Uterine Artery Resistance Research Articles

5 17-Hydroxyprogesterone caproate improves fetal growth restriction possibly by reducing sFlt-1 and placental cytolytic NK cells in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia

Introduction Preeclampsia (PE), new onset hypertension, is characterized by decreased of nitric oxide (NO) elevated anti-angiogenic factor soluble fms-like tyrosine kinase (sFlt-1), cytolytic natural killer (NK) cells and placental ischemia predicted with increased uterine artery resistance (UARI) which are likely culprits for decreased fetal weight during PE pregnancies. Cytolytic NK are an important arm of the immune system killing tumor and infected cells by perforin-granzyme-mediated cytolysis and have been shown to be increased in PE women compared to those with normal pregnancy. Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of spontaneous preterm labor, but is not included in the current management for PE. Objectives The objective of this study was determine whether early administration of 17-OHPC could improve pregnancy outcomes in response to placental ischemia. Methods. To do so, 17-OHPC (3.32 mg/kg) was administered intraperitoneally on gestation day 15 to reduced uterine perfusion pressure (RUPP) rats, UARI was measured using Doppler ultrasound and carotid catheters were inserted on day 18. Results Blood pressure (MAP), sFlt-1, and placental cytolytic NK cells were measured on GD 19. MAP in normal pregnant (NP) rats ( n = 12) was 94 + 2, 126 + 2 in RUPP ( n = 27) and 111 + 1 mmHg in RUPP + 17-OHPC ( n = 15), p p n = 3), 0.8 + 0.03 in RUPP rats ( n = 4), which improved to 0.6 + 0.04 in RUPP + 17-OHPC ( n = 5), p p p n = 5), which was blunted to 110.2 + 11.1 pg/mL in RUPP+17-OHPC, p n = 13) but was improved to 25.5 + 5.2 μM in RUPP + 17-OHPC ( n = 5), p Conclusion Early administration of 17-OHPC improves sFtl-1, UARI, activated cytolytic NK cells, pup weight, NO bioavailability and hypertension in response to placental ischemia. Therefore, 17-OHPC should be further considered for addition to the management of PE.

THE ROLE OF SECOND TRIMESTER UTERINE ARTERY DOPPLER ULTRASOUND,INHIBIN-A AND PLACENTAL GROWTH FACTOR IN PREDICTION OF PREECLAMPSIA.

ABSTRACT Objective: to evaluate the role of second trimester uterine artery Doppler ultrasound velocimetry (UADV), maternal serum Inhibin-A andplacental growth factor (PLGF) concentrations and as predictors of preeclampsia. Study design: Cohort study. Methodology: This prospective study was conducted at Obstetrics & Gynecology department, Alazhar University hospitals, Cairo, Egypt between May 2012 and May 2014. Ninety low risk normotensive singleton pregnant women were recruited for the study. Blood samples were collected at 16- 18 weeks, centrifuged to extract the serum then stored at – 80 °C until tested for inhibin-A and free PLGF levels. At 22-24 weeks, bilateral uterine artery Doppler velocimetry were recorded. The primary outcome was preeclampsia defined as hypertension with proteinuria after 20 weeks gestation. Women who developed preeclampsia were compared against normotensive control group. Statistical analysis: Receiver operating characteristics (ROC) curves were used for detection of the sensitivity and specificity and cut off value for each predictor using SPSS version 21 for analysis (IBM Inc., Chicago, Illinois, USA). Results: Eight cases out of 90 had developed preeclampsia. Women who developed preeclampsia had significantly higher median uterine artery resistance index (UARI) (0.645 ± 0.3 vs. 0.485 ± 0.16, P = 0.009) and significantly lower median uterine artery pulsitility index (UAPI) (0.625 ± 0.24 vs. 1.0 ± 0.68 with P= 0.001) than normotensive control group.Maternal serum inhibin-A level was significantly higher in women with preeclampsia than the normotensive control group (1375 ± 1431 vs. 540 ± 1900 with P = 0.016) while level of PLGF was non-significantly lower in women with preeclampsia than the normotensive control group (275.5 ± 369 vs. 390 ± 583 with P = 0.156). ROC curves were analysed for cases and control groups, areas under the curve (AUC) was 0.709 (95% CI, 0.527– 0.891, P = 0.016) for UARI with sensitivity of 87.5%, specificity 74% at cut off value ≥ 0.5650, AUC was 0.848 (95% CI, 0.742– 0.955, P = 0.001) for UAPI with sensitivity of 80%, specificity 74% at cut off value ≤ 0.735, AUC was 0.758 (95% CI, 0.566 - 0.951, P = 0.016) for Inhibin-A with a sensitivity of 75%, specificity of 80% at cut off value of ≥ 832.5 pg/ml and finally AUC was 0.652 (95% CI, 0.447 – 0.858 and P = 0.165) for PLGF with a sensitivity of 74% and specificity of 50% at cut off value of ≤ 205 pg/ml. Conclusion: second-trimester uterine artery Doppler indices, serum Inhibin-A and PLGF and may be helpful as a predicting markers for preeclampsia. Key words: Inhibin-A, placental growth factor, Doppler indices, uterine artery, Preeclampsia.

