Developmental retardation in neonates of aldehyde reductase (AKR1A)-deficient mice is associated with low ascorbic acid and high corticosterone levels.

Aldehyde reductase encoded by the Akr1a gene catalyzes the NADPH-dependent reduction of a variety of aldehyde compounds, and it plays a role in the biosynthesis of ascorbic acid (AsA) by converting D-glucuronate to L-gulonate. Although supplementing drinking water with AsA (1.5 mg/mL) ameliorates the fertility of Akr1a-/- (KO) female mice, litter sizes in the KO mice are typically smaller than those for Akr1a+/+ (WT) mice, and about one-third of the neonates have a reduced stature. Half of the neonates in the smallest, developmentally retarded group died before weaning, and the remaining half (less than 6 g in weight) also barely grew to adulthood. While no difference was found in the number of fetuses between the KO and WT mice at 14.5-embryonic days, the sizes of the KO fetuses had already diverged. Among the organs of these retarded KO neonates at 30 d, the spleen and thymus were characteristically small. While an examination of spleen cells showed the normal proportion of immune cells, apoptotic cell death was increased in the thymus, which would lead to thymic atrophy in the retarded KO neonates. Plasma AsA levels were lower in the small neonates despite the fact that their mothers had received sufficient AsA supplementation, and the corticosterone levels were inversely higher compared to wild-type mice. Thus, insufficient AsA contents together with a defect in corticosterone metabolism might be the cause of the retarded growth of the AKR1A-deficient mice embryos and neonates.

Altered Bioavailability of Nitric Oxide and L-Arginine Is a Key Determinant of Endothelial Dysfunction in Preeclampsia.

BACKGROUND: Preeclampsia is a major cause of maternal and neonatal morbidity and mortality in sub-Saharan Africa. Evidence indicates that endothelial dysfunction is central to the pathogenesis of preeclampsia. This study assessed the level of the components of the arginine-nitric oxide pathway to evaluate endothelial dysfunction in normotensive pregnancies and pregnancies complicated with preeclampsia. METHODS: This case-control study was conducted among pregnant women who visited Comboni Hospital from January 2017 to May 2018. A total of 180 pregnant women comprising 88 preeclamptic women (PE) and 92 healthy normotensive pregnant women (NP) were recruited. Sociodemographic, clinical, and obstetric data were obtained using validated questionnaires. Blood pressure and anthropometrics were measured, and blood samples were collected for the estimation of nitric oxide (NO∙), L-arginine, asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine using an enzyme-linked immunosorbent assay technique. RESULTS: The mean NO∙ (p = 0.010) and L-arginine/ADMA ratio (p < 0.0001) was significantly lower in PE compared to NP while mean L-arginine (p = 0.034), ADMA (p < 0.0001), and 3-nitrotyrosine (p < 0.0001) were significantly higher in PE than NP. ADMA showed a significant positive association with systolic blood pressure (ß = 0.454, p = 0.036) in severe PE. Women with PE had significant intrauterine growth restriction (p < 0.0001) and low birth weight infants (p < 0.0001) when compared to NP. CONCLUSION: Preeclampsia is associated with reduced NO∙ bioavailability, L-arginine/ADMA ratio, and elevated levels of ADMA and 3-nitrotyrosine. Measurements of the levels of these parameters can help in the early prediction of endothelial dysfunction in preeclampsia. Exogenous therapeutic supplementation with L-arginine during pregnancy to increase the L-arginine/ADMA ratio should be considered to improve endothelial function in preeclampsia and pregnant women at risk of developing preeclampsia.

The role of parathyroid hormone during pregnancy on the relationship between maternal vitamin D deficiency and fetal growth restriction: a prospective birth cohort study.

