Correction: Rondinone et al. Extensive Placental Methylation Profiling in Normal Pregnancies. Int. J. Mol. Sci. 2021, 22, 2136.

In the original publication [...].

Prophylactic intraoperative uterine artery embolization for the management of major placenta previa.

PURPOSE: Placenta previa is a major cause of maternal morbidity and mortality, associated to a high risk of peripartum hemorrhage and hysterectomy. We aimed to verify if prophylactic intraoperative uterine artery embolization in patients with placenta previa and at least one additional risk of bleeding (major placenta previa), can reduce hemorrhage, need for blood transfusions, peripartum hysterectomy and maternal morbidity. MATERIALS AND METHODS: We enrolled 76 patients with major placenta previa; a specific multidisciplinary protocol was designed for management, including ultrasound evaluation, hospitalization at 34 weeks, antenatal corticosteroids and scheduled cesarean section at 35-36 weeks. 44 patients (control group or CTR) were treated with elective cesarean section, 32 patients (embolized group or EMB) underwent selective catheterization of bilateral uterine arteries before cesarean section and subsequent uterine embolization. In both cases cesarean section was performed by a senior surgeon. RESULTS: Significant differences were found in term of intraoperative blood loss (CTR: 1431 ml; EMB: 693 ml); despite an high percentage of CTR patients had a bleeding greater than 1000 ml (56%), the need for blood transfusion was not significantly different between the two groups. Time of surgery was higher in the EMB group, considering that embolization procedure required approximatively 30 min. Three patients from the CTR group needed hysterectomy and ICU admission, compared to none in the EMB group. Duration of hospitalization and neonatal outcome were similar. Uterine embolization was not related to any short or long-term complications; return to normal menses and preservation of fertility were confirmed at follow up. CONCLUSIONS: Our results are promising, although we believe that a major contribution is referable to the multidisciplinary approach rather than the procedure itself. Nevertheless, we demonstrated the feasibility and safety of preventive uterine embolization in patients with placenta previa; in order to establish its prophylactic role in the prevention of peripartum hemorrhage, randomized trial should be carried out, on a larger population.

Assessment of pregnancy dietary intake and association with maternal and neonatal outcomes.

BACKGROUND: Maternal dietary habits are contributors of maternal and fetal health; however, available data are heterogeneous and not conclusive. METHODS: Nutrient intake during pregnancy was assessed in 503 women with uncomplicated pregnancies, using the validated Food Frequency Questionnaire developed by the European Prospective Investigation into Cancer and Nutrition (EPIC-FFQ). RESULTS: In all, 68% of women had a normal body mass index at the beginning of pregnancy, and 83% of newborns had an appropriate weight for gestational age. Maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and placental weight were independently correlated with birth weight. GWG was not related to the pre-pregnancy BMI. EPIC-FFQ evaluation showed that 30% of women adhered to the European Food Safety Authority (EFSA) ranges for macronutrient intake. In most pregnant women (98.1%), consumption of water was below recommendations. Comparing women with intakes within EFSA ranges for macronutrients with those who did not, no differences were found in BMI, GWG, and neonatal or placental weight. Neither maternal nor neonatal parameters were associated with the maternal dietary profiles. CONCLUSIONS: In our population, maternal pre-pregnancy BMI, GWG, and placental weight are determinants of birth weight percentile, while no association was found with maternal nutrition. Future studies should explore associations through all infancy. IMPACT: Maternal anthropometrics and nutrition status may affect offspring birth weight. In 503 healthy women, maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and placental weight were independently correlated to neonatal birth weight. GWG was not related to the pre-pregnancy BMI. In all, 30% of women respected the EFSA ranges for macronutrients. Neither maternal nor neonatal parameters were associated with maternal dietary profiles considered in this study. Maternal pre-pregnancy BMI, GWG, and placental weight are determinants of neonatal birth weight percentile, while a connection with maternal nutrition profiles was not found.

Extensive Placental Methylation Profiling in Normal Pregnancies.