Serum Iron and Total Iron Binding Capacity in Preeclampsia

Preeclampsia (PE) is a pregnancy-specific condition that increases maternal and infant mortality and morbidity. Exact etiology of preeclampsia is still not known but certain hypothesis suggest it may be associated with an increased vascular resistance of uterine artery and decrease in perfusion of placenta. It has been suggested that lipid peroxidation plays an important role in the etiology of preeclampsia. Iron and hematin proteins play important roles as catalysts of lipid peroxidation in tissues. The aim of study was to estimate and compare serum iron and total iron binding capacity in preeclamptic women and normal pregnant women. Study was conducted in Government Medical Hospital Miraj with 120 subjects. The studied population consisted: group I (40 normal pregnant women) and group II (80 pregnant women with preeclampsia). Serum iron and total iron binding capacity values were measured by ferrozine method. We found significantly high serum iron and significantly low total iron binding capacity in preeclamptic women as compare to normal pregnant women (p<0.001). So elevated serum iron and decreased total iron binding capacity may play an important role in the pathogenesis of preeclampsia.

Prenatal stress and hemodynamics in pregnancy: a systematic review.

Maternal prenatal stress is associated with preterm birth, intrauterine growth restriction, and developmental delay. However, the impact of prenatal stress on hemodynamics during pregnancy remains unclear. This systematic review was conducted in order to assess the quality of the evidence available to date regarding the relationship between prenatal stress and maternal-fetal hemodynamics. The PubMed/Medline, EMBASE, PsycINFO, Maternity and Infant Care, Trip, Cochrane Library, and CINAHL databases were searched using the search terms pregnancy; stress; fetus; blood; Doppler; ultrasound. Studies were eligible for inclusion if prenatal stress was assessed with standardized measures, hemodynamics was measured with Doppler ultrasound, and methods were adequately described. A specifically designed data extraction form was used. The methodological quality of included studies was assessed using well-accepted quality appraisal guidelines. Of 2532 studies reviewed, 12 met the criteria for inclusion. Six reported that prenatal stress significantly affects maternal or fetal hemodynamics; six found no significant association between maternal stress and circulation. Significant relationships between prenatal stress and uterine artery resistance (RI) and pulsatility (PI) indices, umbilical artery RI, PI, and systolic/diastolic ratio, fetal middle cerebral artery PI, cerebroplacental ratio, and umbilical vein volume blood flow were found. To date, there is limited evidence that prenatal stress is associated with changes in circulation. More carefully designed studies with larger sample sizes, repeated assessments across gestation, tighter control for confounding factors, and measures of pregnancy-specific stress will clarify this relationship.

Do knowledge of uterine artery resistance in the second trimester and targeted surveillance improve maternal and perinatal outcome? UTOPIA study: a randomized controlled trial.

