic development and the consequences for later life.     

Biochemical profile of fetal blood sampled by cordocentesis in 35 pregnancies complicated by growth retardation

AIM OF THE STUDY: Intra-uterine growth retardation (IUGR) is a frequent pathology in obstetrics characterized by high heterogeneity. Fetal smallness is sometimes constitutional, but can also be accompanied by fetal distress and vital risks for the infant. In 35 pregnancies complicated by IUGR of different etiologies, we measured on fetal blood obtained by cordocentesis, biochemical variables characteristic of the fetuses' respiratory and metabolic status. The aim of the study was to identify the discriminative biological alterations, related to growth retardation and fetal distress. PATIENTS AND METHODS: The studied population includes 27 cases of severe IUGR, of gestational age 30,2+/-4,6 weeks of gestation (WG) (divided into 20 cases of isolated IUGR and 7 cases of IUGR associated with malformative syndrome), as well as 8 cases of moderate IUGR, of gestational age 26+/-4,5 WG; all fetuses had normal karyotypes. A group of 73 normal fetuses, of gestational age 26,3+/-5,7 WG, constituted a reference population. PH, pCO(2), bicarbonate concentration, pO(2) and SaO(2), as well as glucose, pyruvate, lactate, free fatty acids, aceto-acetate, beta-hydroxybutyrate and cholesterol concentrations were measured on umbilical venous blood (UVB). RESULTS: In case of severe but isolated growth retardation, UVB analysis showed the frequency of acid-base and gasometric disturbances: acidemia and hypoxemia (65% of cases), hypercapnia (60% of cases). Metabolic abnormalities were shown: decrease in glycemia (35% of cases), increase in pyruvatemia and lactatemia (40% of cases), increased free fatty acids serum concentration; a diminution of umbilical venous cholesterol level, the most frequent abnormality, can be seen in 70% of fetuses. In case of severe IUGR associated with malformative syndrome, UVB acid-base and metabolic changes were rarely seen; however, UVB cholesterol level is low in some cases. In case of growth retardation classified as moderate, modifications are relatively not frequent and essentially gasometric. CONCLUSION: In about 60% of cases of severe and isolated IUGR, there is a risk of fetal distress, related to an alteration of the transplacental transfer of respiratory gases and nutritional substrates; chronic fetal malnutrition can be involved, with an impact on the growth of the fetus. In case of IUGR associated with malformative syndrome, fetal smallness is probably a result of intrinsic fetal damage, without nutritional origin.     

宫内生长发育受限患儿血清糖皮质激素变化

目的探讨宫内生长发育受限患儿是否存在下丘脑一垂体一’肾上腺轴功能紊乱。方法收集2012-1-1至2013-6-1在北京友谊医院儿科住院的宫内生长发育受限（inttauterine growth re8triction,IUGR）患儿和适于胎龄儿（appropriate for gestational age,AGA）血清,采用ELISA方法检测血清促肾上腺皮质激素（ACTH）、皮质醇、醛固酮激素水平变化。结果IU6R48例,AGA50例,两组性别比无差异。IUGR血清ACTH、皮质醇浓度（均数±标准差）浓度均比AGA组明显升高,且差异有统计学意义（P〈0．05）;IUGR血清醛固酮浓度与AGA组相比,血清水平下降,但差异无统计学意义,P〉0．05。结论宫内生长发育受限患儿血清ACTH、皮质醇浓度均明显高于适于胎龄儿,提示宫内生长发育受限患儿存在下丘脑-垂体-肾上腺轴的功能紊乱。     

Magnesium may mediate the favorable impact of whole grains on insulin sensitivity by acting as a mild calcium antagonist