Previous studies have shown conflicting findings regarding the relationship between maternal vitamin D deficiency (VDD) and fetal growth restriction (FGR). We hypothesised that parathyroid hormone (PTH) may be an underlying factor relevant to this potential association. In a prospective birth cohort study, descriptive statistics were evaluated for the demographic characteristics of 3407 pregnancies in the second trimester from three antenatal clinics in Hefei, China. The association of the combined status of vitamin D and PTH with birth weight and the risk of small for gestational age (SGA) was assessed by a multivariate linear and binary logistic regression. We found that declined status of 25-hydroxyvitamin D is associated with lower birth weight (for moderate VDD: adjusted ß = -49·4 g, 95 % CI -91·1, -7·8, P < 0·05; for severe VDD: adjusted ß = -79·8 g, 95 % CI -127·2, -32·5, P < 0·01), as well as ascended levels of PTH (for elevated PTH: adjusted ß = -44·5 g, 95 % CI -82·6, -6·4, P < 0·05). Compared with the non-VDD group with non-elevated PTH, pregnancies with severe VDD and elevated PTH had the lowest neonatal birth weight (adjusted ß = -124·7 g, 95 % CI -194·6, -54·8, P < 0·001) and the highest risk of SGA (adjusted risk ratio (RR) = 3·36, 95 % CI 1·41, 8·03, P < 0·01). Notably, the highest risk of less Ca supplementation was founded in severe VDD group with elevated PTH (adjusted RR = 4·67, 95 % CI 2·78, 7·85, P < 0·001). In conclusion, elevated PTH induced by less Ca supplementation would further aggravate the risk of FGR in pregnancies with severe VDD through impaired maternal Ca metabolism homoeostasis.

The altered platelet mineral ratios in pregnancy complicated with intrauterine growth restriction.

Altered function of maternal platelets has been evidenced in intrauterine growth restriction (IUGR) but intraplatelet burden of trace elements, factors known to affect platelet activity, remains unknown in IUGR pregnancy. This study assessed the intraplatelet status of Ca, Cu, Mg, Na, K, P, Zn and their ratios (Ca/P, Ca/Mg, Na/K, Cu/Zn) in IUGR pregnancy (n = 35), uncomplicated pregnancy (n = 25) and in non-pregnant females (n = 25). The IUGR group was characterized by the lowest content of Ca, Mg and Zn, and Ca/P ratio (<1.0), and the highest Ca/Mg and Cu/Zn ratios. The studied parameters in non-pregnant women and in uncomplicated pregnancy were comparable except P content and Ca/Mg ratio which were significantly lower in the former group. No differences in Na and K contents, and Na/K ratio between studied groups were found. This study reports that maternal intraplatelet status of selected minerals may be altered in IUGR.

Selected trace elements concentrations in pregnancy and their possible role - literature review.

The aim of this study was to review the role of selected trace elements in pregnancy and fetal development. Citations related to the role of iron (Fe), zinc (Zn), manganese (Mn), copper (Cu) and selenium (Se) during pregnancy were searched in PubMed, Medline, Web of Science, using keywords and MeSH terms. Inadequate supply of trace elements can cause abnormalities of fetal development and predispose a child to disorders later on in life. Trace elements are the key elements of complex enzymes responsible for the modulation of the antioxidant defense system of the organism. It has been suggested that there is a correlation between reduced levels of trace elements essential for antioxidant function in the body of pregnant women, and an increased risk of developing preeclampsia. Trace elements are components of numerous regulatory enzymes and hormones essential to the division and differentiation of fetal cells and their further development. Mineral deficiencies in pregnant women can cause birth defects of the central nervous system, and growth disorders. Future research should be directed to explain the interaction between trace elements, and establish the optimum levels of macro and micronutrients supplementation, as well as determine the reference values for trace elements in the maternal serum, umbilical cord blood and amniotic fluid.

Clinical and Metabolic Response to Selenium Supplementation in Pregnant Women at Risk for Intrauterine Growth Restriction: Randomized, Double-Blind, Placebo-Controlled Trial.

