Maternal angiogenic factor disruptions prior to clinical diagnosis of preeclampsia: insights from the REVAMP study.

Preeclampsia is characterized by impaired angiogenesis and assessment of angiogenic factors can play a crucial role in the early diagnosis of preeclampsia. The current study reports the levels of angiogenic factors longitudinally from early pregnancy in women with preeclampsia and in the subtypes of preeclampsia, to identify their role in early prediction of preeclampsia. A total of 1154 women with singleton pregnancies were recruited in early pregnancy from 2 hospitals. Blood samples were collected, plasma samples were separated and stored at four time points across gestation: V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery. The current study includes a total of 108 women developed preeclampsia (PE), and 216 matched controls. Angiogenic factors were estimated using commercially available ELISA kits. Receiver operating characteristic (ROC) curves were used to evaluate the potential diagnostic value in the prediction of PE. Lower levels of VEGF, PlGF, and higher levels of sEng and sEng/PlGF ratio (p < 0.05 for all) predate clinical diagnosis in women with preeclampsia. sEng levels and sEng/PlGF ratio showed significant correlation with odds of preeclampsia at all the timepoints. This study identifies a cut off of 33.5 for sFlt-1/PlGF and 25.9 for sEng/PlGF for prediction of early onset preeclampsia. This study reports various angiogenic factors serially across gestation in a general population to identify women at risk of developing preeclampsia and its subtypes. The study also reports a potential biomarker and a pragmatic window for estimation of angiogenic markers to identify women at risk.

Longitudinal Assessment of Oxidative Stress Markers in Women with Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder and a major contributor to maternal and fetal morbidity and mortality. Role of oxidative stress in early pregnancy with the pathophysiology of the disorder is unclear. The current study aims to analyse maternal levels of oxidative stress markers (MDA and protein carbonyl) longitudinally across gestation and placental levels of oxidative stress markers (MDA, protein carbonyl and 8-oxo-2'-deoxyguanosine) in women with PE and compare them with non-PE women. 324 pregnant women (216 non-PE and 108 PE women) were longitudinally followed during pregnancy. Women with preeclampsia were stratified as early onset preeclampsia (EOP) and late onset preeclampsia (LOP) Maternal blood at four time points across gestation (11-14 weeks, 18-22 weeks, 26-28 weeks, and at delivery) and placenta were collected. Maternal and placental levels of oxidative stress markers were assessed using commercially available kits. Maternal plasma MDA and protein carbonyl levels were comparable between the PE and non-PE group at all timepoints across gestation. Maternal plasma MDA were significantly higher levels at 26-28 weeks in EOP women when compared to non-PE women (p < 0.05). Placental 8-oxo-dG levels were lower in the EOP group as compared to non-PE (p < 0.05). Elevated plasma MDA levels were positively associated with birth length at 18-22 weeks and 26-28 weeks in the PE group (p < 0.05 for both). Maternal plasma MDA levels were positively associated with systolic blood pressure at 18-22 weeks. Oxidative stress in early pregnancy is not associated with risk of PE.

Fatty acids and their metabolites (resolvins) are altered in women with gestational diabetes mellitus (GDM).

The maternal fatty acid status plays a key role in influencing pregnancy outcomes. Omega-3 fatty acids are the precursors for E-series (RvE) and D-series resolvins (RvD) and possess anti-inflammatory properties. Pregnancy complications like gestational diabetes mellitus (GDM) are associated with excess maternal inflammation. This study reports the levels of maternal fatty acids across gestation in GDM and non-GDM women, placental fatty acids, resolvins and their association with the maternal fatty acid status. Pregnant women were recruited at 11-14 (V1) weeks and followed at 18-22 (V2) and 26-28 (V3) weeks and at delivery (V4). A total of 209 women who were diagnosed as GDM and 207 non-GDM women were included in this study. Fatty acids were estimated using gas chromatography. The protein levels of resolvins (RvE1, RvE2, RvD1 and RvD2) were measured using ELISA kits. Total PUFAs, eicosapentaenoic acid (EPA), omega-6 fatty acids, linoleic acid (LA) and arachidonic acid (AA) were lower, while saturated fatty acid (SFA) and alpha-linolenic acid (ALA) levels were higher in GDM women at 18-22 weeks. Placental AA was lower (p < 0.05) in women with GDM. Placental protein levels of RvE1, RvD1 and RvD2 were lower (p < 0.001 for all) in the GDM group. The maternal delta 5 desaturase index was positively associated, while erythrocyte omega-3 and omega-6 fatty acids were negatively associated with RvE2 at 11-14 weeks. Placental LA and ALA were positively associated with RvD1 and RvD2 (p < 0.05, for both), respectively. Our findings suggest that the maternal fatty acid status influences pro-resolving mediators which may lead to increased inflammation in GDM.