The placental methylation pattern is crucial for the regulation of genes involved in trophoblast invasion and placental development, both key events for fetal growth. We investigated LINE-1 methylation and methylome profiling using a methylation EPIC array and the targeted methylation sequencing of 154 normal, full-term pregnancies, stratified by birth weight percentiles. LINE-1 methylation showed evidence of a more pronounced hypomethylation in small neonates compared with normal and large for gestational age. Genome-wide methylation, performed in two subsets of pregnancies, showed very similar methylation profiles among cord blood samples while placentae from different pregnancies appeared very variable. A unique methylation profile emerged in each placenta, which could represent the sum of adjustments that the placenta made during the pregnancy to preserve the epigenetic homeostasis of the fetus. Investigations into the 1000 most variable sites between cord blood and the placenta showed that promoters and gene bodies that are hypermethylated in the placenta are associated with blood-specific functions, whereas those that are hypomethylated belong mainly to pathways involved in cancer. These features support the functional analogies between a placenta and cancer. Our results, which provide a comprehensive analysis of DNA methylation profiling in the human placenta, suggest that its peculiar dynamicity can be relevant for understanding placental plasticity in response to the environment.

Fetal Oxygen and Glucose Consumption in Human Pregnancy Complicated by Fetal Growth Restriction.

In healthy pregnancy, glucose and oxygen availability are essential for fetal growth and well being. However, how substrate delivery and fetal uptake are affected in human pregnancy complicated by fetal growth restriction (FGR) is still unknown. Here, we show that the human FGR fetus has a strikingly reduced umbilical uptake of both oxygen and glucose. In 30 healthy term and 32 FGR human pregnancies, umbilical volume flow (Qumb) and parallel umbilical vein (uv) and artery (ua) blood samples were obtained at elective Cesarean section to calculate fetal glucose and oxygen uptake as Qumb · Δ (uv-ua) differences. Umbilical blood flow was significantly lower in FGR pregnancy (-63%; P<0.001) but not when normalized for fetal body weight. FGR pregnancy had significantly lower umbilical oxygen delivery and uptake, both as absolute values (delivery: -78%; uptake: -78%) and normalized (delivery: -50%; uptake: -48%) for fetal body weight (all P<0.001). Umbilical glucose absolute delivery and uptake were significantly reduced (delivery: -68%; uptake: -72%) but only glucose uptake was decreased when normalized for fetal body weight (-30%; P<0.05). The glucose/oxygen quotient was significantly increased (+100%; P<0.05) while glucose clearance was significantly decreased (71%; P<0.001) in FGR pregnancy (both P<0.05). The human fetus in FGR pregnancy triggers compensatory mechanisms to reduce its metabolic rate, matching the proportion of substrate consumption relative to oxygen delivery as a survival strategy during complicated pregnancy.

Risk factors for postpartum hemorrhage in a cohort of 6011 Italian women.

INTRODUCTION: Postpartum hemorrhage is responsible for 25% of maternal pregnancy-related deaths and it is the first cause of maternal morbidity and mortality worldwide. OBJECTIVE: To define the prevalence of postpartum hemorrhage and associated risk factors after vaginal birth and to develop a risk model that improves postpartum hemorrhage prediction. PATIENTS AND METHODS: All women who underwent a vaginal delivery at the Obstetric Unit of a large University hospital in Milan (Italy) between July 2007 and September 2009 were enrolled. Postpartum hemorrhage was defined as ≥ 500 mL blood loss. A nomogram tailored to predict postpartum hemorrhage was developed, summarizing the impact of each covariate on the probability of postpartum hemorrhage. RESULTS: 6011 women were studied (24% had blood loss ≥ 500 mL and 4.8% ≥ 1000 mL). Nulliparity, episiotomy, retained placenta and high neonatal body weight were confirmed as risk factors for postpartum hemorrhage. The odds ratio of postpartum hemorrhage was 0.86 (95%CI 0.78-0.90) for each 1 gr/dL increase in ante-partum hemoglobin. An extensive internal validation of the developed nomogram demonstrated a good stability of the risk model. CONCLUSIONS: Low ante-partum hemoglobin is a new potentially modifiable risk factor for postpartum hemorrhage. A nomogram to predict the probability of postpartum hemorrhage is now available for external validation.

Estimation of fetal oxygen uptake in human term pregnancies.