To ascertain whether screening for pre-eclampsia (PE) and intrauterine growth restriction (IUGR) by uterine artery (UtA) Doppler in the second trimester of pregnancy and targeted surveillance improve maternal and perinatal outcomes in an unselected population. This was a multicenter randomized open-label controlled trial. At the routine second-trimester anomaly scan, women were assigned randomly to UtA Doppler or non-Doppler groups. Women with abnormal UtA Doppler were offered intensive surveillance at high-risk clinics of the participating centers with visits every 4 weeks that included measurement of maternal blood pressure, dipstick proteinuria, fetal growth and Doppler examination. The primary outcome was a composite score for perinatal complications, defined as the presence of any of the following: PE, IUGR, spontaneous labor < 37 weeks' gestation, placental abruption, stillbirth, gestational hypertension, admission to neonatal intensive care unit and neonatal complications. Secondary outcomes were a composite score for maternal complications (disseminated intravascular coagulation, maternal mortality, postpartum hemorrhage, pulmonary edema, pulmonary embolism, sepsis), and medical interventions (for example, corticosteroid administration and induction of labor) in patients developing placenta-related complications. In total, 11 667 women were included in the study. Overall, PE occurred in 348 (3.0%) cases, early-onset PE in 48 (0.4%), IUGR in 722 (6.2%), early-onset IUGR in 93 (0.8%) and early-onset PE with IUGR in 32 (0.3%). UtA mean pulsatility index > 90(th) percentile was able to detect 59% of early-onset PE and 60% of early-onset IUGR with a false-positive rate of 11.1%. When perinatal and maternal data according to assigned group (UtA Doppler vs non-Doppler) were compared, no differences were found in perinatal or maternal complications. However, screened patients had more medical interventions, such as corticosteroid administration (relative risk (RR), 1.79 (95% CI, 1.4-2.3)) and induction of labor for IUGR (RR, 1.36 (95% CI, 1.07-1.72)). In women developing PE or IUGR, there was a trend towards fewer maternal complications (RR, 0.46 (95% CI, 0.19-1.11)). Routine second-trimester UtA Doppler ultrasound in an unselected population identifies approximately 60% of women at risk for placental complications; however, application of this screening test failed to improve short-term maternal and neonatal morbidity and mortality. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Associations between first-trimester uterine artery Doppler velocimetry indices and adverse perinatal outcomes in women conceiving via in vitro fertilization

Aim: To explore if first-trimester uterine artery Doppler velocimetric values might predict adverse perinatal outcomes in patients conceiving via in vitro fertilization (IVF).Methods: We evaluated pregnancies in women who conceived via IVF (Group 1, n = 62) and compared these subjects to a control group (spontaneous pregnancies; Group 2, n = 53) in terms of first-trimester uterine artery Doppler velocimetric data. We explored whether these data predicted adverse perinatal outcomes (need for cesarean delivery, preterm birth, low birth weight, lower APGAR score, and need for referral to a neonatal intensive care unit [NICU]).Results: The mean age of Group 1 patients was 29.9 ± 4.7 years and that of Group 2 was 27.2 ± 4.2 years. Gestational age at birth, first-minute APGAR scores, NICU referral rate, birth weight, preterm birth rate, abortion rate, delivery type, the left-side uterine arterial systole–diastole ratio (LUASD), the left-side uterine arterial resistance index (LUARI), the right-side uterine arterial systole–diastole ratio (RUASD), and the right-side uterine arterial resistance index (RUARI) differed significantly between the two groups (all p values < 0.05). In the study group, positive correlations were evident between LUASD, LUARI, RUASD, and RUARI, preterm birth rates, and NICU referral rates. Also, birth weight correlated negatively with LUASD, LUARI, RUASD, and RUARI in the study group.Conclusions: First-trimester uterine artery Doppler velocimetric indices, including the resistance index and systole–diastole ratio, usefully predict adverse perinatal outcomes of IVF pregnancies.

Sex Steroids Modulate Uterine-Placental Vasculature: Implications for Obstetrics and Neonatal Outcomes.