Longitudinal profile of high-sensitivity C-reactive protein in women with pre-eclampsia.

PROBLEM: C-reactive protein (CRP) is a marker for inflammation and its role as a possible biomarker for an early prediction of pre-eclampsia (PE) is unclear. The present study investigates the levels of high-sensitivity CRP (hs-CRP) longitudinally across pregnancy in women with PE and compares them to women without PE (non-PE). METHOD OF STUDY: A total of 324 pregnant women [216 non-PE and 108 PE women] were included in this study. Maternal blood was taken at four different intervals (V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery). RESULTS: Maternal serum hs-CRP levels were higher at V1, V2, and V3 (p < .05 for all) in the PE group compared to the non-PE group. The hs-CRP levels were associated with maternal blood pressure throughout pregnancy. Maternal hs-CRP levels did not differ among early and late onset PE. Higher maternal hs-CRP levels were associated with the increased risk of PE in unadjusted model in early pregnancy. However, there was no significance after adjusting for confounding factors. CONCLUSIONS: Our findings suggest although the levels of hs-CRP were higher in PE in early pregnancy, they are not associated with an increased risk of PE.

Altered expression of nutrient transporters in syncytiotrophoblast membranes in preeclampsia placentae.

INTRODUCTION: Expression of nutrient transporters in the placenta affects fetal growth. This study reports the protein expression of nutrient transporters in the syncytial membranes [microvillous membrane (MVM) and basal membrane (BM)] of normotensive control and preeclampsia placentae. METHODS: Placentae were collected from fourteen normotensive control women and fourteen women with preeclampsia. The syncytiotrophoblast MVM and BM membranes were isolated. The protein expression of glucose transporter (GLUT1), vitamin B12 transporter (CD320) and fatty acid transporters (FATP2, FATP4) was assessed in both the membranes. RESULTS: Comparison between membranes demonstrates similar CD320 protein expression in normotensive group whereas, in preeclampsia placentae it was higher in the BM as compared to MVM (p < 0.05). FATP2&4 protein expression was higher in the BM as compared to their respective MVM fraction in both the groups (p < 0.01 for both). Comparison between groups demonstrates higher GLUT1 expression in the MVM (p < 0.05) and BM (p < 0.05) whereas lower CD320 expression in the MVM (p < 0.05) of preeclampsia placentae as compared to their respective membranes in normotensive control. Furthermore, GLUT1 protein expression was positively associated and CD320 protein expression was negatively associated with maternal body mass index (BMI) (p < 0.05 for both). No difference was observed in the FATP2&4 protein expression. However, FATP4 protein expression was negatively associated with maternal blood pressure (p < 0.05 for MVM; p = 0.060 for BM) and birth weight (p < 0.05 for both membranes). DISCUSSION: The current study for the first time demonstrates differential expression of various transporters in the syncytiotrophoblast membranes of the preeclampsia placentae which may influence fetal growth.

MicroRNAs targeting peroxisome proliferator-activated receptor (PPAR) gene are differentially expressed in low birth weight placentae.

INTRODUCTION: Peroxisome proliferator-activated receptors (PPARs) are activated by natural ligands like fatty acids and influence placental angiogenesis and pregnancy outcome. However, the underlying molecular mechanisms are not clear. This study aims to investigate the association of maternal and placental fatty acid levels with DNA methylation and microRNA regulation of PPARs in the placentae of women delivering low birth weight (LBW) babies. METHODS: This study includes 100 women delivering normal birth weight (NBW) baby and 70 women delivering LBW baby. Maternal and placental fatty acids levels were estimated by gas chromatograph. Gene promoter methylation and mRNA expression of PPARs was analyzed using Epitect Methyl-II PCR assay kit and RT-PCR respectively. Expression of miRNAs targeting PPAR mRNA were analyzed using a Qiagen miRCURY LNA PCR Array on RT-PCR. RESULTS: Placental docosahexaenoic acid (DHA) levels and placental mRNA expression of PPARα and PPARγ were lower (p < 0.05 for all) in the LBW group. Differential expression of miRNAs (upregulated miR-33a-5p and miR-22-5p; downregulated miR-301a-5p, miR-518d-5p, miR-27b-5p, miR-106a-5p, miR-21-5p, miR-548d-5p, miR-17-5p and miR-20a-5p) (p < 0.05 for all) was observed in the LBW group. Maternal and placental polyunsaturated fatty acids and total omega-3 fatty acids were positively associated while saturated fatty acids were negatively associated with expression of miRNAs (p < 0.05 for all). Placental expression of miRNAs were positively associated with birth weight (p < 0.05 for all). DISCUSSION: Our data suggests that maternal fatty acid status is associated with changes in the placental expression of miRNAs targeting PPAR gene in women delivering LBW babies.

