Fetal Growth versus Birthweight: The Role of Placenta versus Other Determinants

in utero. We aimed to study the effects of maternal characteristics on both birthweight and fetal growth in third trimester and introduce placental weight as a possible determinant of both birthweight and fetal growth in third trimester.The STORK study is a prospective cohort study including 1031 healthy pregnant women of Scandinavian heritage with singleton pregnancies. Maternal determinants (age, parity, body mass index (BMI), gestational weight gain and fasting plasma glucose) of birthweight and fetal growth estimated by biometric ultrasound measures were explored by linear regression models. Two models were fitted, one with only maternal characteristics and one which included placental weight.Placental weight was a significant determinant of birthweight. Parity, BMI, weight gain and fasting glucose remained significant when adjusted for placental weight. Introducing placental weight as a covariate reduced the effect estimate of the other variables in the model by 62% for BMI, 40% for weight gain, 33% for glucose and 22% for parity. Determinants of fetal growth were parity, BMI and weight gain, but not fasting glucose. Placental weight was significant as an independent variable. Parity, BMI and weight gain remained significant when adjusted for placental weight. Introducing placental weight reduced the effect of BMI on fetal growth by 23%, weight gain by 14% and parity by 17%.In conclusion, we find that placental weight is an important determinant of both birthweight and fetal growth. Our findings indicate that placental weight markedly modifies the effect of maternal determinants of both birthweight and fetal growth. The differential effect of third trimester glucose on birthweight and growth parameters illustrates that birthweight and fetal growth are not identical entities

Scaling of the surface vasculature on the human placenta

The networks of veins and arteries on the chorionic plate of the human placenta are analyzed in terms of Voronoi cells derived from these networks. Two groups of placentas from the United States are studied: a population cohort with no prescreening, and a cohort from newborns with an elevated risk of developing autistic spectrum disorder. Scaled distributions of the Voronoi cell areas in the two cohorts collapse onto a single distribution, indicating common mechanisms for the formation of the complete vasculatures, but which have different levels of activity in the two cohorts

Maternal risk factors for abnormal placental growth: The national collaborative perinatal project

<p>Abstract</p> <p>Background</p> <p>Previous studies of maternal risk factors for abnormal placental growth have focused on placental weight and placental ratio as measures of placental growth. We sought to identify maternal risk factors for placental weight and two neglected dimensions of placental growth: placental thickness and chorionic plate area.</p> <p>Methods</p> <p>We conducted an analysis of 24,135 mother-placenta pairs enrolled in the National Collaborative Perinatal Project, a prospective cohort study of pregnancy and child health. We defined growth restriction as < 10^thpercentile and hypertrophy as > 90^thpercentile for three placental growth dimensions: placental weight, placental thickness and chorionic plate area. We constructed parallel multinomial logistic regression analyses to identify (a) predictors of restricted growth (vs. normal) and (b) predictors of hypertrophic growth (vs. normal).</p> <p>Results</p> <p>Black race was associated with an increased likelihood of growth restriction for placental weight, thickness and chorionic plate area, but was associated with a reduced likelihood of hypertrophy for these three placental growth dimensions. We observed an increased likelihood of growth restriction for placental weight and chorionic plate area among mothers with hypertensive disease at 24 weeks or beyond. Anemia was associated with a reduced likelihood of growth restriction for placental weight and chorionic plate area. Pre-pregnancy BMI and pregnancy weight gain were associated with a reduced likelihood of growth restriction and an increased likelihood of hypertrophy for all three dimensions of placental growth.</p> <p>Conclusion</p> <p>Maternal risk factors are either associated with placental growth restriction or placental hypertrophy not both. Our findings suggest that the placenta may have compensatory responses to certain maternal risk factors suggesting different underlying biological mechanisms.</p

