Impaired Placentation Research Articles

First-Trimester Markers of Aneuploidy and the Prediction of Small-for-Gestational Age Fetuses

First-trimester estimates of 2 biomarkers of placental origin, pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG), are increasingly used along with ultrasound measurement of nuchal translucency thickness to screen for trisomy 21 and other aneuploidies. There are preliminary indications that reduced levels of these markers—especially PAPP-A—may help to identify at-risk pregnancies including those resulting in delivery of a small-for-gestational age (SGA) infant. The study population included singleton pregnancies with chromosomally normal fetuses that were screened at 11 to 14 weeks’ gestation. Biochemical marker levels were converted to multiples of the expected normal median (MoM) for a pregnancy of the same gestational age. Associations between levels of free β-hCG and PAPP-A and the incidence of SGA were assessed by comparing relative incidence rates at MoM cutoffs and birth weight centile cutoffs. A total of 46,262 pregnancies resulted in live births of infants weighing at or above the 10th centile, whereas 3539 others produced SGA infants weighing less than the 10th centile for gestation. The risk of an SGA infant was significantly and inversely associated with maternal serum PAPP-A MoM, but not with free β-hCG MoM. In pregnancies with PAPP-A levels below the 10th, 5th, and 3rd percentile, the incidence of SGA was 12%, 14%, and 16%, respectively, and the odds ratios for SGA were 2.70, 3.21, and 3.66, respectively. Free β-hCG levels did not predict SGA. The investigators believe that, in the presence of a normal fetal karyotype, low maternal serum levels of PAPP-A are associated with an elevated risk of subsequently delivering a SGA infant. Low levels presumably indicate impaired placentation. Present evidence warrants using low PAPP-A to help identify SGA pregnancies.

Preeclampsia Pathogenesis

Preeclampsia, a major killer of mother and fetuses, has traditionally been called the disease of theories, but research these past decades is changing all of that. Early observations related to this disorder were that all of the signs and symptoms typically resolve rapidly after the delivery of the placenta. Thus, it was natural to focus on this organ as the source of the disease. In this respect, 2 antiangiogenic proteins, overproduced in the placenta, that gain access to the maternal circulation have become candidate molecules responsible for phenotypic preeclampsia. One is soluble Fms-like tyrosine kinase-1 (sFlt1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor signaling that may regulate placental angiogenesis, and the other is soluble endoglin, a circulating coreceptor that may inhibit transforming growth factor-β1 signaling in the vasculature.1 Maternal blood levels of both of these antiangiogenic proteins are increased in preeclamptic patients compared with those in uncomplicated pregnancies weeks to months before overt signs and symptoms.1 Adenoviral overexpression of sFlt1 and soluble endoglin in rodents produces preeclampsia-like phenotypes, including severe hypertension, proteinuria, glomerular endotheliosis, and features resembling the HELLP syndrome (hemolysis, elevated liver enzymes, low platelet syndrome) in humans.2 The increased risk of preeclampsia in women with multifetal pregnancies, trisomy 13, primiparity, high altitudes, and mirror syndrome may also be explained by alterations in circulating antiangiogenic factors (reviewed in Reference 3). However, as data supporting a significant role …

Chronic Tempol Prevents Hypertension, Proteinuria, and Poor Feto-Placental Outcomes in BPH/5 Mouse Model of Preeclampsia

Recently we described a mouse model, BPH/5, that spontaneously develops the hallmark clinical features of preeclampsia. BPH/5 exhibit impaired placentation before the onset of hypertension and proteinuria, supporting a causal role for the placenta in the pathogenesis of preeclampsia. Here we tested the hypothesis that an increase in reactive oxygen species (ROS) early in pregnancy results in placental abnormalities leading to the maternal symptoms of preeclampsia. We further hypothesized that chronic antioxidant therapy would ameliorate both feto-placental abnormalities and maternal symptoms. ROS levels measured by dihydroethidium revealed significant increases in oxidative stress in BPH/5 placentas at midgestation compared with C57 controls. This increase in ROS was correlated with reduced expression and activity of cytoplasmic superoxide dismutase in early and midgestation BPH/5 placentas. These abnormalities in placental oxidant factors occurred before the onset of maternal symptoms, suggesting a possible causal link between increased ROS and maternal and feto-placental pathology in this model. In support of this, chronic treatment of BPH/5 with the superoxide dismutase-mimetic Tempol throughout gestation significantly improved fetal growth and survival. Furthermore, Tempol ameliorated pregnancy-induced increases in blood pressure and proteinuria in BPH/5 mothers. We confirmed that Tempol radical was present in plasma, and it normalized ROS levels in all placental zones in BPH/5. These data for the first time demonstrate an important causative role for increased ROS in the placenta in the pathogenesis of preeclampsia in a model that spontaneously develops the disease. The results also strongly suggest the potential utility of antioxidant therapy in treating preeclampsia.