Association between proNGF receptors and apoptotic factors in human placentae.

INTRODUCTION: Earlier studies have shown higher apoptosis in the pre-term placenta as compared to term. However, the exact mechanisms triggering these are not completely understood. Studies in neuronal and non-neuronal tissues have shown that the precursor form of NGF (proNGF) triggers apoptosis through preferential activation of p75NTR and sortilin receptors. We therefore, investigated placental expression of proNGF, mature NGF, p75NTR, co-receptor sortilin and their association with apoptosis. We further compared the levels of pro-protein convertase, furin between samples having high and low proNGF: mature NGF ratio. METHODS: Placenta samples were collected from women delivering at term (≥37 weeks; n = 41) and preterm (<37 weeks; n = 44). The protein levels of NGF, proNGF, p75NTR, Bax, Bcl-2 and furin were estimated by ELISA. Mean values of variables between different groups were compared using the independent sample t-test and associations were studied by Pearson correlation analysis. RESULTS: The placental mature NGF, proNGF and p75NTR protein levels were comparable between groups. Bax: Bcl-2 ratio was higher in preterm (p < 0.05) compared to term placenta. p75NTR was positively associated with Bax levels and sortilin levels were positively associated with p75NTR in whole cohort as well as individual groups. DISCUSSION: The higher Bax: Bcl-2 ratio in preterm placenta suggests the sensitivity to apoptosis. There were no differences in levels of NGF, proNGF, p75NTR, sortilin, and furin between groups. The observed associations between p75NTR, sortilin and Bax suggest that p75NTR and sortilin mediated signalling may be involved in the mechanisms leading to higher apoptosis in preterm placentae.

Association of maternal vitamin D status with the risk of preeclampsia.

The aim of this study was to examine serum vitamin D concentrations from early pregnancy until delivery in women who did and did not develop preeclampsia. This longitudinal study was carried out in Pune, India. A total of 1154 women with singleton pregnancies were recruited in early pregnancy from two hospitals. Blood samples were collected and stored at four time points across gestation: V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks and V4 = at delivery. 108 women who developed preeclampsia (PE) and 216 who did not develop PE (Non-PE) were randomly selected from the remainder. Serum 25-hydroxy vitamin D concentrations (25(OH)D) were estimated in their samples using commercially available ELISA kits. Independent t-tests were used to compare 25(OH)D between PE and non-PE groups. Logistic and linear regressions were used to examine associations of 25(OH)D with the risk of preeclampsia and birth outcomes, respectively, after adjusting for confounders. The mean (SD) 25(OH)D at V1 was 21.95 (19.64) in the Non-PE group and 17.76 (13.21) in the PE group. A decrease in the concentrations of vitamin D (ng ml-1) in mid-pregnancy (V2) and at delivery was associated with an increased risk of preeclampsia (0.31 [95% CI 0.11, 0.86], p = 0.024 and 0.24 [95% CI 0.08, 0.77], p = 0.016), respectively. Our finding of lower vitamin D concentrations in mid-pregnancy, before women developed clinical preeclampsia, suggests that vitamin D may have a role in its pathophysiology.