Data on the effects of selenium supplementation on clinical signs and metabolic profiles in women at risk for intrauterine growth restriction (IUGR) are scarce. This study was designed to assess the effects of selenium supplementation on clinical signs and metabolic status in pregnant women at risk for IUGR. This randomized double-blind placebo-controlled clinical trial was performed among 60 women at risk for IUGR according to abnormal uterine artery Doppler waveform. Participants were randomly assigned to intake either 100 µg selenium supplements as tablet (n = 30) or placebo (n = 30) for 10 weeks between 17 and 27 weeks of gestation. After 10 weeks of selenium administration, a higher percentage of women in the selenium group had pulsatility index (PI) of <1.45) (P = 0.002) than of those in the placebo group. In addition, changes in plasma levels of total antioxidant capacity (TAC) (P < 0.001), glutathione (GSH) (P = 0.008), and high-sensitivity C-reactive protein (hs-CRP) (P = 0.004) in the selenium group were significant compared with the placebo group. Additionally, selenium supplementation significantly decreased serum insulin (P = 0.02), homeostasis model of assessment-estimated insulin resistance (HOMA-IR) (P = 0.02), and homeostatic model assessment for B-cell function (HOMA-B) (P = 0.02) and significantly increased quantitative insulin sensitivity check index (QUICKI) (P = 0.04) and HDL-C levels (P = 0.02) compared with the placebo. We did not find any significant effect of selenium administration on malondialdehyde (MDA), nitric oxide (NO), fasting plasma glucose (FPG), and other lipid profiles. Overall, selenium supplementation in pregnant women at risk for IUGR resulted in improved PI, TAC, GSH, hs-CRP, and markers of insulin metabolism and HDL-C levels, but it did not affect MDA, NO, FPG, and other lipid profiles.Clinical trial registration number http://www.irct.ir : IRCT201601045623N64.

Magnesium in pregnancy.

Magnesium deficiency is prevalent in women of childbearing age in both developing and developed countries. The need for magnesium increases during pregnancy, and the majority of pregnant women likely do not meet this increased need. Magnesium deficiency or insufficiency during pregnancy may pose a health risk for both the mother and the newborn, with implications that may extend into adulthood of the offspring. The measurement of serum magnesium is the most widely used method for determining magnesium levels, but it has significant limitations that have both hindered the assessment of deficiency and affected the reliability of studies in pregnant women. Thus far, limited studies have suggested links between magnesium inadequacy and certain conditions in pregnancy associated with high mortality and morbidity, such as gestational diabetes, preterm labor, preeclampsia, and small for gestational age or intrauterine growth restriction. This review provides recommendations for further study and improved testing using measurement of red cell magnesium. Pregnant women should be counseled to increase their intake of magnesium-rich foods such as nuts, seeds, beans, and leafy greens and/or to supplement with magnesium at a safe level.

Puerarin affects bone biomarkers in the serum of rats with intrauterine growth restriction.

OBJECTIVE: To investigate serum bone biomarkers in rats with intrauterine growth restriction (IUGR) in order to determine the effects of puerarin on bone metabolism. METHODS: A rat model of IUGR was induced using a low protein diet during pregnancy. The offspring were given puerarin or an identical volume of saline via subcutaneous abdominal injection. All rats were studied at 1, 3, and 8 weeks of age. Serum biomarkers of bone formation, including insulin-like growth factor-1 (IGF-1), bone-specific alkaline phosphatase (BALP), osteocalcin (OC), osteoprotegerin (OPG), receptor-activator of nuclear factor-κB Iigand (RANKL), as well as blood levels of calcium and phosphorus were measured. RESULTS: Serum BALP, OPG, IGF-1, and OC levels, as well as the OPG/RANKL ratio, were lower in the IUGR group compared with the control group at 1 week of age (P = 0.024, 0.011, 0.014, 0.004, and 0.002, respectively). At 3 weeks of age, the serum BALP and OC levels were higher in the protein-restricted group compared with the control group (P = 0.003 and 0.001, respectively). A comparison between the IUGR plus puerarin intervention group and the IUGR group revealed differences in the levels of BALP and IGF-1 at 3 weeks of age (P = 0.008 and 0.003, respectively). In addition, serum OPG and OC levels and the OPG/RANKL ratio were higher at 8 weeks of age (P = 0.044, 0.007, and 0.016, respectively). No differences in serum calcium and phosphorus levels were observed among the three groups. CONCLUSION: Our study demonstrates that the bone microenvironment of the fetus can be altered by a low protein maternal diet and that puerarin can reverse these effects. These results indicate that the nutritional environment plays an important role in early skeletal development and that the bone turnover of IUGR rats can be altered by puerarin treatment.