Is three‐dimensional power Doppler ultrasound useful in the assessment of placental perfusion in normal and growth‐restricted pregnancies?

To investigate three-dimensional (3D) power Doppler ultrasound indices in the assessment of placental perfusion and their relationship to gestational age (GA), placental position and umbilical artery Doppler flow velocity waveform (FVW) patterns in normal and intrauterine growth-restricted (IUGR) pregnancies. Forty-five pregnant women at 23-37 weeks' gestation were studied, of whom 30 had IUGR and 15 were controls. Nine of the IUGR group had normal umbilical FVWs (NED), nine had abnormal patterns but positive end-diastolic velocities (PED) and 12 had absent or reversed end-diastolic velocities (AED). Placental position was assessed as being posterior, anterior or lateral. 3D power Doppler indices related to placental perfusion (vascularization index (VI), vascularization flow index (VFI) and flow index (FI)) were obtained from five different sampling sites in each placenta. VI, VFI and FI were not significantly dependent on GA or placental position. VI and VFI were significantly lower in PED and AED cases compared with controls, while FI was reduced in the AED group only. VI and VFI showed high variability between different sampling sites within each placenta, while the variability of FI was much lower. 3D power Doppler sonography can provide new insights into placental pathophysiology. FI, which identifies the most severe cases of placental impairment, appears to be the most reliable index because of its low intraplacental variability. Further studies are needed to verify its accuracy when applied in clinical practice as a substitute for or an adjunct to umbilical artery Doppler studies.

441. Renin angiotensin system polymorphisms are associated with pregnancy complications

Preeclampsia (PE), small for gestational age (SGA) and preterm birth (PTB) together affect 20% of first pregnancies. Currently there is no reliable way to identify women at risk. Polymorphims in genes in the renin angiotensin system (RAS) may be associated with impaired placentation and poor maternal response to pregnancy and hence predict risk for pregnancy complications. We aimed to determine if three functional polymorphisms in RAS genes, namely, AGT M235T, ACE (I/D) and AT1R A1166C are associated with pregnancy complications. Pregnancy trios were prospectively recruited from two public hospitals in Adelaide. Pregnancies were classified into normal (n = 110), PE (n = 26), SGA (n = 47), PE+SGA (n = 12), gestational hypertension (GH, n = 17), PTB (n = 20). PE, PE +SGA and GH were also grouped together as hypertension. Parental blood and maternal blood pressure was sampled or measured at 15 weeks gestation. Cord blood was sampled after delivery. DNA was extracted from buffy coats and genotyped using high resolution melt analyses. Maternal plasma [ACE] was measured by ELISA. Data were analysed by ANOVA and Fisher's exact test. Likelihood ratios (LR) were calculated where appropriate. Maternal ACE I/D was associated with hypertension (P = 0.001, LR = 14.8) and SGA (P = 0.019, LR = 10). Paternal AT1R A1166C was associated with PTB (P = 0.01, LR = 7.4). For ACE I/D, plasma [ACE] in women with DD was 33% and 62% higher than ID and II, respectively (both P < 0.001). Systolic blood pressure in women with DD was 6% higher than II (P = 0.04). Our data suggest that RAS polymorphisms are associated with pregnancy complications. Furthermore, maternal ACE genotype determines plasma [ACE] and affects blood pressure at 15 weeks gestation, well before symptoms manifest. Our data also suggest that paternal genotype may be important in determining risk for pregnancy complications, consistent with the role of paternity in their aetiology.