Recent epidemiology has linked high consumption of whole grains with reduced risk for diabetes, coronary disease, stroke, and various types of cancer; there is reason to suspect that improved insulin sensitivity is largely responsible for this protection. This phenomenon may be partially explained by the lower glycemic indices of some whole grain food products in comparison to their fiber-depleted analogs. Nonetheless, the fact that whole wheat flour promotes insulin sensitivity relative to white flour--and yet has a near-identical glycemic index--suggests that certain nutrients or phytochemicals in whole wheat, depleted by the refining process, promote preservation of insulin sensitivity. Magnesium is a likely candidate in this regard; magnesium deficiency promotes insulin resistance in rodents and in humans, whereas supplemental magnesium has been found to prevent type 2 diabetes in rodent models of this syndrome, and to improve the insulin sensitivity of elderly or diabetic humans. Magnesium-rich diets as well as above-average serum magnesium are associated with reduced diabetes risk in prospective epidemiology, and with greater insulin sensitivity in cross-sectional studies; moreover, other types of magnesium-rich foods--dairy products, legumes, and nuts--have been linked to decreased diabetes risk in prospective studies. The biochemical role of magnesium in support of insulin function is still poorly understood. In light of evidence that magnesium can function as a mild natural calcium antagonist, it is interesting to note suggestive evidence that increases in intracellular free calcium may compromise the insulin responsiveness of adipocytes and skeletal muscle, and may indeed play a pathogenic role in the insulin resistance syndrome. Thus, it is proposed that some or all of the favorable impact of good magnesium status on insulin function may reflect antagonism of the induction or effects of increased intracellular free calcium. Further research concerning the potential health benefits of long-term magnesium supplementation is clearly warranted. These considerations, however, should not detract from efforts to better inform the public regarding the strong desirability of choosing whole grain products in preference to refined grains.     

High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation.

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenic factor in the development of metabolic syndrome. Pro-inflammatory molecules produced by adipose tissue have been implicated in the development of insulin resistance. The present review will discuss experimental evidence showing that the metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. In many ways, fructose-fed rats display the changes observed in the metabolic syndrome and recent studies indicate that high-fructose feeding is associated with NADPH oxidase and renin-angiotensin activation. The production of reactive oxygen species results in the initiation and development of insulin resistance, hyperlipemia and high blood pressure in this model. In this rat model, a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration. Potential mechanisms include the priming of phagocytic cells, the opening of calcium channels, activation of N-methyl-D-aspartate (NMDA) receptors, the activation of nuclear factor-kappaB (NFkB) and activation of the renin-angiotensin system. Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress.     

Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet

Intrauterine growth restriction (IUGR) represents an important risk factor for perinatal complications and for adult disease. IUGR is associated with a down-regulation of placental amino acid transporters; however, whether these changes are primary events directly contributing to IUGR or a secondary consequence is unknown. We investigated the time course of changes in placental and fetal growth, placental nutrient transport in vivo and the expression of placental nutrient transporters in pregnant rats subjected to protein malnutrition, a model for IUGR. Pregnant rats were given either a low protein (LP) diet ( n = 64) or an isocaloric control diet ( n = 66) throughout pregnancy. Maternal insulin, leptin and IGF-I levels decreased, whereas maternal amino acid concentrations increased moderately in response to the LP diet. Fetal and placental weights in the LP group were unaltered compared to control diet at gestational day (GD) 15, 18 and 19 but significantly reduced at GD 21. Placental system A transport activity was reduced at GD 19 and 21 in response to a low protein diet. Placental protein expression of SNAT2 was decreased at GD 21. In conclusion, placental amino acid transport is down-regulated prior to the development of IUGR, suggesting that these placental transport changes are a cause, rather than a consequence, of IUGR. Reduced maternal levels of insulin, leptin and IGF-1 may link maternal protein malnutrition to reduced fetal growth by down-regulation of key placental amino acid transporters.     