Fatty acids, inflammation and angiogenesis in women with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnancy whose prevalence is on the rise. Reports suggest a likely association between inflammation and maternal GDM. A balance between pro and anti-inflammatory cytokines is necessary for the regulation of maternal inflammation system throughout pregnancy. Along with various inflammatory markers, fatty acids also act as pro-inflammatory molecules. However, studies reporting the role of inflammatory markers in GDM are contradictory, suggesting the need of more studies to better understand the role of inflammation in pregnancies complicated by GDM. Inflammatory response can be regulated by angiopoietins suggesting a link between inflammation and angiogenesis. Placental angiogenesis is a normal physiological process which is tightly regulated during pregnancy. Various pro and anti-angiogenic factors influence the regulation of the feto-placental vascular development. Studies evaluating the levels of angiogenic markers in women with GDM are limited and the findings are inconsistent. This review summarizes the available literature on fatty acids, inflammatory markers and angiogenesis in women with GDM. We also discuss the possible link between them and their influence on placental development in GDM.

Hypoxia Inducible Factors (HIF1α and HIF3α) are differentially methylated in preeclampsia placentae and are associated with birth outcomes.

Preeclampsia is a placental vascular pathology and hypoxia is known to influence placental angiogenesis. Hypoxia Inducible Factors (HIF1α and HIF3α) mediate the response to cellular oxygen concentration and bind to hypoxia response element of target genes. However the mechanism regulating above activity is not well-understood. We investigated if placental DNA methylation (DNAm) and expression of HIF1α and 3α genes are altered and associated with pre-eclampsia, placental weight and birth outcomes. Using a cohort comprising women with preeclampsia [N = 100, delivering at term (N = 43) and preterm (N = 57)] and normotensive controls (N = 100), we analysed DNAm in HIF1α and 3α, and their mRNA expression in placentae, employing pyrosequencing and quantitative real-time PCR, respectively. We observed significant hypermethylation at cg22891070 of HIF3α in preeclampsia placentae compared to controls (ß = 1.5%, p = 0.04). CpG8 in the promoter region of HIF1α, showed marginally significant hypomethylation in preterm preeclampsia compared to controls (ß = - 0.15%, p = 0.055). HIF1α expression was significantly lower in preterm preeclampsia compared to controls (mean ± SE = 10.16 ± 2.00 vs 4.25 ± 0.90, p = 0.04). Further, DNAm in HIF1α promoter region was negatively associated with its expression levels (ß = - 0.165, p = 0.024). Several CpGs in HIF1α were negatively associated with placental weight and birth outcomes including birth weight (ß range = - 0.224-0.300) and birth length [ß range = - 0.248 to - 0.301 (p < 0.05 for all)]. Overall, we demonstrate altered DNAm in HIF1α and HIF3α in preeclampsia placentae, also associated with various birth outcomes. Correlation of DNAm in HIF1α and its expression suggests a possible role in the pathogenesis of pre-eclampsia. Further investigations on interactions between HIF1α and HIF3α in preeclampsia would be interesting.

Assisted reproductive technology (ART) and epigenetic modifications in the placenta.

Assisted reproductive technology (ART) has become common amongst couples with infertility issues. ART is known to be successful, but epidemiological data indicates that ART is associated with placental disorders. Additionally, reports show increased risks of short- and long-term complications in children born to mothers undergoing ART. However, the mechanisms responsible for these events are obscure. The placenta is considered as a key organ for programming of diseases and ART procedures are suggested to alter the placental function and intrauterine growth trajectories. Epigenetic changes in maternal and foetal tissues are suggested to be the underlying mechanisms for these outcomes. Epigenetic regulation is known to evolve following fertilisation and before implantation and subsequently across gestation. During these critical periods of epigenetic 'programming', DNA methylation and chromatin remodelling influence the placental structure and function by regulating the expression of various genes. ART treatment coinciding with epigenetic 'programming' events during gametogenesis and early embryo development may alter the programming phases leading to long-term consequences. Thus, disruptions in placental development observed in ART pregnancies could be associated with altered epigenetic regulation of vital genes in the placenta. The review summarises available literature on the influence of ART procedures on epigenetic changes in the placenta.

Longitudinal Assessment of Calcium and Magnesium Levels in Women with Preeclampsia.

The present study reports the levels of maternal serum calcium and magnesium from early pregnancy until delivery, along with cord levels, in women who developed preeclampsia (PE) and compares them with those without PE. A total of 324 pregnant women (216 non-PE and 108 PE women) were included in this retrospective case-control study of prospectively collected data nested in an observational cohort study. Maternal blood was collected at 4 time points during pregnancy (V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery) and umbilical cord blood at delivery. Independent t tests were used to compare calcium, magnesium, and their ratio between two groups, and their associations with PE were studied using regression models. Calcium levels were similar between groups at all time points. Magnesium levels were lower (p = 0.021) at V2 in PE group as compared with non-PE group. Maternal calcium and magnesium levels were negatively associated, with blood pressure in early pregnancy. In fully adjusted logistic regression analysis, lower magnesium levels were associated with an increased risk of PE at V2 (OR 0.25 [95% CI 0.07, 0.94] p = 0.04). Lower magnesium in mid-pregnancy was associated with higher risk of PE. These changes were observed before the diagnosis of PE, thereby suggesting that they may have a role in the etiology of PE.