Embryonic mortality and intrauterine growth retardation (IUGR) associated with placental alterations in pregnant rats treated with methyl methanesulfonate (MMS) at the peri-implantation stage

Embryonic mortality and intrauterine growth retardation (IUGR) are induced by exposure of rodents to xenobiotic agents during the pregastrulation period of development. We examined the time course of the effects of methyl methanesulfonate (MMS), an alkylating agent, on conceptus development in order to clarify the relative roles of the embryo and the placenta in their induction. Pregnant rats were treated orally with a single dose of MMS (200 mg/kg) in the morning of gestation day (GD) 6 (peri-implantation stage). Embryonic mortality was increased on GD12 and thereafter by MMS treatment, with newly dead embryos showing placental hypoplasia at GD12. Embryo or fetal weight was also smaller for MMS-treated dams than for control dams from GD14 to GD20. The labyrinth zone and junctional zone (JZ) of the placenta were thinner in MMS-treated rats from GD12 to GD17 and from GD12 to GD20 (except for GD17), respectively. Furthermore, MMS-treated dams showed a smaller number of glycogen cells in the JZ on GD14. In contrast, the placental glycogen concentration was higher and the expression of glucose transporter 1 in the JZ remained at GD20. These results indicate that exposure of pregnant rats to MMS at the peri-implantation stage of embryogenesis affects placental development and growth. The placental impairment induced by MMS was likely responsible for the embryonic death observed 6 days after exposure of dams to this agent as well as for the IUGR of surviving embryos or fetuses throughout the gestation period.

Impaired Placentation in Fetal Alcohol Syndrome

Intrauterine growth restriction (IUGR) is one of the key features of fetal alcohol syndrome (FAS), and IUGR can be mediated by impaired placentation. Insulin-like growth factors (IGF) regulate placentation due to stimulatory effects on extravillous trophoblasts, which are highly motile and invasive. Previous studies demonstrated that extravillous trophoblasts express high levels of aspartyl-(asparaginyl) β-hydroxylase (AAH), a gene that is regulated by IGF and has a critical role in cell motility and invasion. The present study examines the hypothesis that ethanol impaired placentation is associated with inhibition of AAH expression in trophoblasts. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 37% ethanol by caloric content. Placentas harvested on gestation day 16 were used for histopathological, mRNA, and protein studies to examine AAH expression in relation to the integrity of placentation and ethanol exposure. Chronic ethanol feeding prevented or impaired the physiological conversion of uterine vessels required for expansion of maternal circulation into placenta, a crucial process for adequate placentation. Real-time quantitative RT-PCR analysis demonstrated significant reductions in IRS-1, IRS-2, and significant increases in IGF-II and IGF-II receptor mRNA levels in ethanol-exposed placentas. These abnormalities were associated with significantly reduced levels of AAH expression in trophoblastic cells, particularly within the mesometrial triangle (deep placental bed) as demonstrated by real time quantitative RT-PCR, Western blot analysis, ELISA, and immunohistochemical staining. Ethanol-impaired placentation is associated with inhibition of AAH expression in trophoblasts. This effect of chronic gestational exposure to ethanol may contribute to IUGR in FAS.

Some thoughts on the true value of ultrasound

Fetal abnormalities, premature birth and impaired placentation account for more than 90% of perinatal deaths. These problems are as common today as they were more than 30 years ago and our failure to reduce their prevalence is essentially the consequence of inadequate methods of screening and lack of effective strategies for their prevention. Extensive research in the last 20 years has now established that ultrasonography can identify the majority of affected fetuses and women at high risk for these problems. The remaining challenge is to ensure that this knowledge finds a practical application in a service for the benefit of pregnant women and forms the basis for further research to develop effective therapeutic interventions.