Adequate blood supply to the uterine-placental region is crucial to ensure the transport of oxygen and nutrients to the growing fetus. Multiple factors intervene to achieve appropriate uterine blood flow and the structuring of the placental vasculature during the early stages of pregnancy. Among these factors, oxygen concentrations, growth factors, cytokines, and steroid hormones are the most important. Sex steroids are present in extremely high concentrations in the maternal circulation and are important paracrine and autocrine regulators of a wide range of maternal and placental functions. In this regard, progesterone and estrogens act as modulators of uterine vessels and decrease the resistance of the spiral uterine arteries. On the other hand, androgens have the opposite effect, increasing the vascular resistance of the uterus. Moreover, progesterone and estrogens modulate the synthesis and release of angiogenic factors by placental cells, which regulates trophoblastic invasion and uterine artery remodeling. In this scenario, it is not surprising that women with pregnancy-related pathologies, such as early miscarriages, preterm delivery, preeclampsia, and fetal growth restriction, exhibit altered sex steroid concentrations.

Vitamin D Lowers Blood Pressure, ET‐1 and sFlt‐1 in AT1 Autoantibody Induced Hypertension During Pregnancy

Autoantibodies to the angiotensin II type I receptor (AT1‐AA) play a role in hypertension associated with preeclampsia (PE). We found that Vitamin D (VD) reduces AT1‐AA and blood pressure (MAP) in a rat model of PE. Here we tested the hypothesis that VD would improve MAP and endothelial dysfunction markers associated with AT1‐AA during PE. We infused AT1‐AA (1:40 in saline) via osmotic minipump on gestational day (GD) 12–19 in pregnant rats. Either VD2 (270 IU/day) or VD3 (15 IU/day) were given on GD14–18 by oral gavage. Uterine artery resistance index (UARI) was measured by Doppler sonography on GD18 and MAP measured on GD19 by indwelling catheter. MAP increased in AT1‐AA (121±4 mmHg) compared to normal pregnant (NP) (101±2) but was decreased in AT1‐AA+VD2 (105±2) and AT1‐AA+VD3 (109±2). UARI increased in AT1‐AA rats to 0.57±0.01 compared to NP (0.41±0.02). VD3 reduced UARI to 0.49±0.03. Placental preproendothelin‐1 (ET‐1) mRNA expression increased in AT1‐AA (18.1±2.9‐fold) from NP and was decreased with VD2 (4.3±1.4) and VD3 (1.3±0.3). Plasma 8‐isoprostanes (ROS) increased in AT1‐AA to 1633±179 pg/ml compared to NP (634±197) but was decreased with VD2 (436±81) and VD3 (752±94). sFlt‐1 increased in AT1‐AA (715±189 pg/ml) compared to NP (94±12) and was reduced with both VD2 (77±16) and VD3 (195±7). We have demonstrated that VD improved ET‐1, ROS and sFlt‐1 in response to AT1‐AA in pregnant rats. We believe reducing these factors led to reduced vascular resistance and MAP responses commonly seen in elevated AT1‐AA, as in the case of PE, thereby supporting a role for VD supplementation as a prevention for PE.Support or Funding InformationProject funded by NIH RO1HD067541 and T32HL105324

Utility of Placental Laterality and Uterine Artery Doppler Abnormalities for Prediction of Preeclampsia.

To find out whether placental laterality and abnormal uterine artery waveform and resistance index, as determined by antenatal ultrasonography and Doppler, can be used as a predictor for the development of preeclampsia. This prospective observational cohort study was conducted from August 2013 to October 2014. Two hundred and one (201) normotensive, primigravida women with singleton pregnancies attending the antenatal clinics without any high-risk factor for development of hypertension were subjected to ultrasonography at 18-22weeks of gestation to determine the placenta location. All the subjects with lateral placentas were subjected to Doppler ultrasonography to look for abnormal Doppler waveform and resistance index. They were followed for the development of preeclampsia till 40weeks of gestation or delivery. Out of the total 201 women, 71 (24.5%) had laterally located placentas and of them 37 (52%) developed preeclampsia, while the remaining 130 (75.5%) had centrally located placentas and of them 14 (10.8%) developed preeclampsia (p<0.001). In subjects with lateral placentas alone (n=33), 2 (6%) developed preeclampsia while as those with lateral placentas with Doppler abnormality (n=38), 35 (92%) developed preeclampsia (p<0.001). The overall risk of developing preeclampsia with laterally located placenta was 9.27 (odds ratio), and 95% confidence interval was (4.30-19.98). Pregnant women with lateral placentas are at significant risk for development of preeclampsia. Lateral placentas when associated with uterine artery Doppler abnormality, risk for development of preeclampsia increases significantly as compared to lateral placentas alone.