Gestational weight gain in the REVAMP pregnancy cohort in Western India: Comparison with international and national references.

Objective: To determine the trimester specific gestational weight gain (GWG) in a population of pregnant women from Western India and compare it with the Intergrowth-21st international and an Indian reference (GARBH-Ini cohort-Group for Advanced Research on BirtH outcomes). Study design: A prospective longitudinal observational study was undertaken in Pune, West India and data for gestational weight gain was collected [the REVAMP study (Research Exploring Various Aspects and Mechanisms in Preeclampsia)]. Generalized Additive Models for Location, Scale and Shape method (GAMLSS model) were used to create GWG centile curves according to gestational age, stratified by BMI at recruitment (n = 640) and compared with Intergrowth-21st reference and GARBH-Ini cohort. Multivariable regression analysis was used to evaluate the relationship between GWG and antenatal risk factors. Results: The median GWG was 1.68, 5.80, 7.06, and 11.56 kg at gestational ages 18, 26, 30, and 40 weeks, respectively. In our study, pregnant women gained less weight throughout pregnancy compared to Intergrowth-21st study, but more weight compared to the GARBH-Ini cohort centile curves in all the BMI categories. GWG in overweight/obese women (BMI ≥ 25) was significantly lower (<0.001) as compared to underweight (BMI < 18.5), or normal weight women (BMI ≥ 18.5 and <25). The median GWG at 40 weeks in underweight, normal and overweight/obese women was 13.18, 11.74, and 10.48 kg, respectively. Higher maternal BMI, older maternal age, higher parity and higher hemoglobin concentrations were associated with lower GWG, while taller maternal height was associated with greater GWG. Conclusion: GWG of Indian women is lower than the prescriptive standards of the Intergrowth charts.

Association of placental fatty acid desaturase 2 (FADS2) methylation with maternal fatty acid levels in women with preeclampsia.

INTRODUCTION: Biosynthesis of long-chain polyunsaturated fatty acids requires sequential activities of desaturases and elongases for conversion of fatty acid precursors to products. The delta-6 desaturase enzyme, encoded by FADS2 gene, is a rate limiting enzyme in this pathway. Alterations in D6D enzyme activity can lead to altered fatty acid profiles. OBJECTIVES: To examine differences in placental DNA methylation (DNAm) and expression of FADS2 gene in preeclampsia women compared to normal women and their association with maternal variables (plasma fatty acids, desaturase enzyme index, blood pressure), placental weight and birth outcomes. METHODS: DNAm and expression of FADS2 gene were examined in placentae of normotensive (n = 100) control and preeclampsia (n = 100) women using pyrosequencing and quantitative real-time PCR respectively. Women with preeclampsia included those delivering at term (n = 43, gestation ≥ 37 weeks; T-PE) or preterm (n = 57, gestation < 37 weeks; PT-PE). A total of 26 CpGs in FADS2 promoter and region around it, were analysed in two PCR reactions (region 1 and 2). RESULTS: Out of 13 CpGs in region 1, significant hypermethylation was noted at CpG3 in T-PE (p = 0.03) and of 13 CpGs in region 2, CpG2 (p = 0.008), CpG11 (p = 0.04), CpG12 (p = 0.001) were hypomethylated and CpG13 (p = 0.001) was hypermethylated in preeclampsia group, as compared to controls. FADS2 expression was lower in PT-PE as compared to controls (p = 0.04). DNAm at various CpGs in the FADS2 were associated with maternal plasma FADS2 enzyme index and also associated with maternal fatty acid levels. However, we did not observe any association of DNAm with maternal blood pressure, placental weight and birth outcomes. CONCLUSIONS: This study for the first time reports differential methylation of FADS2 and its association with impaired maternal fatty acid metabolism in preeclampsia and provides a mechanistic basis to our earlier observations of altered maternal LCPUFA levels in women with preeclampsia.