Transabdominal uterine arteries doppler between 11-14 weeks of gestation for prediction of outcome in high risk pregnancies

ObjectiveTo assess the value of early transabdominal uterine arteries Doppler ultrasound for prediction of gestational outcomes in pregnancies at high risk for preeclampsia.Study designObservational study. Doppler ultrasound of uterine arteries at 11-14 weeks' gestation was performed in 76 women. Presence of diastolic notch and resistance index (RI) were investigated. Abnormal uterine Doppler was defined by presence of bilateral notching or by mean RI > 0.80. Adverse outcomes evaluated were preeclampsia, fetal growth restriction, placental abruption, intrauterine death and complications associated with impaired placentation requiring delivery before 34 weeks of gestation.ResultsAmong 76 women 30 had abnormal uterine Doppler indices and 46 had normal RI and normal Doppler waveform configuration at 11-14 weeks' gestation. Abnormal uterine flow was related to a significantly higher incidence of preeclampsia (16.6% vs 0%; p= 0.0041), fetal growth restriction (26.6% vs 0%; p= 0.0002), intrauterine death (13.3% vs 0%; p= 0.0109) and iatrogenic preterm delivery (20% vs 2.15% ; p= 0.0087).Among pregnancies with normal Doppler indices no one was complicated by preeclampsia or fetal growth restriction. Normal waveform configuration had 97.8% of negative predictive value for complications requiring elective delivery before 34 weeks.ConclusionNormal Doppler indices in the first trimester are strongly related to normal outcome of pregnancy in women at high risk for preeclampsia. Results of this study support a change in the antepartum care of already identified high risk women with normal uterine Doppler waveform configuration at 11-14 weeks of gestation. ObjectiveTo assess the value of early transabdominal uterine arteries Doppler ultrasound for prediction of gestational outcomes in pregnancies at high risk for preeclampsia. To assess the value of early transabdominal uterine arteries Doppler ultrasound for prediction of gestational outcomes in pregnancies at high risk for preeclampsia. Study designObservational study. Doppler ultrasound of uterine arteries at 11-14 weeks' gestation was performed in 76 women. Presence of diastolic notch and resistance index (RI) were investigated. Abnormal uterine Doppler was defined by presence of bilateral notching or by mean RI > 0.80. Adverse outcomes evaluated were preeclampsia, fetal growth restriction, placental abruption, intrauterine death and complications associated with impaired placentation requiring delivery before 34 weeks of gestation. Observational study. Doppler ultrasound of uterine arteries at 11-14 weeks' gestation was performed in 76 women. Presence of diastolic notch and resistance index (RI) were investigated. Abnormal uterine Doppler was defined by presence of bilateral notching or by mean RI > 0.80. Adverse outcomes evaluated were preeclampsia, fetal growth restriction, placental abruption, intrauterine death and complications associated with impaired placentation requiring delivery before 34 weeks of gestation. ResultsAmong 76 women 30 had abnormal uterine Doppler indices and 46 had normal RI and normal Doppler waveform configuration at 11-14 weeks' gestation. Abnormal uterine flow was related to a significantly higher incidence of preeclampsia (16.6% vs 0%; p= 0.0041), fetal growth restriction (26.6% vs 0%; p= 0.0002), intrauterine death (13.3% vs 0%; p= 0.0109) and iatrogenic preterm delivery (20% vs 2.15% ; p= 0.0087).Among pregnancies with normal Doppler indices no one was complicated by preeclampsia or fetal growth restriction. Normal waveform configuration had 97.8% of negative predictive value for complications requiring elective delivery before 34 weeks. Among 76 women 30 had abnormal uterine Doppler indices and 46 had normal RI and normal Doppler waveform configuration at 11-14 weeks' gestation. Abnormal uterine flow was related to a significantly higher incidence of preeclampsia (16.6% vs 0%; p= 0.0041), fetal growth restriction (26.6% vs 0%; p= 0.0002), intrauterine death (13.3% vs 0%; p= 0.0109) and iatrogenic preterm delivery (20% vs 2.15% ; p= 0.0087).Among pregnancies with normal Doppler indices no one was complicated by preeclampsia or fetal growth restriction. Normal waveform configuration had 97.8% of negative predictive value for complications requiring elective delivery before 34 weeks. ConclusionNormal Doppler indices in the first trimester are strongly related to normal outcome of pregnancy in women at high risk for preeclampsia. Results of this study support a change in the antepartum care of already identified high risk women with normal uterine Doppler waveform configuration at 11-14 weeks of gestation. Normal Doppler indices in the first trimester are strongly related to normal outcome of pregnancy in women at high risk for preeclampsia. Results of this study support a change in the antepartum care of already identified high risk women with normal uterine Doppler waveform configuration at 11-14 weeks of gestation.