Effect of hydrosalpinx on uterine and ovarian hemodynamics in women with tubal factor infertility

ObjectiveTo evaluate the effect of hydrosalpinx on uterine and ovarian blood flows in women with tubal factor infertility. Study designIn a cross-sectional study at a university teaching hospital, 60 women with hydrosalpinx-related tubal infertility (hydrosalpinx group) were compared with 60 women with male or unexplained infertility (non-hydrosalpinx group). In the mid-luteal (peri-implantation) phase of the cycle, endometrial thickness, uterine and ovarian artery pulsatility index (PI) and resistance index (RI), and endometrial and ovarian volume and 3D power Doppler vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured in both groups. ResultsThe endometrial VI (p=0.002), FI (p=0.041), and VFI (p=0.018), and ovarian VI (p=0.011), and VFI (p=0.015) were significantly lower in the hydrosalpinx group than in the non-hydrosalpinx group. However, the endometrial thickness, uterine artery PI and RI, ovarian artery PI and RI, endometrial volume, and ovarian volume and FI were not significantly different between the two groups. ConclusionHydrosalpinx is associated with impaired endometrial and ovarian blood flows which may adversely affect endometrial receptivity and oocyte quality.

Relationship between first-trimester serum placental protein-13 and maternal characteristics, placental Doppler studies and pregnancy outcome.

To examine potential correlations between maternal serum placental protein-13 (PP-13) and first trimester maternal and placental factors, and to evaluate the association of this marker with adverse pregnancy outcome. Serum samples from prospectively enrolled patients between 11 and 13 weeks and 6 days were analyzed for PP-13 using an ELISA assay. The relationships between maternal serum PP-13 levels and gestational age, maternal age, ethnicity, parity, smoking status, body mass index (BMI), mean arterial blood pressure, uterine and umbilical artery Doppler parameters were examined. The association between first-trimester PP-13 levels and subsequent pre-eclampsia and delivery of a small for gestational age (SGA) neonate was also investigated, after excluding patients who received aspirin. In 908 patients, PP-13 levels ranged from 8.0 to 537.5 pg/mL. A significant negative correlation was identified between PP13 and BMI (Spearman rho -0.20, P<0.0001). Smoking significantly decreased PP-13 (P<0.01). No relationship was identified with the other parameters. In a subgroup of 668 low-risk patients who did not receive aspirin, PP-13 levels were not associated with development of pre-eclampsia, SGA or the combination of them. First-trimester PP-13 levels are significantly correlated with BMI and smoking. These correlations appear independent of uterine and umbilical artery resistance. In low risk patients, PP-13 levels fail to predict the risk for pre-eclampsia or SGA.

SFlt-1, PlGF, sFlt-1/PlGF ratio and uterine artery Doppler for preeclampsia diagnostics

Background and objectiveAngiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) play a key role in the pathogenesis of preeclampsia. Uterine artery (UA) blood flow is important for preeclamptic pregnancy outcome, but small amount of evidence suggests UA dopplerometry for preeclampsia diagnostics and management. The aim of our study was to compare the value of angiogenic factors and UA dopplerometry in preeclampsia diagnosis and determine cut-off values to obtain the highest sensitivity and specificity of the parameter. Materials and methodsWe performed a case controlled study of 72 pregnant women with preeclampsia and 72 healthy matched controls. SFlt-1 and PlGF were measured in serum samples, the sFlt-1/PlGF ratio was calculated and UA pulsatility (PI) and resistance (RI) indexes were registered. ResultsSignificantly higher levels of sFlt-1, sFlt-1/PlGF ratio and mean UAPI and UARI and lower levels of PlGF were found in preeclampsia group when compared to controls. The highest sensitivity and specificity for preeclampsia had SFlt-1/PlGF and PlGF with the cut-off values of ≥35 (sensitivity of 95.8% and specificity of 96.2%, respectively) and ≤138.6pg/mL (sensitivity of 95.8% and specificity of 93.7%, respectively). For diagnostics of early-onset preeclampsia, all factors sFlt-1, PlGF and sFlt-1/PlGF had equal significance with the cut-off values of ≥7572pg/mL (specificity of 97.5%, sensitivity 92.3%), ≤100.5pg/mL (specificity 96.2%, sensitivity of 100%) and ≥54.6 (specificity 97.5%, sensitivity 97.5%) respectively. ConclusionsThe sFlt-1/PlGF ratio and PlGF are superior to sFlt-1, UAPI and UARI for preeclampsia diagnosis. For early-onset preeclampsia diagnostics either sFlt-1 or PlGF is sufficient.