宫内发育迟缓大鼠胰腺肝脏骨骼肌中胰岛素受体底物的表达

目的分析宫内发育迟缓（IUGR）大鼠胰腺、肝脏、骨骼肌中胰岛素受体底物1（IRS-1）和2（IRS-2）mRNA和蛋白水平的表达,探讨IUGR个体发生胰岛素抵抗的机制。方法采用母孕期低蛋白饮食法建立IUGR大鼠模型,以模型鼠产下的仔鼠为IUGR组;以孕期予正常饮食母鼠产下的仔鼠为对照组。应用RT-PCR法检测各组仔鼠在出生后0、3和8周时点胰腺、肝脏和骨骼肌中IRS-1、IRS-2 mRNA表达水平,采用Western blot检测IRS-1和IRS-2蛋白表达水平。检测3和8周时点仔鼠空腹血糖和血清胰岛素水平,计算胰岛素抵抗指数。结果①IUGR组出生后0和3周体重显著低于对照组;8周时点IUGR组体重显著高于对照组。②IUGR组出生后0、3和8周时点胰腺、肝脏IRS-2 mRNA和蛋白表达水平低于对照组;IRS-1 mRNA和蛋白表达水平与对照组差异无统计学意义;骨骼肌IRS-1 mRNA和蛋白表达水平均显著低于对照组;IRS-2蛋白表达水平与对照组差异无统计学意义。③至8周时点,骨骼肌IRS-1 mRNA和蛋白表达水平的下降幅度较胰腺和肝脏组织更为明显;肝脏IRS-2 mRNA和蛋白表达水平的下降幅度较胰腺和骨骼肌组织更为明显。④至8周时点,IUGR组空腹血糖水平与对照组差异无统计学意义,胰岛素水平和空腹胰岛素抵抗指数较对照组显著升高。结论 IUGR大鼠胰腺、肝脏和骨骼肌组织均存在IRS-1或IRS-2 mRNA和蛋白表达水平的下降,可能是发生胰岛素抵抗的机制之一。     

Intrauterine growth restriction delays cardiomyocyte maturation and alters coronary artery function in the fetal sheep

There is now extensive evidence suggesting that intrauterine perturbations are linked with an increased risk of developing cardiovascular disease. Human epidemiological studies, supported by animal models, have demonstrated an association between low birth weight, a marker of intrauterine growth restriction (IUGR), and adult cardiovascular disease. However, little is known of the early influence of IUGR on the fetal heart and vessels. The aim of this study was to determine the effects of late gestational IUGR on coronary artery function and cardiomyocyte maturation in the fetus. IUGR was induced by placental embolization in fetal sheep from 110 to 130 days of pregnancy (D110–130); term ∼D147; control fetuses received saline. At necropsy (D130), wire and pressure myography was used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in small branches of left descending coronary arteries. Myocardium was dissociated for histological analysis of cardiomyocytes. At D130, IUGR fetuses (2.7 ± 0.1 kg) were 28% lighter than controls (3.7 ± 0.3 kg; P = 0.02). Coronary arteries from IUGR fetuses had enhanced responsiveness to the vasoconstrictors, angiotensin II and the thromboxane analogue U46619, than controls ( P < 0.01). Endothelium-dependent and -independent relaxations were not different between groups. Coronary arteries of IUGR fetuses were more compliant ( P = 0.02) than those of controls. The incidence of cardiomyocyte binucleation was lower in the left ventricles of IUGR fetuses ( P = 0.02), suggestive of retarded cardiomyocyte maturation. We conclude that late gestational IUGR alters the reactivity and mechanical wall properties of coronary arteries and cardiomyocyte maturation in fetal sheep, which could have lifelong implications for cardiovascular function.     

H-reflex and motor nerve conduction studies in growth retarded newborn babies

OBJECTIVE: To demonstrate the accelerated postnatal maturation/myelination in growth retarded babies compensating the deficit suffered by them during intrauterine life. METHODS: We studied 16 babies within the first 3 days of birth. These included 6 full term appropriate for gestational age babies (FT AGA) and 10 full term intrauterine growth retarded (FT IUGR). A separate group of 16 babies was examined at 2 months of age. In this group 7 were FT AGA and 9 were FT IUGR at the time of birth. H-reflex latency (HRL), motor nerve conduction velocity (MNCV) and H-reflex excitability (H/M) were measured in the right lower limb. Anthropometric measurements of the babies were also recorded meticulously. All the babies were neurologically normal on clinical evaluation. RESULT: At birth, MNCV was significantly lower in FT IUGR babies compared to FT AGA babies. However at the age of 2 months the MNCV of both FT AGA and FT IUGR was comparable. Other parameters (HRL and H/M) in the IUGR babies were comparable with normal babies both at birth and 2 months of age. In FT IUGR babies crown-heel length and weight was significantly lower than FT AGA babies both at the time of birth and at 2 months of age. CONCLUSION AND SIGNIFICANCE: The findings suggest that FT IUGR babies demonstrate accelerated postnatal peripheral neural maturation. At 2 months of age, the motor nerve conduction velocity of these growth retarded babies was comparable to that observed in normal AGA babies of similar age. This provides an insight into the functional aspect of the proven theories of decreased peripheral myelination in FT IUGR babies with subsequent rapid postnatal myelination that renders these babies neurologically equivalent to FT AGA babies despite not achieving comparable anthropometric parameters.     