Increased antiangiogenic activity in early compared with late preeclampsa

PREECLAMPSA ANNA-KARIN WIKSTROM, MATTS OLOVSSON, Uppsala University, Women’s and Children’s health, Uppsala, Sweden OBJECTIVE: The antiangiogenic substance soluble VEGF receptor 1 (s-Flt1), has been suggested to be involved in the pathogenesis of preeclampsia (PE). Early onset PE is generally more aggressive in clinical practice than late onset PE, and shows a stronger association to impaired placentation. The aim of this study was to determine if the maternal s-Flt-1 levels are different in early compared to late onset disease. STUDY DESIGN: Serum samples were collected from two groups of cases:

Suramin-Restricted Blood Volume in the Placenta of Normal and Diabetic Rats is Normalized by Vitamin E Treatment

Previously maternal and fetal alterations resembling human pre-eclampsia were induced in pregnant rats by injections of the angiogenesis inhibitor Suramin. These alterations were aggravated by maternal diabetes and partly rectified by vitamin E supplementation. In the present study we evaluated the morphology of placentae and kidneys in this model. Non-diabetic and streptozotocin-induced diabetic pregnant rats of two rat strains (U and H) were treated with Suramin or saline, and given standard or vitamin E-enriched food. On gestational day 20 one placenta and the left kidney of the mother were collected for morphological and stereological analysis. In the placental trophospongium Suramin treatment caused cysts, which were further enhanced by maternal diabetes. Vitamin E treatment had no effect on the vacuolization. In the placental labyrinth of the non-diabetic rats Suramin treatment restricted maternal placental blood volume and increased the interface between maternal and fetal circulation. These changes were reversed by vitamin E treatment. Diabetes increased slightly the interface between the circulations in both rat strains. Suramin treatment decreased the interface, and vitamin E further decreased the interface in the diabetic U rats, whereas neither treatment affected the maternal-fetal interface in the diabetic H rats. The kidneys of Suramin-treated and diabetic rats were heavier compared to controls. Suramin treatment and maternal diabetes damaged renal glomeruli to a similar extent. Vitamin E treatment diminished the Suramin- and diabetes-induced glomerular damage in U rats, but not in H rats. The average cell count per glomerulus was decreased by Suramin in the U rats. Vitamin E treatment did not affect cell number per glomerulus in any group. We conclude that Suramin-injected pregnant rats constitute a valid animal model for placental dysfunction and pre-eclampsia, also from the histological perspective. The present work supports the notion that one important effect of untreated maternal diabetes may be impaired placentation, leading to oxidative stress, morphological damage, and compromised placental function.

Maternal serum concentration of soluble fms-like tyrosine kinase 1 and vascular endothelial growth factor in women with abnormal uterine artery Doppler and in those with fetal growth restriction

This study was undertaken to determine whether maternal serum concentration of the angiogenic factor vascular endothelial growth factor (VEGF) and its circulating antagonist, soluble fms-like tyrosine kinase 1 (sFlt-1), which have been implicated in the pathogenesis of preeclampsia (PE), are altered in pregnancies that subsequently develop PE and in those with established fetal growth restriction (FGR). Three groups of healthy pregnant women at 23 to 25 weeks of gestation were examined: group A (n = 42) with normal uterine artery Doppler waveforms, group B (n = 49) with abnormal uterine artery Doppler waveforms, and group C (n = 15) with abnormal Doppler results and established FGR. Comparisons between multiple groups were performed by using 1-way analysis of variance or Kruskal-Wallis test. In group C, compared with group A, the median sFlt-1 was significantly higher (P < .0001) and VEGF was lower (P < .001). Group C included 3 women who had PE develop. In group B, 19 women had a normal outcome, 13 had PE develop, and 17 had FGR develop. There were no significant differences in sFlt-1 levels between any of the subgroups of group B and group A. Maternal serum concentration of sFlt-1 in pregnancies with FGR is increased but this increase is not evident in pregnancies with impaired placentation that subsequently had either FGR or PE develop.