A comparative analysis of arterial blood flow in unexplained infertility, tubal infertility and fertile groups

We aimed to compare ovarian (O), uterine (U) and spiral (S) artery (A) resistance of patients diagnosed as fertile, unexplained infertility (UI) and tubal factor infertility (TFI) in the peri-implantation period and independent from the impact of the treatment. UI (n = 70), TFI (n = 75) and fertile (n = 72) patients’ ovarian, uterine and spiral artery pulsatility index (PI), resistance index (RI) and the endometrial thickness, serum estradiol and progesterone levels were compared. The specificity and sensitivity values were calculated according to determined cutoff values. Both TFI and control groups’ UA PI values were significantly lower than the UI group’s PI values. The highest UA RI values were found in UI group and the lowest values were in the control group. UI and TFI groups’ OA PI/RI values were significantly higher than the control group. Both the control and TFI groups’ SA PI/RI values were significantly lower than UI group’s PI/RI values. UI patients’ uterine and spiral arteries PI values >1.86 and >0.85, RI values >0.80 and >0.53 can be used as a valuable test showing reduced uterine perfusion. Ovarian artery PI values >0.96 and RI values >0.58 can be used as tests showing decreased ovarian perfusion in patients with TFI. In these patients, embryo cryopreservation can be considered.

185: Serelaxin improves endothelial dysfunction and uterine artery resistance in response to placental ischemia during pregnancy

185: Serelaxin improves endothelial dysfunction and uterine artery resistance in response to placental ischemia during pregnancy

A Comparison of Color Doppler Sonography Findings in Polycystic Ovarian Syndrome Patients and Healthy Women

BACKGROUND AND OBJECTIVE: Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. The assessment of uterine and ovarian artery resistance indices (RI) can provide additional information on pathophysiology of the syndrome, and can be applied as a diagnosis criterion in suspected cases of PCOS. This study aims to compare the parameters of uterine artery blood flow and ovarian stromal artery in PCOS patients and healthy women. METHODS: This cross-sectional study was performed on 20 women with PCOS (PCOS group) and 20 healthy women (control group). In the initial evaluations, age, body mass index, levels of follicle stimulating and luteinizing hormones, as well as severity of hirsutism and acne were recorded. Then, ovarian volume, uterine and ovarian artery RI and the rate of vascularization of ovarian stromal arteries were measured and compared with each other using Gray-scale and color Doppler sonography (CDS). FINDINGS: Uterine artery RI on both sides in the PCOS patients (0.94) was significantly higher than the healthy women (0.86) (p<0.001). Ovarian artery RI on both sides in the PCOS group (0.65) was lower than the control group (0.71) (p<0.001). The rate of vascularization of ovarian stromal arteries was higher in the PCOS patients (45%), as compared to the healthy women (0%) (p<0.001). CONCLUSION: According to the CDS findings, ovarian stromal and uterine blood flow parameters were significantly different in the PCOS and control groups.

Evaluation of maternal serum progranulin levels in normotensive pregnancies, and pregnancies with early- and late-onset preeclampsia