Effects of maternal folic acid supplementation on gene methylation and being small for gestational age.

BACKGROUND: Being small for gestational age (SGA), a foetal growth abnormality, has a long-lasting impact on childhood health. Its aetiology and underlying mechanisms are not well understood. Underlying epigenetic changes of imprinted genes have emerged as a potential pathological pathway because they may be associated with growth, including SGA. As a common methyl donor, folic acid (FA) is essential for DNA methylation, synthesis and repair, and FA supplementation is widely recommended for women planning pregnancy. The present study aimed to investigate the inter-relationships among methylation levels of two imprinted genes [H19 differentially methylated regions (DMRs) and MEST DMRs], maternal FA supplementation and SGA. METHODS: We conducted a case-control study. Umbilical cord blood was taken from 39 SGA infants and 49 controls whose birth weights are appropriate for gestational age (AGA). DNA methylation levels of H19 and MEST DMRs were determined by an analysis of mass array quantitative methylation. RESULTS: Statistically significantly higher methylation levels were observed at sites 7.8, 9 and 17.18 of H19 (P = 0.030, 0.016 and 0.050, respectively) in the SGA infants compared to the AGA group. In addition, the association was stronger in male births where the mothers took FA around conception at six H19 sites (P = 0.004, 0.005, 0.048, 0.002, 0.021 and 0.005, respectively). CONCLUSIONS: Methylation levels at H19 DMRs were higher in SGA infants compared to AGA controls. It appears that the association may be influenced by maternal peri-conception FA supplementation and also be sex-specific.

Early pregnancy B vitamin status, one carbon metabolism, pregnancy outcome and child development.

Periconception supplementation with folic acid is recommended until 12 gestational weeks to prevent neural tube defects. Doses of folic acid contained in supplements and timing and length of use during pregnancy vary. The effects of status in periconception and pregnancy folate, cobalamin, betaine and their interactions on one carbon metabolism (1C), as well as the global effect of 1C on foetal growth and pregnancy outcome, are reviewed. Results from prospective studies are reviewed. Cessation of folic acid supplement use after the first trimester is associated with a sharp drop in plasma folate status and enhanced conversion of betaine to dimethylglycine. Dimethylglycine production is also higher in mothers with low folate status than in those with normal-high folate status. The effects of high doses of folic acid on one carbon metabolism in mothers with low early pregnancy cobalamin status and on foetal growth are also reviewed. Several studies report that moderately elevated early pregnancy fasting plasma total homocysteine (tHcy) is inversely associated with birth weight and a predictor of intrauterine growth retardation. There is also evidence for increased risk of preterm birth when maternal folate status is low.

Heritable IUGR and adult metabolic syndrome are reversible and associated with alterations in the metabolome following dietary supplementation of 1-carbon intermediates.

Metabolic syndrome (MetS), following intrauterine growth restriction (IUGR), is epigenetically heritable. Recently, we abrogated the F2 adult phenotype with essential nutrient supplementation (ENS) of intermediates along the 1-carbon pathway. With the use of the same grandparental uterine artery ligation model, we profiled the F2 serum metabolome at weaning [postnatal day (d)21; n = 76] and adulthood (d160; n = 12) to test if MetS is preceded by alterations in the metabolome. Indicative of developmentally programmed MetS, adult F2, formerly IUGR rats, were obese (621 vs. 461 g; P < 0.0001), dyslipidemic (133 vs. 67 mg/dl; P < 0.001), and glucose intolerant (26 vs. 15 mg/kg/min; P < 0.01). Unbiased gas chromatography-mass spectrometry (GC-MS) profiling revealed 34 peaks corresponding to 12 nonredundant metabolites and 9 unknowns to be changing at weaning [false discovery rate (FDR) < 0.05]. Markers of later-in-life MetS included citric acid, glucosamine, myoinositol, and proline (P < 0.03). Hierarchical clustering revealed grouping by IUGR lineage and supplementation at d21 and d160. Weanlings grouped distinctly for ENS and IUGR by partial least-squares discriminate analysis (PLS-DA; P < 0.01), whereas paternal and maternal IUGR (IUGR(pat)/IUGR(mat), respectively) control-fed rats, destined for MetS, had a distinct metabolome at weaning (randomForest analysis; class error < 0.1) and adulthood (PLS-DA; P < 0.05). In sum, we have found that alterations in the metabolome accompany heritable IUGR, precede adult-onset MetS, and are partially amenable to dietary intervention.