Superoxide scavenging improves early placental development and fetal growth and survival in a mouse model of pre‐eclampsia (PE)

We have described a mouse model of PE (BPH5) that exhibits impaired placentation prior to onset of hypertension and proteinuria. The mechanisms of placental dysfunction in BPH5 are not known. Initial studies showed that CuZnSOD activity is reduced by half in mid-gestation BPH5 placenta compared to controls (32.2±3.3 U/mg protein BPH5 vs 61.6±2.2 C57, p<0.05, n=5). Early gestation treatment of BPH5 mice with the SOD mimic Tempol (1mM in drinking water) prevented late-gestational hypertension and proteinuria. Here we hypothesized that amelioration of PE in BPH5 occurred because Tempol restored the oxidative balance in placenta. EPR studies showed significant levels of Tempol in placenta of treated BPH5 (83.7±65.9 peak height/mg protein, n=6), whereas it was undetectable in controls. Early survival of implanted conceptuses was significantly improved from 61.9±4.2% (n=23) in untreated BPH5 to 84.9±3.2% (n=47, p<0.05) in Tempol-treated BPH5. Tempol also normalized media:lumen ratios of decidual arteries in placental sections (2.47±0.3 BPH5, 1.69±0.2 BPH5 + Tempol, 1.34±0.2 C57, n=14–23, p<0.05), and this was associatedwith increases in mid-gestation placental weights (66.0±4.5 mg BPH5 vs. 95.5±6.5 BPH5 + Tempol, n=46 & 28, p<0.05). These placental changes were paralleled by normalization of term fetal weight. These results demonstrate oxidative stress plays a key role in abnormal placentation in PE, and O2.- scavenging starting early in gestation normalizes feto-placental outcomes. AHA #0510021Z

The Scottish Perinatal Neuropathology Study—clinicopathological correlation in stillbirths

To examine the neuropathology of fetuses dying before birth, to determine the timing of any brain damage seen and to ascertain clinical associations of pre-existing brain damage. Population-based observational study. All 22 delivery units within Scotland, 1995-1998. All stillborn fetuses > or =24 weeks of gestation excluding those with chromosomal abnormality or central nervous system/cardiothoracic malformation. Clinical detail was collected on all stillborn fetuses. Requests for postmortem included separate request for detailed neuropathological examination. Stillborn fetuses were classified as full term antepartum (normal growth/growth restricted), preterm antepartum (normal growth/growth restricted), intrapartum (full term/preterm), multiple births and stillborn fetuses following abruptions. Clinicopathological correlation attempted to define the timing of brain insult. Placentas were examined for each case where available. Presence of established and/or recent brain damage. RESULTS Clinical details were available for 471 stillborn fetuses, and detailed neuropathology was possible in 191 cases. Of these 191, 13 were multiple births, 9 died following abruption, 12 were intrapartum deaths and 157 were antepartum stillborn fetuses (99 preterm and 58 full term). Recent or established brain damage was seen in 66% of the entire cohort. Thirty-five percent of all cases showed well-established hypoxic damage predating the last evidence of fetal life, and this was more common in preterm fetuses (P = 0.015), those fetuses with evidence of recent damage (P < 0.001), in pregnancies complicated by pregnancy-induced hypertension (P = 0.044) and those in whom the placenta was <10th centile (P = 0.002). Brain damage is commonly seen in stillborn infants, and in around one-third of cases, damage predates the period immediately before death. Factors suggesting suboptimal placental function are associated with such damage. Early identification of placental impairment may lead to improved pregnancy outcome.