Acute Histologic Chorioamnionitis at Term: Nearly Always Noninfectious

Background: The link between histologic acute chorioamnionitis and infection is well established in preterm deliveries, but less well-studied in term pregnancies, where infection is much less common. Methodology/Principal Findings We conducted a secondary analysis among 195 low-risk women with term pregnancies enrolled in a randomized trial. Histologic and microbiologic evaluation of placentas included anaerobic and aerobic cultures (including mycoplasma/ureaplasma species) as well as PCR. Infection was defined as ≥1,000 cfu of a single known pathogen or a ≥2 log difference in counts for a known pathogen versus other organisms in a mixed culture. Placental membranes were scored and categorized as: no chorioamnionitis, Grade 1 (subchorionitis and patchy acute chorioamnionitis), or Grade 2 (severe, confluent chorioamnionitis). Grade 1 or grade 2 histologic chorioamnionitis was present in 34% of placentas (67/195), but infection was present in only 4% (8/195). Histologic chorioamnionitis was strongly associated with intrapartum fever >38°C [69% (25/36) fever, 26% (42/159) afebrile, P<.0001]. Fever occurred in 18% (n = 36) of women. Most febrile women [92% (33/36)] had received epidural for pain relief, though the association with fever was present with and without epidural. The association remained significant in a logistic regression controlling for potential confounders (OR = 5.8, 95% CI = 2.2,15.0). Histologic chorioamnionitis was also associated with elevated serum levels of interleukin-8 (median = 1.3 pg/mL no histologic chorioamnionitis, 1.5 pg/mL Grade 1, 2.1 pg/mL Grade 2, P = 0.05) and interleukin-6 (median levels = 2.2 pg/mL no chorioamnionitis, 5.3 pg/mL Grade 1, 24.5 pg/mL Grade 2, P = 0.02) at admission for delivery as well as higher admission WBC counts (mean = 12,000cells/mm$^3$ no chorioamnionitis, 13,400cells/mm$^3$ Grade 1, 15,700cells/mm$^3$ Grade 2, P = 0.0005). Conclusion/Significance: Our results suggest histologic chorioamnionitis at term most often results from a noninfectious inflammatory process. It was strongly associated with fever, most of which was related to epidural used for pain relief. A more ‘activated’ maternal immune system at admission was also associated with histologic chorioamnionitis

Preterm Birth in Caucasians Is Associated with Coagulation and Inflammation Pathway Gene Variants

Spontaneous preterm birth (<37 weeks gestation—PTB) occurs in ∼12% of pregnancies in the United States, and is the largest contributor to neonatal morbidity and mortality. PTB is a complex disease, potentially induced by several etiologic factors from multiple pathophysiologic pathways. To dissect the genetic risk factors of PTB a large-scale high-throughput candidate gene association study was performed examining 1536 SNP in 130 candidate genes from hypothesized PTB pathways. Maternal and fetal DNA from 370 US Caucasian birth-events (172 cases and 198 controls) was examined. Single locus, haplotype, and multi-locus association analyses were performed separately on maternal and fetal data. For maternal data the strongest associations were found in genes in the complement-coagulation pathway related to decidual hemorrhage in PTB. In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB. These include factor V (FV) that was previously associated with PTB, factor VII (FVII), and tissue plasminogen activator (tPA). The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30×10−3) and genotypic association (p = 2.0×10−6) with PTB. The odds ratio (OR) for this SNP was 2.80 [CI 1.77–4.44] for a recessive model. Given that 6 of 8 markers in tPA were statistically significant, sliding window haplotype analyses were performed and revealed an associating 4 marker haplotype in tPA (p = 6.00×10−3). The single strongest effect in fetal DNA was observed in the inflammatory pathway at rs17121510 in the interleukin-10 receptor antagonist (IL-10RA) gene for allele (p = 0.01) and genotype (p = 3.34×10−4). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15–3.19] (p = 2.00×10−3). Finally, exploratory multi-locus analyses in the complement and coagulation pathway were performed and revealed a potentially significant interaction between a marker in FV (rs2187952) and FVII (rs3211719) (p<0.001). These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB

Differences in Gene Expression between First and Third Trimester Human Placenta: A Microarray Study