Genital flora in pregnancy and its association with intrauterine growth retardation.

A study of risk factors for intrauterine growth retardation (IUGR) was conducted among a cohort of 13,914 pregnant women enrolled in the multicenter Vaginal Infections and Prematurity Study. From 23 through 26 weeks of gestational age, cultures of specimens from the vagina and cervix were done for group B streptococci, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Candida albicans, Gardnerella vaginalis, Mycoplasma hominis, Ureaplasma urealyticum, and anaerobic gram-negative rods belonging to the genera Bacteroides, Porphyromonas, and Prevotella. Newborns who were small for their gestational age were delivered by 1,251 women, and infants of the appropriate weight for their gestational age were delivered by 10,332 women. When controlling for ethnicity and smoking and excluding women treated with antibiotics, the Mantel-Haenszel adjusted relative risk of IUGR was 1.16 for Bacteroides, Prevotella, and Porphyromonas spp. (95% confidence interval [95% CI], 1.01 to 1.33), 1.16 for M. hominis (95% CI, 1.04 to 1.29), 1.20 for U. urealyticum (95% CI, 1.05 to 1.38), and 1.22 for T. vaginalis (95% CI, 1.05 to 1.42). There was also a strong and significant trend for an increasing risk of IUGR with the number of these four microbes recovered. Among women colonized with all four isolates, the adjusted odds ratio of IUGR was 1.79 (95% CI, 1.27 to 2.52) in comparison with women not colonized with any of these microorganisms. Group B streptococci, N. gonorrhoeae, C. trachomatis, and C. albicans were not significantly associated with IUGR. These results suggest that infection is associated with some cases of IUGR and that specific microorganisms, alone or in combination, are involved. Since genital isolates are highly correlated with each other, the relative contribution of each microbe is difficult to determine.     

The thrombophilic fetus

Thrombophilia is the increased tendency to thrombosis. Inherited and acquired factors may determine thrombophilia. Some physiologic conditions, such as pregnancy are themselves "thrombophilic". In pregnancy, in fact, there is a decrease of all natural anticoagulant systems, such as antithrombin, protein C and protein S that are partially compensated by an increased fibrinolysis. It has been well established that women with thrombophilic disorders are at greater risk of venous thromboembolism in pregnancy and puerperium. It has also been observed that those women have higher prevalence of those obstetric complications in which microplacental thrombosis may play a pathogenetic role, such as placental abruption, preeclampsia, intrauterine growth restriction, intrauterine fetal death, repeated spontaneous miscarriage. Given that those complications are not always associated with maternal thrombophilia, controversy still exists on the exact impact of the disorders with the adverse pregnancy outcomes. While we are convinced that thrombophilias are extensively implicated in pregnancy complications, we feel that there has not been completely elucidated the role of the different factors, the gestational age at which those factors may intervene, nor has been given enough relevance to the weight of fetal thrombophilias in the origin of some specific form of those obstetric complications. We should bear in mind that some thrombophilias may be inherited from the mother, the father or both. Our hypothesis is that maternal thrombophilias may be responsible for venous thromboembolism, preeclampsia HELLP and eclampsia, whereas fetal thrombophilia, may account for IUGR or stillbirth. This last would also explain some stillbirth or repeated late (>10 gestational weeks) miscarriage observed in non-thrombophilic mothers. The two sides of thrombophilia may, of course, concur, resulting in the more severe clinical presentations.     