Uterine artery Doppler screening for adverse pregnancy outcome

This article reviews publications in the area of uterine artery Doppler screening that were published during the past year. Studies have shown that assessment of a woman's level of risk for pre-eclampsia by uterine artery Doppler performs better than maternal history alone. Combination of maternal history and uterine artery Doppler findings leads to even more accurate assessment of risk, and allows calculation of patient-specific risk. Combining screening with uterine artery Doppler and maternal serum biochemical markers has been explored in some studies, but data remain limited and larger prospective longitudinal studies are needed to asses the effectiveness of these techniques. A number of promising markers for development of the disease have been identified, however, including pregnancy associated plasma protein-A, inhibin-A, activin-A and fibronectin, as well as placental growth factor, vascular endothelial growth factor and soluble fms-like tyrosine kinase 1. Uterine artery Doppler has proved useful in identifying women at high and low risk for developing complications of uteroplacental insufficiency and may aid in stratifying antenatal care. In addition, it can identify women in whom biochemical markers should be measured in order to develop screening tests and aid in evaluation of the pathophysiology of impaired placentation and pre-eclampsia. Whether pharmacological intervention in women identified to be at high risk for pre-eclampsia on the basis of Doppler is effective in reducing the incidence of the disease remains to be established.

Pregnancy Characteristics and Maternal Risk of Breast Cancer

During pregnancy, serum levels of estrogen, progesterone, and other hormones are markedly higher than during other periods of life. Pregnancy hormones primarily are produced in the placenta, and signs of placental impairment may serve as indirect markers of hormone exposures during pregnancy. During pregnancy, these markers have been inconsistently associated with subsequent risk of breast cancer in the mother. To examine associations between indirect markers of hormonal exposures, such as placental weight and other pregnancy characteristics, and maternal risk of developing breast cancer. Population-based cohort study using data from the Swedish Birth Register, the Swedish Cancer Register, the Swedish Cause of Death Register, and the Swedish Register of Population and Population Changes. Women included in the Sweden Birth Register who delivered singletons between 1982 and 1989, with complete information on date of birth and gestational age. Women were followed up until the occurrence of breast cancer, death, or end of follow-up (December 31, 2001). Cox proportional hazards models were used to estimate associations between hormone exposures and risks of breast cancer. Incidence of invasive breast cancer. Of 314,019 women in the cohort, 2216 (0.7%) developed breast cancer during the follow-up through 2001, of whom 2100 (95%) were diagnosed before age 50 years. Compared with women who had placentas weighing less than 500 g in 2 consecutive pregnancies, the risk of breast cancer was increased among women whose placentas weighed between 500 and 699 g in their first pregnancy and at least 700 g in their second pregnancy (or vice versa) (adjusted hazard ratio, 1.82; 95% confidence interval [CI], 1.07-3.08), and the corresponding risk was doubled among women whose placentas weighed at least 700 g in both pregnancies (adjusted hazard ratio, 2.05; 95% CI, 1.15-3.64). A high birth weight (> or =4000 g) in 2 successive births was associated with an increased risk of breast cancer before but not after adjusting for placental weight and other covariates (adjusted hazard ratio, 1.10; 95% CI, 0.76-1.59). Placental weight is positively associated with maternal risk of breast cancer. These results further support the hypothesis that pregnancy hormones are important modifiers of subsequent maternal breast cancer risk.

TNF-receptor levels in preeclampsia—results of a longitudinal study in high-risk women

Objective. Tumor necrosis factor-alpha (TNF-α) is thought to play a role in immune activation in preeclampsia. The objective of this study was to establish if soluble TNF-receptor I (sTNF-rI) levels relate to the onset and severity of preeclampsia.Methods. Maternal plasma sTNF-rI levels were studied throughout pregnancy in 68 women with a history of severe preeclampsia or intra-uterine growth restriction (IUGR), and primigravidas with chronic hypertension. Data are presented as mean (SD) in ng/ml.Results. In the second trimester there was a significant difference in sTNF-rI levels between preeclamptic pregnancies with and without IUGR (means 1.33 (0.20) and 1.11 (0.15) respectively, p < 0.005). In severe preeclampsia with delivery before 34 weeks of gestation, sTNF-rI levels were higher than in mild preeclampsia in the second and third trimesters (means 1.40 (0.16) vs. 1.16 (0.19), p < 0.02 and 1.82 (0.47) vs. 1.42 (0.22), p < 0.05, respectively).Conclusion. sTNF-rI levels were higher in preeclampsia with fetal involvement, suggesting that increased TNF-α production in preeclampsia is related to impaired placentation rather than to the maternal syndrome.