Folate, vitamin B12, vitamin B6 and homocysteine: impact on pregnancy outcome.

Good clinical practice recommends folic acid supplementation 1 month prior to pregnancy and during the first trimester to prevent congenital malformations. However, high rates of fetal growth and development in later pregnancy may increase the demand for folate. Folate and vitamins B12 and B6 are required for DNA synthesis and cell growth, and are involved in homocysteine metabolism. The primary aim of this study was to determine if maternal folate, vitamin B12, vitamin B6 and homocysteine concentrations at 18-20 weeks gestation are associated with subsequent adverse pregnancy outcomes, including pre-eclampsia and intrauterine growth restriction (IUGR). The secondary aim was to investigate maternal B vitamin concentrations with DNA damage markers in maternal lymphocytes. A prospective observational study was conducted at the Women's and Children's Hospital, Adelaide, South Australia. One hundred and thirty-seven subjects were identified prior to 20 weeks gestation as at high or low risk for subsequent adverse pregnancy outcome by senior obstetricians. Clinical status, dietary information, circulating micronutrients and genome damage biomarkers were assessed at 18-20 weeks gestation. Women who developed IUGR had reduced red blood cell (RBC) folate (P < 0.001) and increased plasma homocysteine concentrations (P < 0.001) compared with controls. Maternal DNA damage, represented by micronucleus frequency and nucleoplasmic bridges in lymphocytes, was positively correlated with homocysteine (r = 0.179, P = 0.038 and r = 0.171, P = 0.047, respectively). Multivariate regression analysis revealed RBC folate was a strong predictor of IUGR (P = 0.006). This study suggests that low maternal RBC folate and high homocysteine values in mid pregnancy are associated with subsequent reduced fetal growth.

Physiologic changes in homocysteine metabolism in pregnancy: a longitudinal study in Spain.

OBJECTIVE: The aim was to investigate whether pregnancy-induced changes in total homocysteine (tHcy) are associated with folate and vitamin B12 nutritional status, genetic C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) enzyme, and gestation outcome at a time when folic acid supplementation started to be recommended in the Spanish health system. METHODS: In total 154 pregnant women were recruited from among gynecologic patients of the Alcorcón Public Hospital Outpatient Clinic (Madrid, Spain). Blood tests were performed at weeks 15, 24, and 32 of pregnancy. Total Hcy, folate, and vitamin B12 serum fasting concentrations were measured using an IMx system. Genotype analyses were done by polymerase chain reaction/restriction fragment/length polymorphism analysis. RESULTS: Folate and vitamin B12 serum concentrations decreased significantly (P < 0.01) through pregnancy and reached the lowest values in the third trimester. Serum tHcy concentrations were significantly (P < 0.01) lower in the second trimester but increased in the third trimester. Frequencies of MTHFR C667T genotype were CC (35.7%), CT (57.2%), and TT (7.1%). Total Hcy concentration was not statistically influenced by maternal genotype. Plasma folate was the single negative predictor of maternal tHcy in the first trimester of pregnancy; 11.1% of gestations resulted in intrauterine growth restriction, 7.9% in gestational diabetes mellitus, and 4.8% in gestational hypertension. No significant differences in serum folate, vitamin B12, or tHcy concentrations were found in complicated pregnancies and these were unrelated to MTHFR genotype. CONCLUSION: Although tHcy seems to be physiologically low in this Spanish population and unrelated to folate and B12 nutritional status, C677T MTHFR genotype, and some pregnancy complications, we support the statement that appropriate folate concentration may be important throughout pregnancy to prevent abnormalities associated with altered status (e.g., neural tube defects). According to our study, supplementation with folic acid seems to achieve this purpose because diet alone may be insufficient. In addition, a poor vitamin B12 status, as measured by plasma levels, may indicate that supplementation of both vitamins is needed.