OBJECTIVE: Umbilical oxygen (O(2)) uptake is a parameter of basic physiologic interest. It has been extensively studied in chronically catheterized animals but very few data have been obtained acutely in humans. Recent developments in ultrasound technology allow the estimation of umbilical venous blood flow in utero. METHODS: In all, 26 normal term pregnancies were studied at the time of elective cesarean section in order to evaluate fetal O(2) uptake as the product of umbilical blood flow and umbilical O(2) veno-arterial difference. An ultrasound evaluation was performed within 1 h from delivery: umbilical vein area and flow velocity were recorded to calculate umbilical vein volume flow (Q(umb)). Blood samples from the umbilical vein (uv) and artery (ua) were obtained at the time of fetal extraction for respiratory gases and acid-base evaluation. RESULTS: Umbilical O(2) uptake was calculated as Q(umb) • (uv-ua)O(2) content: an average value of 0.84 ± 0.40 mmol/min was obtained. Umbilical O(2) uptake per kg was 0.25 ± 0.12 mmol/kg/min, significantly related to fetal O(2) delivery. CONCLUSIONS: We estimated umbilical blood flow by ultrasound and we measured umbilical O(2) uptake at term obtaining a value of umbilical O(2) uptake/kg similar to what previously reported in human pregnancies and chronically catheterized animals.

Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy.

OBJECTIVE: The objective of the study was to determine the feasibility of detecting fetal brain lactate, a marker of fetal metabolic acidemia, using a noninvasive technique, proton magnetic resonance spectroscopy ((1)H MRS), in intrauterine growth-restricted (IUGR) fetuses. STUDY DESIGN: In vivo human fetal brain lactate detection was determined by (1)H MRS in 5 fetuses with IUGR. Oxygenation and acid-base balance data were obtained at birth. RESULTS: (1)H MRS analysis showed the presence of a lactate peak in the brain of the most severely affected IUGR fetus, with abnormal umbilical artery Doppler and fetal heart rate tracing. This finding was consistent with the low oxygen content and high lactic acid concentration observed in umbilical blood obtained at delivery. CONCLUSION: (1)H MRS allows the noninvasive detection of cerebral lactate in IUGR fetuses. Lactate detected by (1)H MRS may represent a possible marker of in utero cerebral injury or underperfusion.

Relationship between in utero sonographic evaluation and subcutaneous plicometry after birth in infants with intrauterine growth restriction: an exploratory study.

BACKGROUND: Intrauterine growth restriction (IUGR) is associated with several medical complications before and after delivery. The aim of this study was to evaluate the concordance between the fetal ultrasonographic measurement of subcutaneous tissue thicknesses and the skinfold thicknesses assessment in intrauterine growth restricted newborns. METHODS: We designed an exploratory study. Fetal ultrasonographic measurement of subcutaneous tissue thicknesses, according to Bernstein's and Galan's method, and neonatal skinfold thicknesses were evaluated in 13 intrauterine growth restricted newborns within 4 hours before delivery and on the first day of life, respectively. Concordance between fetal and neonatal measurements was assessed using the Lin's correlation coefficient and the Bland-Altman method. RESULTS: The data obtained by the measurements of neonatal skinfold thicknesses was significantly correlated with the prenatal measurements (Lin's coefficients, arm: 0.60; subscapular: 0.72; abdomen: 0.51). Bland-Altman analysis showed moderate agreement between the fetal ultrasonographic measurement of subcutaneous tissue thicknesses and the neonatal skinfold thicknesses assessment. CONCLUSIONS: The present study provides preliminary evidence that fetal sonographic measurements may represent additional indices of intrauterine growth restriction.

Hormonal and metabolic factors associated with variations in insulin sensitivity in human pregnancy.

OBJECTIVE: The objective of this study was to determine maternal hormonal and metabolic factors associated with insulin sensitivity in human pregnancy. RESEARCH DESIGN AND METHODS: This was a prospective observational cross-sectional study of 180 normal pregnant women, using samples collected at the time of a blinded oral glucose tolerance test (OGTT) between 24 and 32 weeks' gestation as an ancillary to the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The study was conducted at two public university teaching hospitals, Cleveland, Ohio, and Brisbane, Australia. Fasting maternal serum cholesterol, triglycerides, free fatty acids, insulin, leptin, tumor necrosis factor-alpha, placental growth hormone (PGH), insulin-like growth factors (IGFs) 1 and 2, and insulin-like growth factor binding proteins (IGFBPs) 1 and 3 were assayed. Correlation and multiple regression analyses were used to determine factors associated with maternal insulin sensitivity (IS) estimated using both OGTT-derived (IS(OGTT)) and fasting (using the homeostasis model assessment [HOMA]; IS(HOMA)) insulin and glucose concentrations. RESULTS: Insulin sensitivity correlated (r = x and y for IS(OGTT) and IS(HOMA,) respectively) with fasting maternal serum leptin (-0.44 and -0.52), IGFBP1 (0.42 and 0.39), and triglycerides (-0.31 and -0.27). These factors were significantly associated with insulin sensitivity in multiple regression analyses (adjusted R(2) 0.44 for IS(OGTT) and IS(HOMA)). These variables explained more than 40% of the variance in estimates of insulin sensitivity. CONCLUSIONS: Maternal hormonal and metabolic factors related to the placenta, adipose tissue, and the growth hormone axis are associated with the variation in insulin sensitivity seen during normal human pregnancy.