Aims: To investigate the possible pathophysiological associations between progranulin (PGRN) and preeclampsia (PE), early-onset PE (EOPE) and late-onset PE (LOPE).Study design: A cross-sectional study was designed to include consecutive patients with uncomplicated pregnancy (n = 28), EOPE (n = 30) and LOPE (n = 22). Maternal levels of serum PGRN were measured with the use of an enzyme-linked immunosorbent assay kit.Results: The mean serum PGRN level was significantly higher in women with PE compared to the control group (54.17 ± 4.20 pg/ml versus 42.37 ± 5.64 pg/ml, p < 0.001), in the LOPE group compared to the control group (51.63 ± 4.61 pg/ml versus 42.37 ± 5.64 pg/ml, p < 0.001) and also in women with EOPE compared to women with LOPE (56.03 ± 2.68 pg/ml versus 51.63 ± 4.61 pg/ml, p < 0.001). Serum PGRN was negatively correlated with gestational age at birth (r = −0.669, p = 0.001) and birth weight (r = −0.653, p = 0.001); and positively correlated with systolic (r = 0.653, p = 0.001) and diastolic blood pressure (r = 0.601, p = 0.001), C-reactive protein (r = 0.519, p = 0.001), uterine artery pulsatility (r = 0.441, p = 0.001) and resistance indices (r = 0.441, p = 0.001).Conclusions: Serum PGRN levels increase significantly in women with PE as an indirect sign of placental dysfunction. This increase is even more prominent in women with EOPE. The serum PGRN in the third trimester is positively correlated with gestational age at birth and birth weight.

Abstract 076: Early Administration of 17-hydroxyprogesterone Caproate Improves Fetal Growth Restriction Possibly by Reducing Sflt-1 and Placental Cytolytic Nk Cells in Response to Placental Ischemia During Pregnancy

Preeclampsia (PE), new onset hypertension, is characterized by elevated anti-angiogenic factor soluble fms-like tyrosine kinase (sFlt-1), cytolytic natural killer (NK) cells and placental ischemia predicted with increased uterine artery resistance (UARI) which are likely culprits for decreased fetal weight during PE pregnancies. Cytolytic NK are an important arm of the immune system killing tumor and infected cells by perforin-granzyme-mediated cytolysis and have been shown to be increased in PE women compared to those with normal pregnancy. Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of spontaneous preterm labor, but is not included in the current management for PE. This study was designed to test the hypothesis that early administration of 17-OHPC could improve pregnancy outcomes in response to placental ischemia. To do so, 17-OHPC (3.32mg/kg) was administered intraperitoneally on gestation day 15 to reduced uterine perfusion pressure (RUPP) rats, UARI was measured using Doppler ultrasound and carotid catheters were inserted on day 18. Blood pressure (MAP), sFlt-1, and placental cytolytic NK cells were measured on GD 19. MAP in normal pregnant (NP) rats (n=12) was 94 ± 2, 126 ± 2 in RUPP (n=27) and 111±1 mmHg in RUPP+17-OHPC (n=15), p &lt;0.05. Pup weight was 2.3±0.09 in NP, 1.9± 0.04 in RUPP rats, which improved to 2.1±0.06 grams in RUPP+17-OHPC p &lt;0.05. UARI was 0.6±0.01 in NP (n=3), 0.8±0.03 in RUPP rats (n=4), which improved to 0.6±0.04 in RUPP+17-OHPC (n=5), p&lt;0.05. Total number of placental NK cells was 8.6 ± 3.1 in NP, 20.2 ±2.4 in RUPP rats, which decreased to 1.6 ± 0.54 % in RUPP+17-OHPC, p&lt;0.05. Activated placental NK cells was 3.8 ± 2.2 in NP, 11.9±2.01 in RUPP , which improved to 0.4 ± 0.2 % in RUPP+17-OHPC, p &lt;0.05. Plasma sFlt-1 was 36.1±7.5, 385.9±141 in RUPP rats (n=5), which was blunted to 110.2±11.1 pg/mL in RUPP+17-OHPC, p&lt;0.05. In conclusion, early administration of 17-OHPC improves sFtl-1, UARI, activated cytolytic NK cells, pup weight and hypertension in response to placental ischemia. Therefore, 17-OHPC should be further considered for addition to the management of PE.