Effect of maternal multiple micronutrient supplements on cord blood hormones: a randomized controlled trial.

BACKGROUND: Fetal growth improves in pregnant women who take daily maternal multiple micronutrients [United Nations International Multiple Micronutrient Preparation (UNIMMAP)] rather than iron and folic acid (IFA) alone. OBJECTIVE: Our objective was to test whether such an effect was mediated by changes in concentrations of cord hormones. DESIGN: In a double-blind, controlled trial carried out in Burkina Faso, we randomly assigned 1426 pregnant women to receive UNIMMAP or IFA supplements. We measured concentrations of insulin-like growth factor I (IGF-I), leptin, insulin, free thyroxine, and cortisol in cord serum in a subsample of 294 live single newborns. We performed mediation analysis with an Aroian test. RESULTS: UNIMMAP supplementation had no significant effect on cord hormone concentrations. However, UNIMMAP supplementation significantly affected concentrations of IGF-I (+30%; 95% CI: 8%, 52%; P = 0.009) and leptin in male newborns. In these infants, 51.1% (P = 0.08) of the effect of UNIMMAP supplementation on birth weight was mediated through IGF-I, whereas for female newborns, this proportion was negligible. UNIMMAP supplementation also increased cortisol concentrations by 36% (P = 0.009) in cord blood in primiparae (P for interaction = 0.02). Growth-retarded infants had 41.2% lower IGF-I (P < 0.0001) and 27.3% lower leptin (P = 0.04) than did infants with normal growth. Offspring of primiparae had reduced IGF-I and insulin concentrations, and their cortisol concentrations were 25% higher (P = 0.05). Male newborns had lower concentrations of IGF-I, leptin, and insulin than did female newborns. CONCLUSIONS: UNIMMAP supplementation had sex-specific effects on cord IGF-I and leptin concentrations that were of unclear clinical significance. Other pathways may have been involved in the action of UNIMMAP on fetal growth. The specific hormonal pattern in primiparae could be related to constrained fetal growth. Confirmatory studies are warranted. This trial was registered at clinicaltrials.gov as NCT00642408.

Effect of multiple-micronutrient supplementation on maternal nutrient status, infant birth weight and gestational age at birth in a low-income, multi-ethnic population.

Poor nutrient intake during pregnancy can adversely affect both infant and maternal health. The aim was to investigate the efficacy of multiple-micronutrient supplementation during pregnancy in a socially deprived population in the developed world. We conducted a randomised, double-blind, placebo-controlled trial of multiple-micronutrient supplementation including 20 mg Fe and 400 microg folic acid, from the first trimester of pregnancy in 402 mothers, in East London, UK. Nutrient status was measured at recruitment, and at 26 and 34 weeks of gestation. Infants were weighed at birth. At recruitment the prevalence of anaemia was 13 %, vitamin D insufficiency 72 %, thiamin deficiency 12 % and folate deficiency 5 %, with no differences between groups. Only 39 % of women completed the study; rates of non-compliance were similar in both groups. Intention-to-treat analysis showed that participants receiving treatment had higher mean Hb at 26 weeks of gestation (110 (sd 10) v.108 (sd 10) g/l; P = 0.041) and 34 weeks of gestation (113 (sd 12) v.109 (sd 10) g/l; P = 0.003) and packed cell volume concentrations at 26 weeks of gestation (0.330 (sd 0.025) v. 0.323 (sd 0.026) l/l; P = 0.011) and 34 weeks of gestation (0.338 (sd 0.029) v. 0.330 (sd 0.028) l/l; P = 0.014) compared with controls. Analysis of compliant women showed supplemented women had higher median concentrations of serum ferritin, erythrocyte folate and 25-hydroxyvitamin D later in gestation than controls. In the compliant subset (n 149), placebo mothers had more small-for-gestational age (SGA) infants (eight SGA v. thirteen; P = 0.042) than treatment mothers. Baseline micronutrient deficiencies were common; the multiple-micronutrient supplement was well-tolerated and improved nutrient status. Multiple-micronutrient supplements from early pregnancy may be beneficial and larger studies are required to assess impact on birth outcomes and infant development.