Estimates of insulin sensitivity using glucose and C-Peptide from the hyperglycemia and adverse pregnancy outcome glucose tolerance test.

OBJECTIVE To determine if glucose and C-peptide values obtained as part of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study could be used to estimate insulin sensitivity during late pregnancy. RESEARCH DESIGN AND METHODS A total of 78 women enrolled in the HAPO study were recruited for this ancillary study. Venous plasma samples were drawn after an 8- to 10-h fast (time 0) and at 30, 60, 90, and 120 min after a 75-g glucose challenge, which was performed at 24-32 weeks' gestation. Samples were analyzed for plasma glucose, insulin, and C-peptide. Insulin sensitivity was estimated using the established Matsuda and DeFronzo insulin sensitivity index for oral glucose tolerance tests (IS(OGTT)). Insulin sensitivity was also calculated from two other commonly used indexes of insulin sensitivity (that for homeostasis model assessment [IS(HOMA)] and that for quantitative insulin sensitivity check index [IS(QUICKI)]). A new insulin sensitivity index was calculated using the glucose and C-peptide concentrations at 0 and 60 min to derive IS(HOMA C-pep), IS(QUICKI C-pep), and IS(OGTT C-pep). These indexes were then correlated with insulin sensitivity estimated from the IS(OGTT). RESULTS The strongest correlation with the IS(OGTT) was obtained for IS(OGTT C-pep) (r = 0.792, P < 0.001). Further, the correlations of IS(HOMA) (C-pep) and IS(QUICKI C-pep) with IS(OGTT) were also significant (r = 0.676, P < 0.001 and r = 0.707, P < 0.001, respectively). CONCLUSIONS These data suggest that calculated IS(OGTT C-pep) is an excellent predictor of insulin sensitivity in pregnancy and can be used to estimate insulin sensitivity in over 25,000 women participating in the HAPO study.

Maternal and fetal fatty acid profile in normal and intrauterine growth restriction pregnancies with and without preeclampsia.

The aim of this study was to evaluate maternal and fetal lipid profile in intrauterine growth restriction (IUGR) pregnancies with and without preeclampsia (PE). Thirteen normal pregnancies studied during the third trimester (control M) and 29 at elective cesarean section (control CS) were compared with 18 pregnancies complicated by IUGR (IUGR only) and with seven pregnancies complicated by both IUGR and PE (IUGR-PE). Total plasma fatty acids, triglycerides, cholesterol, and nonesterified fatty acids (NEFA) were determined in maternal and fetal plasma. Nutritional intake was analyzed. IUGR only mothers had lower percentage of linoleic acid (LA) and higher arachidonic acid (AA) than controls, partly explained by higher AA dietary intake. Higher levels of NEFA were observed both in IUGR only and in IUGR-PE mothers whereas triglyceride levels were increased in IUGR-PE mothers only. In IUGR-PE fetuses, LA and AA were significantly decreased, whereas triglyceride and NEFA concentrations were significantly increased compared with normal fetuses. In conclusion, IUGR only is associated with altered fatty acids profile not completely accounted by dietary changes. We hypothesize that the differences observed in IUGR with PE for triglycerides and other lipids could be related to a difference in maternal phenotype.

Evaluation of fetal growth and fetal well-being.

This article reviews the actual knowledge and future developments of ultrasound techniques for the evaluation of fetal growth and well-being. Sonography allows the visualization of the fetus in utero and is utilized worldwide for the evaluation of fetal growth and well-being. Fetal biometry assessment is performed in the second half of pregnancy when deviations of fetal growth can be best recognized through alterations of fetal abdominal circumference growth. Doppler velocimetry of utero-placental vessels identifies alterations of placental perfusion and is valuable in the assessment of fetal brain, heart, and liver perfusion, thus being utilized in the timing of delivery. Recently, three-dimensional ultrasound evaluation of fetal organs and placenta is being developed.

Activation of phospholipase A2 is associated with generation of placental lipid signals and fetal obesity.