Abstract P091: Vitamin D Supplementation Inhibits Blood Pressure and Uterine Artery Resistance Induced by Autoantibodies to the AT1 Receptor

Studies in our lab have previously shown that Vitamin D supplementation in the RUPP rat model of preeclampsia lowers blood pressure and reduces autoantibodies to the AT1 receptor (AT1-AA). Therefore, we sought to determine if the effects of Vitamin D supplementation to inhibit endothelial dysfunction and hypertension during pregnancy were mediated by AT1-AA reduction. We hypothesized that Vitamin D supplementation to AT1-AA-induced hypertensive pregnant rats would reduce anti-angiogenic factor soluble FMS-like tyrosine kinase-1 (sflt-1) and uterine artery resistance index (UARI) while improving blood pressure (MAP). Purified rat AT1-AA was infused (1:40) into Sprague-Dawley rats via miniosmotic pump from gestational day (GD) 12 to GD19. On GD14-18 we administered Vitamin D2 or D3 (VD2 or VD3) to AT1-AA rats (50ul/ml) by oral gavage. On GD18 indwelling carotid catheters were inserted and UARI assessed by Doppler sonography and MAP was measured on GD19. Consistent with previous studies, MAP was 119.0 mmHg in AT1-AA infused pregnant rats. MAP was unchanged with VD2 treatment at 121.7 mmHg (n=3), however, reduced to 109.3 mmHg (n=3) in AT1-AA+VD3 rats. Pup and placental weights were 1.79 and 0.46 g (n=3), respectively, in AT1-AA rats and were increased with VD2 treatment to 2.33 and 0.54 g (n=3) and to 2.39 and 0.56 g (n=3) in AT1-AA+VD3 rats. UARI was 0.577 (n=2) in AT1-AA rats but reduced with VD2 treatment to 0.491 (n=3) and VD3 to 0.452 (n=2). Plasma sflt-1, which is increased with AT1-AA infusion, was measured with ELISA and was &gt;1050 pg/ml in AT1-AA rats (n=3) and greatly reduced in both AT1-AA+VD2 at 42.3 pg/ml (n=2) and AT1-AA+VD3 at 241.0 pg/ml (n=3). Our preliminary data demonstrate that Vitamin D supplementation improves uterine artery vascular resistance and sflt-1 and that these are potential mechanisms for improving fetal weight and hypertension that is induced by AT1-AA during pregnancy.

Abstract 049: Preeclampsia in the Dahl Salt Sensitive Rat is Associated with Increased Uterine Artery Resistance and Reduced Placental Microvascular Density

We showed that the Dahl salt sensitive (Dahl S) rat is a spontaneous model of preeclampsia superimposed on chronic kidney disease and hypertension. This model exhibits intrauterine growth restriction, decreased pup weight, increased fetal death, and placental hypoxia; however, the underlying mechanisms are unknown. We hypothesized that a pathological remodeling and rarefaction in the maternal placental bed drives the development of preeclampsia in this model. Pregnant Dahl S and Sprague-Dawley (SD) rats were used in this study. Uterine artery resistance index (UARI) was calculated via Doppler ultrasound (Vevo 770) on day 18 of pregnancy (UARI=(peak systolic flow velocity - end diastolic flow velocity)/ peak systolic flow velocity). On day 20 of pregnancy, placentas were perfused through the uterine circulation with a silicon-polymer contrast (Microfil MV122). Individual placentas were then excised, scanned using a micro-CT scanner (SkyScan 1076), and 3D reconstructed for analysis and quantification of the placental vasculature on the maternal side. Microvascular density was calculated for vessels of diameters in the 0-500 μm ranges. UARI was higher in the Dahl S compared to the SD (0.71±0.02 vs 0.51±0.02, n=4-12, p&lt;0.05). Density of placental microvessels in the 200-500 μm range was significantly decreased in placentas from Dahl S rats, and we observed a strong trend towards a decrease in density of microvessels in the 0-200 μm range (n=3-5, Figure). These results suggest that the impaired fetal growth and placental hypoxia in the Dahl S rat may be mediated by insufficient placental vascularization and reduced blood flow to the feto-placental unit.

Repeated implantation failure relates to circulatory abnormalities

A diminished pre-pregnant plasma volume as marker of reduced cardiovascular reserves may influence embryo implantation by circulatory redistribution at the expense of uterine perfusion. In this pilot study we tested the hypothesis that recurrent implantation failure in in-vitro-fertilization (IVF) patients is associated with decreased plasma volume and increased uterine arteries resistance as proxy measures for circulatory anomalies.