Influence of maternal one carbon metabolites on placental programming and long term health.

Studies have shown that the maternal nutrition during critical periods of development not only influences fetal growth but also plays a significant role in determining the risk of chronic disease in later life through developmental 'programming'. The placenta acts as a tool for 'programming' as it has the ability to adapt according to the maternal environment. There are morphological adaptations and also alterations in the expression of genes as a consequence of placental adaptations; which are critical for both placental and fetal development. Maternal nutrients especially the micronutrients (folate, vitamin B12) of the one carbon cycle and long chain polyunsaturated fatty acids (LCPUFA) are essential for placental and fetal growth and development. They are interconnected through the one carbon cycle and play a critical role in determining pregnancy outcome. A disturbed one carbon cycle leads to altered methylation of genes which play an important role in placental development and fetal growth. This review discusses the role of maternal one carbon metabolites and its influence on placental 'programming' and long term health.

Cognitive function and behavioral problems in children born to mothers with preeclampsia: an Indian study.

Studies from high-income countries report associations of preeclampsia (PE) with reduced cognitive function and adverse behavioural outcomes in children. We examined these associations in Indian children aged 5-7 years. Children of mothers with PE (n=74) and without PE (non-PE; n=234) were recruited at delivery at Bharati Hospital, Pune, India. The cognitive performance was assessed using 3 core tests from the Kaufman Assessment Battery and additional tests including Verbal fluency, Kohs block design, and Coding A (from Wechsler Intelligence Scale for Children). The parent-reported Strengths and Difficulties Questionnaire (SDQ) was used to assess children's behavioral characteristics. Scores were compared between children from PE and non-PE groups, and associations analyzed further using regression models, adjusted for potential confounders. After adjusting for age, sex, socio-economic status and maternal education, children of PE mothers had lower Kohs block design scores (adjusted odds ratio per score category 0.57, [95% CI 0.34-0.96] p=0.034; 0.62 [95%CI (0.36, 1.07), p=0.09 on further adjustment for birth weight and gestation) compared to children of mothers without PE. In the SDQ, there was a lower prevalence of abnormal 'conduct problem' scores in PE group than non-PE group (OR=0.33, 95% CI 0.13-0.83, p=0.018, in the fully adjusted model); there were no differences for other behavioral domains. This preliminary study in Indian children suggests that fetal exposure to maternal PE may have an adverse impact on visuo-spatial performance but does not adversely affect behavior. Further studies with larger sample sizes are essential to understand effects of maternal PE on cognitive/behavioral outcomes in children.

Role of Placental Glucose Transporters in Determining Fetal Growth.

Maternal nutrient availability and its transport through the placenta are crucial for fetal development. Nutrients are transported to the fetus via specific transporters present on the microvillous (MVM) and basal membrane (BM) of the placenta. Glucose is the most abundant nutrient transferred to the fetus and plays a key role in the fetal growth and development. The transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations, and is mediated by glucose transporter family proteins (GLUTs). Maternal glucose concentration influences expression and activity of GLUTs in the MVM (glucose uptake) and BM (glucose delivery). Alteration in the number and function of these transporters may affect the growth and body composition of the fetus. The thin-fat phenotype of the Indian baby (low ponderal index, high adiposity) is proposed as a harbinger of future metabolic risk. We propose that placental function mediated through nutrient transporters contributes to the phenotype of the baby, specifically that glucose transporters will influence neonatal fat. This review discusses the role of various glucose transporters in the placenta in determining fetal growth and body composition, in light of the above hypothesis.