Ventricular myocardium in control and growth-retarded human fetuses: growth in different tissue compartments and variation with fetal weight, gestational age, and ventricle size.

The aim of this study was to assess the growth of different tissue compartments in ventricular myocardium of control and intrauterine growth-retarded (IUGR) human subjects. Stereological counting and sizing methods were applied to cross-sectional samples of hearts collected post mortem at 16 to 35 (control) and 32 to 42 (IUGR) gestational weeks. Total tissue volumes and total numbers of myocyte, connective tissue, and endothelial cell nuclei were estimated. In control hearts, the volume of each tissue compartment increased linearly over the period of gestation, and this was due to proliferation, because in each case the tissue volume per nucleus remained constant. In IUGR subjects, fetal weight, ventricle volume, myocyte volume, connective tissue volume, and endothelial nuclear number were less than expected for gestational age up to at least 35 weeks. Between this age and 8 postnatal weeks, these variables are predicted to achieve equivalence with values found in control fetuses. Similar deficits were found when variables were related to fetal weight, and it is predicted that equivalence with control values would be reached at weights of between 2.3 and 3.6 kg. No such differences between groups were detected when variables were related to ventricle size. These findings indicate that growth deficits in cardiomyocytes are accompanied, and may be influenced, by developmental delays that involve the intramyocardial interstitium (capillary bed, endothelium, and surrounding connective tissues). The delays and deficits exhibit "catch-up" to control values between 35 weeks and term.     

Placental adaptive responses and fetal programming

Fetal programming occurs when the normal pattern of fetal development is disrupted by an abnormal stimulus or 'insult' applied at a critical point in in utero development. This then leads to an effect, for example diabetes or hypertension, which manifests itself in adult life. As the placenta is the regulator of nutrient composition and supply from mother to fetus and the source of hormonal signals that affect maternal and fetal metabolism, appropriate development of the placenta is crucial to normal fetal development. Placental function evolves in a carefully orchestrated developmental cascade throughout gestation. Disruption of this cascade can lead to abnormal development of the placental vasculature or of the trophoblast. Timing of a developmental 'insult' will be critical in consequent placental function and hence programming of the fetus. The 'insults' that alter placental development include hypoxia and abnormal maternal nutrient status, to which the placenta may adapt by alterations in transporter expression and activity to maintain fetal growth or by epigenetic regulation of placental gene expression. Hypoxia is physiological for organogenesis and placental tissue normally exists in a relatively hypoxic environment, but intrauterine growth restriction (IUGR) and pre-eclampsia are associated with a greater degree of trophoblast hypoxia. The metabolic activity of placental mitochondria leads to oxidative stress even in normal pregnancy which is exacerbated further in IUGR, diabetic and pre-eclamptic pregnancies and may also give nitrative stress known to lead to covalent modification and hence altered activity of proteins. Hypoxia, oxidative and nitrative stress all alter placenta development and may be a general underlying mechanism that links altered placental function to fetal programming.     

Distal villous immaturity

Distal villous immaturity (DVI) is a placental phenotype characterized by enlarged distal villi with excessive stroma, hypercellular villous trophoblast, paucity of vasculosyncytial membranes, and a decreased fetoplacental weight ratio. It is predominantly observed in term or near-term placentas and is associated with specific maternal conditions including impaired glucose tolerance, obesity, and excessive pregnancy weight gain. A similar phenotype is observed in placentas with hypercoiling of the umbilical cord. DVI is also occasionally seen in the placentas of preterm infants with idiopathic fetal growth restriction, congenital malformations, and genetic or chromosomal abnormalities. In infants of diabetic mothers, DVI may in part be a consequence of excessive maternal glucose leading to release of fetal insulin and other growth factors that promote excessive placental growth at the expense of villous maturation. Adverse outcomes associated with DVI include intrauterine fetal death (IUFD), fetal growth restriction (FGR), and, more speculatively, late gestational hypoxia and chronic diseases of childhood and later adult life.