Screening test for preeclampsia through assessment of uteroplacental blood flow and biochemical markers of oxidative stress and endothelial dysfunction

This study was undertaken to evaluate whether screening through a uterine artery (UtA) Doppler and biochemical markers of oxidative stress and endothelial dysfunction predict preeclampsia. UtA Doppler was performed at 11 to 14 and 22 to 25 weeks on 1447 asymptomatic pregnant women. Oxidative stress, endothelial dysfunction, and antiangiogenic state were assessed in women who later developed preeclampsia and normotensive controls. There was a significantly increased of UtA pulsatility index (PI), plasma levels of soluble fms-like tyrosine kinase 1 (sFlt1), PAI-1/PAI-2 ratio, and F-2 isoprostane in women who subsequently developed preeclampsia compared with control pregnancies. Multivariate logistic regression showed that increased UtA PI performed at 23 weeks was the best predictor for preeclampsia. This study demonstrates early changes in markers of impaired placentation, antiangiogenic state, oxidative stress, and endothelial dysfunction suggesting that these derangements may play a role in the pathogenesis of preeclampsia. Our data point to UtA as the best test to predict preeclampsia at 23 weeks of gestation.

Placental dysfunction in Suramin-treated rats – a new model for pre-eclampsia

Impaired placentation and oxidative stress are proposed to play major roles in the pathogenesis of placental dysfunction and pre-eclampsia. This study was carried out to evaluate if inhibited angiogenesis by Suramin injections in early pregnancy may cause a condition resembling pre-eclampsia in rats. Rats of two different Sprague–Dawley strains, U and H, were given intraperitoneal injections of Suramin or saline in early pregnancy. The outcome of pregnancy was evaluated on gestational day 20. Suramin injections caused increased blood pressure and decreased renal blood flow in the U rats. In both rat strains Suramin decreased the placental blood flow and caused fetal growth retardation. In both strains the placental concentration of the isoprostane 8- epi-PGF 2α was increased, indicating oxidative stress. The serum concentration of Endothelin-1 was increased in the U rats. The U strain had a lower basal placental blood flow, and the effects of Suramin were more pronounced in this strain. We conclude, that Suramin injections to pregnant rats cause a state of placental insufficiency, which partly resembles human pre-eclampsia. The induction of this condition is at least partly mediated by oxidative stress, and is subject to varied genetic susceptibility.

Spiral artery associated restricted growth (SPAARG): a computer model of pathophysiology resulting from low intervillous pressure having fetal programming implications

Failure of adequate trophoblastic conversion of maternal spiral arteries is associated with intrauterine growth restriction (IUGR). In addition to poor oxygen delivery, raised spiral artery resistance reduces placental intervillous pressure. An iterative type computer model was formed by linking an existing model of the fetus and a new nine cotyledon placental model. Simulation of compression cuffing of the spiral arteries to progressively restrict uteroplacental flow was performed, while observing various fetal and placental variables. Water moved to the fetus in the cotyledonary core villi, and to the mother in the outer villous layers. While the fetus could match villous capillary pressure to changes in intervillous pressure, net transplacental water movement was minimal, but when spiral artery resistance was increased sufficiently to cause mean intervillous pressure to fall below that which the fetus could match, a net flow to the mother appeared. That continued until the resulting fetal blood hemoconcentration produced a sufficient increase in colloid osmotic pressure to restrict further loss. All cells within the fetal-placental unit are then required to operate in an abnormal ionic environment, which may significantly affect systems such as the renin–angiotensin set-point, with implications for post-natal homeostasis such as control of adult blood pressure. Furthermore, in vivo, cells of the feto-placental unit respond to the increased intravascular osmotic pressure by production of intracellular osmolytes in order to match intracellular and vascular/interstitial osmotic pressures. This may explain the observed effects on postnatal water balance in growth restricted infants and could also provide a possible mechanism for the association of the systemic maternal complications associated with impaired placentation and reduced intervillus flow.