Blood rheology at term in normal pregnancy and in patients with adverse outcome events.

Plasma volume expansion of more than 1.5 l and sustainable activation of the hemostatic system that results in a steady rise of the fibrinogen/fibrin turnover are contemporary physiological events during normal pregnancy. In contrast, adverse outcome of pregnancy i.e. pre-eclampsia commonly coincide with hemo concentration and over activation of blood coagulation both of which alter blood rheology. On the basis of 4,985 consecutively recorded singleton pregnancies values range of blood rheological parameters in women with normal and complicated outcome of pregnancy at the time of their delivery were compared. Plasma viscosity (pv) was determined using KSPV 1 Fresenius and RBC aggregation (stasis: E0 and low shear: E1) using MA1-Aggregometer; Myrenne. Seventy-nine point four percent (n=3,959) had normal pregnancy outcome and 1,026 with adverse outcome of pregnancy had pre-eclampsia (8.4%; n=423), had newborn with a birth-weight < 2,500 g (9.5%; n=473), had early-birth before week 37 (9.3%; n=464), and/or were diagnosed with intra uterine growth retardation (IUGR) (5.0%; n=250). In women with normal pregnancy outcome mean (+/-SD) of pv was 1.31+/-0.09 mPa s, of E0 was 21.6+/-5.3, and of E1 was 38.4+/-7.9 while in women with adverse outcome means for rheological parameters were statistically significantly different i.e. pv: 1.32+/-0.08 mPa s; p=0.006, E0: 22.1+/-5.5; p=0.002 and E1: 39.5+/-8.5; p=0.0006. Subgroup analysis revealed statistical significant lower pv in women who either had pre term delivery or a low birth-weight child (p<0.005) as compared to women who had normal pregnancy outcome while patients with pre-eclampsia had markedly higher low shear and stasis RBC aggregation (p<0.0001). None of the rheological results at term were correlated with either maternal age (r<0.04), BMI (r<0.09), maternal weight gain until delivery (r<0.04), or fetal outcome such as APGAR-score (r<0.09) art. pH in the umbilical cord (-0.05

Study of hypothalamic leptin receptor expression in low-birth-weight piglets and effects of leptin supplementation on neonatal growth and development.

Low birth weight resulting from intrauterine growth retardation (IUGR) is a risk factor for further development of metabolic diseases. The pig appears to reproduce nearly all of the phenotypic pathological consequences of human IUGR and is likely to be more relevant than rodents in studies of neonatal development. In the present work, we characterized the model of low-birth-weight piglets with particular attention to the hypothalamic leptin-sensitive system, and we tested whether postnatal leptin supplementation can reverse the precocious signs of adverse metabolic programming. Our results demonstrated that 1) IUGR piglets present altered postnatal growth and increased adiposity; 2) IUGR piglets exhibit abnormal hypothalamic distribution of leptin receptors that may be linked to further disturbance in food-intake behavior; and 3) postnatal leptin administration can partially reverse the IUGR phenotype by correcting growth rate, body composition, and development of several organs involved in metabolic regulation. We conclude that IUGR may be characterized by altered leptin receptor distribution within the hypothalamic structures involved in metabolic regulation and that leptin supplementation can partially reverse the IUGR phenotype. These results open interesting therapeutic perspectives in physiopathology for the correction of defects observed in IUGR.

Screening for pre-eclampsia by oxidative stress markers and uteroplacental blood flow.