CONTEXT: Obesity and diabetes during pregnancy are associated with increased insulin resistance and higher neonatal adiposity. In turn, insulin resistance triggers inflammatory pathways with accumulation of placental cytokines. OBJECTIVE: To determine placental signals that translate into development of excess adipose tissue, we investigated the role of phospholipases A2 (PLA2) as targets of inflammatory mediators. SETTING: The study was conducted at Case Western Reserve University, Department of Reproductive Biology. SUBJECTS: Volunteers gave informed written consent in accordance with the Institutional Review Board guidelines. Placenta and cord blood samples were obtained at the time of elective cesarean section in 15 term pregnancies. INTERVENTION: Neonatal anthropometric measurements were performed within 48 h of delivery. Placentas were grouped based on neonatal percentage body fat as obese (body fat > or = 16%) and lean control (body fat < or = 8%). MAIN OUTCOME MEASURES: The primary outcomes were placenta PLA2 expression and fatty acid concentration. RESULTS: Expression of PLA2G2A and PLA2G5, the main placenta phospholipases, was greater (P < 0.05) in placenta of obese compared with control neonates and was associated with increased 20:3 and 20:5 omega-3 polyunsaturated fatty acids. TNF-alpha and leptin content was increased 3-fold in placenta of obese neonates. TNF-alpha and leptin both induced a time-dependent activation of PLA2G2 and PLA2G5 in placental cells. CONCLUSION: Accumulation of omega-3 fatty acids through secretory PLA2 activation is associated with high neonatal adiposity. We propose that the generation of placental lipid mediators through TNF-alpha and leptin stimulation represents a key mechanism to favor excess fetal fat accretion.

Maternal interleukin-6: marker of fetal growth and adiposity.

Fetal overgrowth and higher adiposity are hallmarks of pregnancy with maternal obesity and poor glucose tolerance, two conditions associated with decreased maternal insulin sensitivity. In non-pregnant individuals, adipokines, vasoactive peptides, and components of the immune system crosstalk with metabolic factors to generate signals triggering obesity and impaired insulin action. We have investigated circulating maternal and fetal cytokines and growth-factors as potential biochemical markers of fetal adiposity. Mothers and neonates were classified into three tertiles (T1-T3) using total neonatal fat mass as the outcome with 309 +/- 25 g in T1, 478 +/- 40 g in T2, and 529 +/- 39 g in T3. Umbilical cord endothelin-1 (ET-1), C-peptide, and leptin were higher in T3 and T2 versus T1. Only cord leptin was strongly associated with fetal fat mass (P < .01), whereas neonatal lean body mass was negatively correlated with maternal insulin-like growth factor binding protein-I (IGFBP-I) (r = -0.53, P < .04). This study shows an association between increased fetal adiposity and maternal systemic interleukin-6 (IL-6). No such correlation was found with factors circulating in cord blood, suggesting that the stimuli favoring fetal fat accretion derive from maternal or placental sources rather than from the fetus.

eNOS, COX-2, and prostacyclin production are impaired in endothelial cells from diabetics.

The vascular endothelium is a well-recognized target of damage for factors leading to increased cardiovascular risk. Among the agents playing an important role in cardiovascular homeostasis, nitric oxide and prostacyclin represent key markers of endothelial integrity. In the present work, we report for the first time the reduced expression of both endothelial nitric oxide synthase and cyclooxygenase-2 (COX-2) proteins, as well as decreased prostacyclin production, in unstimulated human endothelial cells from insulin-dependent diabetic mothers when compared to cells from non-diabetic, control subjects. According to a major role of COX-2 as a source of prostacyclin production even in unstimulated endothelial cells, prostacyclin production was concentration-dependently inhibited by the selective COX-2 inhibitor SC236. Overall, our results suggest a possible link between reduced endothelial COX-2 and NO-synthase expression and the increased risk of cardiovascular diseases affecting diabetic patients, and point to the use of endothelial cells from diabetic patients as a tool for investigating early dysfunction in pathological endothelium.

Fetal nutrition: a review.

Knowledge of fetal nutrient supply has greatly increased in the last decade due to the availability of fetal blood samples obtained under relatively steady-state conditions. These studies, together with studies utilizing stable isotope methodologies, have clarified some aspects of the supply of the major nutrients for the fetus such as glucose, amino acids and fatty acids. At the same time, the relevance of intrauterine growth has been recognized not only for the well-being of the neonate and child, but also for later health in adulthood. The major determinants of fetal nutrient availability are maternal nutrition and metabolism together with placental function and metabolism. The regulation of the rate of intrauterine growth is the result of complex interactions between genetic inheritance, endocrine environment and availability of nutrients to the fetus.

Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus.

OBJECTIVE: This study was undertaken to compare amino acid concentrations in normal pregnancies and pregnancies with gestational diabetes (GDM), a condition associated with altered fetal growth. STUDY DESIGN: Maternal and fetal amino acids were evaluated by high-performance liquid chromatograph at the time of delivery in 16 normal and 17 GDM pregnancies. Fetal weights were not different, but placental weights were significantly higher and fetal/placental weight ratios were significantly lower in GDM compared with normal. RESULTS: Ornithine was significantly increased in GDM mothers. In umbilical vein and artery of GDM significant increases were observed for valine, methionine, phenylalanine, isoleucine, leucine, ornithine, glutamate, proline, and alanine, whereas glutamine was significantly decreased. CONCLUSION: Placental amino acid exchange is altered in GDM pregnancies. Moreover, the changes observed for glutamine and glutamate in the umbilical samples suggest that in GDM the fetal hepatic production of glutamate is increased, likely as a consequence of the endocrine changes in the fetal compartment.

Excess of amniotic fluid: pathophysiology, correlated diseases and clinical management.

The evaluation of amniotic fluid volume represents, together with the evaluation of fetal growth, one of the most important indicators of fetal wellbeing. Amniotic fluid is produced by fetal urines with small aliquots from fetal membranes and lung fluids. The main determinant of its turnover is fetal swallowing together with a small absorption through fetal skin and membranes. The pathologic conditions that lead to an excess of amniotic fluid are represented by excessive production or by a reduction of the physiologic turnover. The most frequent cause is gestational diabetes. This complication can be diagnosed in 2-3% of pregnancies, as a result of increased insulin resistance, most frequently found in association with risk factors such as high maternal BMI. Placental hormones, such as HPL, act indeed to increase insulin resistance and can therefore lead to post-prandial hyperglycemia in predisposed mothers. Maternal hyperglicemia leads in turn to fetal hyperglycemia and fetal hyperinsulinemia. Increased amniotic fluid volume is not a constant feature, being associated with the most severe cases, but its evaluation is very useful in the clinical management. The resulting increase in uterine volume, also related to accelerated fetal growth, is a potential cause of premature delivery, a severe complication also considering the delay in fetal lung maturation observed with fetal hyperinsulinemia. The evaluation of the degree of polyhydramnios has to be pursued by ultrasound. Precise diagnostic steps must be followed in order to rule out other potentially associated causes. Amongst these, malformations of the intestinal tract, such as hesophageal atresia, that are associated with decreased or absent fetal swallowing, must be considered. The clinical workout must therefore include an ultrasound evaluation of fetal morphology together with an oral glucose tolerance test. The therapeutic approach will be defined according to the definition of the underlying cause. Many cases will benefit from bedrest, tocolysis and induction of lung maturation.

Gestational diabetes induces placental genes for chronic stress and inflammatory pathways.

A physiological state of insulin resistance is required to preferentially direct maternal nutrients toward the feto-placental unit, allowing adequate growth of the fetus. When women develop gestational diabetes mellitus (GDM), insulin resistance is more severe and disrupts the intrauterine milieu, resulting in accelerated fetal development with increased risk of macrosomia. As a natural interface between mother and fetus, the placenta is the obligatory target of such environmental changes. However, the molecular basis for the imbalance that leads to fetal, neonatal, and adult metabolic compromises is not well understood. We report that GDM elicits major changes in the expression profile of placental genes with a prominent increase in markers and mediators of inflammation. Within the 435 transcripts reproducibly modified, genes for stress-activated and inflammatory responses represented the largest functional cluster (18.5% of regulated genes). Upregulation of interleukins, leptin, and tumor necrosis factor-alpha receptors and their downstream molecular adaptors indicated an activation of pathways recruiting stress-activated protein/c-Jun NH(2)-terminal kinases. Transcriptional activation of extracellular matrix components and angiogenic activators pointed to a major structural reorganization of the placenta. Thus, placental transcriptome emerges as a primary target of the altered environment of diabetic pregnancy. The genes identified provide the basis to elucidate links between inflammatory pathways and GDM-associated insulin resistance.