BACKGROUND: The human placenta is a rapidly developing organ that undergoes structural and functional changes throughout the pregnancy. Our objectives were to investigate the differences in global gene expression profile, the expression of imprinted genes and the effect of smoking in first and third trimester normal human placentas. MATERIALS AND METHODS: Placental samples were collected from 21 women with uncomplicated pregnancies delivered at term and 16 healthy women undergoing termination of pregnancy at 9-12 weeks gestation. Placental gene expression profile was evaluated by Human Genome Survey Microarray v.2.0 (Applied Biosystems) and real-time polymerase chain reaction. RESULTS: Almost 25% of the genes spotted on the array (n = 7519) were differentially expressed between first and third trimester placentas. Genes regulating biological processes involved in cell proliferation, cell differentiation and angiogenesis were up-regulated in the first trimester; whereas cell surface receptor mediated signal transduction, G-protein mediated signalling, ion transport, neuronal activities and chemosensory perception were up-regulated in the third trimester. Pathway analysis showed that brain and placenta might share common developmental routes. Principal component analysis based on the expression of 17 imprinted genes showed a clear separation of first and third trimester placentas, indicating that epigenetic modifications occur throughout pregnancy. In smokers, a set of genes encoding oxidoreductases were differentially expressed in both trimesters. CONCLUSIONS: Differences in global gene expression profile between first and third trimester human placenta reflect temporal changes in placental structure and function. Epigenetic rearrangements in the human placenta seem to occur across gestation, indicating the importance of environmental influence in the developing feto-placental unit

Multidimensional Proteomics Analysis of Amniotic Fluid to Provide Insight into the Mechanisms of Idiopathic Preterm Birth

Though recent advancement in proteomics has provided a novel perspective on several distinct pathogenetic mechanisms leading to preterm birth (inflammation, bleeding), the etiology of most preterm births still remains elusive. We conducted a multidimensional proteomic analysis of the amniotic fluid to identify pathways related to preterm birth in the absence of inflammation or bleeding.A proteomic fingerprint was generated from fresh amniotic fluid using surface-enhanced laser desorbtion ionization time of flight (SELDI-TOF) mass spectrometry in a total of 286 consecutive samples retrieved from women who presented with signs or symptoms of preterm labor or preterm premature rupture of the membranes. Inflammation and/or bleeding proteomic patterns were detected in 32% (92/286) of the SELDI tracings. In the remaining tracings, a hierarchical algorithm was applied based on descriptors quantifying similarity/dissimilarity among proteomic fingerprints. This allowed identification of a novel profile (Q-profile) based on the presence of 5 SELDI peaks in the 10-12.5 kDa mass area. Women displaying the Q-profile (mean+/-SD, gestational age: 25+/-4 weeks, n = 40) were more likely to deliver preterm despite expectant management in the context of intact membranes and normal amniotic fluid clinical results. Utilizing identification-centered proteomics techniques (fluorescence two-dimensional differential gel electrophoresis, robotic tryptic digestion and mass spectrometry) coupled with Protein ANalysis THrough Evolutionary Relationships (PANTHER) ontological classifications, we determined that in amniotic fluids with Q-profile the differentially expressed proteins are primarily involved in non-inflammatory biological processes such as protein metabolism, signal transduction and transport.Proteomic profiling of amniotic fluid coupled with non-hierarchical bioinformatics algorithms identified a subgroup of patients at risk for preterm birth in the absence of intra-amniotic inflammation or bleeding, suggesting a novel pathogenetic pathway leading to preterm birth. The altered proteins may offer opportunities for therapeutical intervention and future drug development to prevent prematurity

Maternal Perception of Reduced Fetal Movements Is Associated with Altered Placental Structure and Function

Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). DFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency. To date there have been no studies of placental structure in cases of DFM.To determine whether maternal perception of reduced fetal movements (RFM) is associated with abnormalities in placental structure and function.Placentas were collected from women with RFM after 28 weeks gestation if delivery occurred within 1 week. Women with normal movements served as a control group. Placentas were weighed and photographs taken. Microscopic structure was evaluated by immunohistochemical staining and image analysis. System A amino acid transporter activity was measured as a marker of placental function. Placentas from all pregnancies with RFM (irrespective of outcome) had greater area with signs of infarction (3.5% vs. 0.6%; p<0.01), a higher density of syncytial knots (p<0.001) and greater proliferation index (p<0.01). Villous vascularity (p<0.001), trophoblast area (p<0.01) and system A activity (p<0.01) were decreased in placentas from RFM compared to controls irrespective of outcome of pregnancy.This study provides evidence of abnormal placental morphology and function in women with RFM and supports the proposition of a causal association between placental insufficiency and RFM. This suggests that women presenting with RFM require further investigation to identify those with placental insufficiency

A population-based study of race-specific risk for placental abruption

<p>Abstract</p> <p>Background</p> <p>Efforts to elucidate risk factors for placental abruption are imperative due to the severity of complications it produces for both mother and fetus, and its contribution to preterm birth. Ethnicity-based differences in risk of placental abruption and preterm birth have been reported. We tested the hypotheses that race, after adjusting for other factors, is associated with the risk of placental abruption at specific gestational ages, and that there is a greater contribution of placental abruption to the increased risk of preterm birth in Black mothers, compared to White mothers.</p> <p>Methods</p> <p>We conducted a population-based cohort study using the Missouri Department of Health's maternally-linked database of all births in Missouri (1989–1997) to assess racial effects on placental abruption and the contribution of placental abruption to preterm birth, at different gestational age categories (n = 664,303).</p> <p>Results</p> <p>Among 108,806 births to Black mothers and 555,497 births to White mothers, 1.02% (95% CI 0.96–1.08) of Black births were complicated by placental abruption, compared to 0.71% (95% CI 0.69–0.73) of White births (aOR 1.32, 95% CI 1.22–1.43). The magnitude of risk of placental abruption for Black mothers, compared to White mothers, increased with younger gestational age categories. The risk of placental abruption resulting in term and extreme preterm births (< 28 weeks) was higher for Black mothers (aOR 1.15, 95% CI 1.02–1.29 and aOR 1.98, 95% CI 1.58–2.48, respectively). Compared to White women delivering in the same gestational age category, there were a significantly higher proportion of placental abruption in Black mothers who delivered at term, and a significantly lower proportion of placental abruption in Black mothers who delivered in all preterm categories (p < 0.05).</p> <p>Conclusion</p> <p>Black women have an increased risk of placental abruption compared to White women, even when controlling for known coexisting risk factors. This risk increase is greatest at the earliest preterm gestational ages when outcomes are the poorest. The relative contribution of placental abruption to term births was greater in Black women, whereas the relative contribution of placental abruption to preterm birth was greater in White women.</p

Proteomics Mapping of Cord Blood Identifies Haptoglobin “Switch-On” Pattern as Biomarker of Early-Onset Neonatal Sepsis in Preterm Newborns

Intra-amniotic infection and/or inflammation (IAI) are important causes of preterm birth and early-onset neonatal sepsis (EONS). A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns.We studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3) versus GA-matched controls (n = 3). Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1(st)-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP) in newborns with EONS (presumed and culture-confirmed) independent of GA at birth and birthweight (P<0.001). Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood ("switch-on pattern") as opposed to non-EONS newborns who had near-absent "switch-off pattern" (P<0.001). Fetal Hp phenotype independently impacted Hp&HpRP. A bayesian latent-class analysis (LCA) was further used for unbiased classification of all 180 cases based on probability of "antenatal IAI exposure" as latent variable. This was then subjected to 2(nd)-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input), interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20%) versus high (≥70%) probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses lowering the number needed to harm and increasing the odds ratios for several adverse outcomes including intra-ventricular hemorrhage.Antenatal exposure to IAI results in precocious switch-on of Hp&HpRP expression. As EONS biomarker, cord blood Hp&HpRP has potential to improve the selection of newborns for prompt and targeted treatment at birth