Maternal vitamin D deficiency reduces docosahexaenoic acid, placental growth factor and peroxisome proliferator activated receptor gamma levels in the pup brain in a rat model of preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy disorder characterized with abnormal placental angiogenesis. Vitamin D and long chain polyunsaturated fatty acids (LCPUFA) play a crucial role in pregnancy and are required for normal placental and fetal growth and development. This study reports the effect of maternal vitamin D on LCPUFA levels in the mother and offspring brain fatty acid levels and angiogenic markers in a rat model of preeclampsia. METHODS: Female rats were divided into four groups from pre-pregnancy to pregnancy, viz Control; Preeclampsia (PE); Vitamin D deficient with PE (VDD-PE) and Vitamin D supplemented with PE (VDS-PE). Preeclampsia was induced by administering l-nitroarginine methyl ester (L-NAME) at the dose of 50 mg/kg body weight/day from day 14 to day 19 of gestation. Dams were sacrificed at d20 of gestation to collect dam blood, placenta and pup brain. LCPUFA levels from dam plasma, erythrocytes and placenta and its transcription factor peroxisome proliferator activated receptor gamma (PPAR-g) from placenta were estimated. Pup brain LCPUFA levels, angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and transcription factor hypoxia inducible factor (Hif-1α) and PPAR-g were also estimated. RESULTS: Maternal vitamin D status influences fatty acid levels. Placental PPAR-g levels were lower in the VDD-PE group as compared to the VDS-PE groups (p < 0.01). In the offspring brain, both PE and VDD-PE group showed lower levels of DHA (p < 0.05 for both) while saturated fatty acids (SFA) levels in the VDD-PE group were higher as compared to the control group (p < 0.05). VDD-PE group also showed lower levels of PlGF and PPAR-g (p < 0.01 and p < 0.05, respectively) in the pup brain while vitamin D supplementation demonstrated levels similar to control. CONCLUSION: This study for the first time demonstrates that maternal vitamin D status influences LCPUFA metabolism and angiogenesis in the offspring brain.

Placental apoptotic markers are associated with placental morphometry.

INTRODUCTION: Preeclampsia is a hypertensive disorder affecting both mother and the fetus and is a major cause of maternal and neonatal morbidity and mortality. Abnormal placentation is a common feature in preeclampsia that contributes to placental dysfunction. It is likely that increased homocysteine and oxidative stress influence apoptosis in preeclampsia. Increased placental apoptosis may aggravate the symptoms of preeclampsia through disruption of the placental structure. The current study aims to examine the association between various placental apoptotic markers with placental dimensions and maternal and neonatal characteristics in women with preeclampsia. METHODS: A total of 80 pregnant women [preeclampsia (n = 40); normotensive control (n = 40)] were included in the study. Placental characteristics such as its major axis, minor axis, breadth, thickness (at centre, cord insertion and periphery) and trimmed placental weight were recorded.Placental protein levels of caspase-3, caspase-8, BAX and Bcl-2 were estimated by ELISA and gene expression were examined by real time quantitative PCR. RESULT: Protein levels of proapoptotic markers such as caspase-8 and 3 were higher (p < 0.01) in the preeclampsia group compared to control whereas, the level of antiapoptotic marker Bcl-2 (p < 0.05) was lower in the preeclampsia group. Caspase-3 and Bcl-2 protein levels were negatively associated with thickness of placenta at cord insertion (p < 0.01). Protein levels of caspase-8 and caspase-3 were positively associated with placental MDA levels (p < 0.01). Caspase-8 was negatively associated with baby length (p = 0.055). DISCUSSION: This study demonstrates the association of various apoptotic markers with oxidative stress and placental dimensions.

Cell death mechanisms and their roles in pregnancy related disorders.

Autophagy and apoptosis are catabolic pathways essential for homeostasis. They play a crucial role for normal placental and fetal development. These cell death mechanisms are exaggerated in placental disorders such as preeclampsia, intrauterine growth restriction (IUGR) and gestational diabetes mellitus (GDM). Apoptosis is widely studied, highly controlled and regulated whereas; autophagy is an orderly degradation and recycling of the cellular components. Cellular senescence may be initiated by a variety of stimuli, including hypoxia, oxidative stress, reduction in survival signals and nutrition deprivation. Apoptosis is regulated by two types of pathways intrinsic and extrinsic. Extrinsic pathway is initiated by apoptosis inducing cells such as macrophages, natural killer cells whereas; intrinsic pathway is initiated in response to DNA damage, cell injury and lack of oxygen. In autophagy, the cell or organelles undergo lysosomal degradation. Placental apoptosis increases as the gestation progresses while autophagy plays a role in trophoblast differentiation and invasion. In pregnancy disorders like preeclampsia and IUGR, proapoptotic markers such as caspase 3, 8, BAX are higher and antiapoptotic markers like Bcl-2 are lower. In GDM, apoptotic markers are reduced resulting in increased placental mass and fetal macrosomia. Apoptosis in the pathological pregnancies is also influenced by the reduced levels of micronutrients and long chain polyunsaturated fatty acids resulting in disturbed placental biology. This chapter describes the role of various key molecular events involved in cellular senescence and the various factors influencing them. This will help identify future therapeutic strategies for better management of these processes.