Recent evidence suggests that the oxidative stress is an important factor in the pathophysiology of pre-eclampsia. The purpose of this study was to evaluate the possible relationship between increased resistance at the Doppler assessment of the uterine arteries between 20-23 gestational weeks and biochemical markers of oxidative stress, with the development of pre-eclampsia and/or growth restricted infants. This was a prospective study of 34 pregnant women with normal uteroplacental flow and 30 women with abnormal uterine arteries Doppler analysis (mean PI >or= 1.60) during the transvaginal assessment of the uterine arteries at the routine anomaly scan. Blood samples were obtained in order to assess the plasma oxidative stress, namely malondialdehyde (MDA) and uric acid levels. The MDA was significantly higher in the group of women with abnormal uterine arteries Dopplers. This group is at increased risk for the development of pre-eclampsia. The uric acid levels did not differ significantly between the two groups of women. There was no significant difference regarding the sensitivity or the specificity of the uterine arteries Doppler examination in detecting pre-eclampsia in comparison to the combination of oxidative stress and Doppler's. Our study provides additional evidence regarding the role of oxidative stress in the pathophysiology of pre-eclampsia. Whether antioxidant supplementation in the group of women with abnormal uterine Doppler's is effective in reducing the incidence of the disease remains to be established.

Effects of maternal vitamin B12 deficiency from end of gestation to weaning on the growth and haematological and immunological parameters in mouse dams and offspring.

Vitamin B12-deficiency may induce specific symptoms as neurological alterations and unspecific symptoms such as anaemia and growth retardation. In this study, maternal vitamin B12 deficiency from end of gestation to weaning was evaluated in mouse dams, which was provoked by feeding a vitamin B12-deficient diet. The animals were divided into two groups (control and deficient). The control group received the vitamin B12-deficient diet supplemented with commercial vitamin B12. Compared to the control, the vitamin B12-deficient dams and their offspring showed a significant decrease of body weight (by 20 and 39%, respectively), serum vitamin B12 concentration (by 61 and 67%, respectively), haematological values as haematocrit (25 and 26%, respectively), and IgA producer cells (by 36 and 54%, respectively). In both, vitamin B12-deficient mouse dams and their offspring, histological alterations of small intestine were observed, whereas growth retardation occurred in the offspring only. This experimental murine model allows assessing the incidence of maternal cobalamin deficiency in offspring and would be useful for evaluating novel adjuncts such as functional foods to prevent vitamin B12 deficiency.

Folate, vitamin B12, and homocysteine levels in South Asian women with growth-retarded fetuses.

OBJECTIVE: To investigate whether intrauterine growth retardation (IUGR) and preterm delivery in a poor population of South Asia was associated with altered maternal and fetal levels of folate, vitamin B12, and homocysteine. SUBJECTS AND METHODS: Hundred and twenty-eight pregnant women from a low socio-economic strata in the city of Lahore, Pakistan were followed with ultrasound of fetal growth from the 12th week of pregnancy. Blood samples were drawn from the woman and the cord at delivery. Serum was analyzed by a chemiluminescent immunoassay for folate and vitamin B12 and by fluorescence polarization immunoassay for total homocysteine (tHcy). RESULTS: Fourty-six infants showed IUGR. In term, but not preterm, deliveries with IUGR, maternal and cord blood folate levels were half of those in deliveries of normal birth weight infants (P=0.004 and P=0.005). The risk of IUGR was reduced among women with folate levels in the highest quartile (OR 0.31, 95% CI 0.10--0.84). There was no association between vitamin B12 and IUGR. Total homocysteine levels were higher in women delivering IUGR infants (P=0.02). There was an inverse correlation between cord blood folate and tHcy levels (r=-0.26, P=0.006). We also found increased risks for hypertensive illness (OR 3.5, 95% CI 1.4--8.6) and premature delivery (OR 2.5, 95% CI 1.1--6.2) in women in the highest quartile of tHcy. CONCLUSIONS: The occurrence of IUGR increased with low maternal and cord concentrations of folate and high maternal levels of tHcy. Further studies on the effects of vitamin B supplementation through pregnancy are warranted.