Deep trophoblast invasion and spiral artery remodelling in the placental bed of the chimpanzee

Deep trophoblast invasion is usually considered to be a unique feature of human placentation as compared to other primates. Because of the occasional occurrence of preeclampsia in great apes, which in the human is associated with impaired deep invasion, this uniqueness may be questioned. The availability of two well-documented pregnant chimpanzee uteri in the Hubrecht Collection (Museum für Naturkunde, Berlin) allowed us to evaluate the extent of trophoblast invasion in this species. By adjusting currently used protocols, we obtained successful immunohistochemical staining for cytokeratin and α-actin, as well as Ulex europaeus agglutinin 1 (UEA1) lectin staining, in this archival material. In both specimens interstitial trophoblast invasion had occurred in both decidua and myometrium. Because of a lack of published data on fetal growth for this species, fetal sizes (7 cm and 13 cm) could not be strictly related to gestational ages and thus be compared with the time-course of human trophoblast invasion. However, since the earlier specimen did not show any endovascular trophoblast invasion in spiral arteries - in contrast to pregnant human uteri with equivalent fetal sizes - endovascular migration seems to begin at a different gestational age in the chimpanzee. In the later specimen endovascular trophoblast was associated with spiral artery remodelling in the inner myometrium, and this invasion was extended to include a radial artery, which at that stage still showed relatively intact vascular smooth muscle and elastic lamina. We conclude that invasion depth and spiral artery remodelling are basically similar in chimpanzees and humans, although the seemingly different time of onset may have implications for uteroplacental oxygen supply and fetal development.     

Deep trophoblast invasion and spiral artery remodelling in the placental bed of the lowland gorilla

In contrast to baboon or rhesus macaque, trophoblast invasion in the human placental bed occurs by the interstitial as well as the endovascular route and reaches as deep as the inner myometrium. We here describe two rare specimens of gorilla placenta. In the light of recent findings in the chimpanzee, we postulated the occurrence of deep invasion in gorilla pregnancy. Tissues were processed for histology (PAS, orcein), lectin staining (Ulex europaeus agglutinin 1) and immunohistochemistry (cytokeratin 7/17, α-actin). A specimen of young but undetermined gestational age included deep placental bed tissue, showing interstitial and spiral artery invasion of the inner myometrium as well as the decidua. The cell density and depth of trophoblast invasion was equivalent to a human placental bed of 10-14 weeks. Intraluminal trophoblasts were not seen in any of the invaded vessels, allowing no definite conclusions about the origin of the intramural trophoblast and the time-course of spiral artery invasion. A different late second trimester placenta specimen showed scattered extravillous trophoblast in the basal plate and underlying decidua, as well as a remodelled spiral artery containing intramural trophoblast. Absence of inner myometrial tissue precluded assessment of invasion depth in this later specimen. Despite the limited material we can conclude that key aspects of trophoblast invasion are shared by the three hominid species: gorilla, chimpanzee and human.     

The Placental Bed

Objectives: To review critically published data concerning fetalmdash;maternal interaction at the placental bed level in normal and complicated pregnancies. Emphasis is placed on the adaptive changes of the uteroplacental vasculature of the placental bed.

Methods: Histopathological and immunohistochemical data form the basis of this review. The relevance of recent studies on cultured trophoblast is considered in the light of histological findings.

Results: The findings of recent experimental studies on invasive processes and trophoblastmdash;extracellular matrix interaction relate mainly to interstitial trophoblast, since no in vitro model is available for the study of vascular changes. The endovascular pathway of vascular invasion is emphasized, and mechanisms of arterial wall destruction need to be reconsidered since vascular disorganization and disruption may precede trophoblast invasion. There is a need for blood flow studies in relation to histopathological findings. Currently the role of various cytokines in trophoblast-maternal interaction is being intensively investigated, since disturbances in the cytokine network may be responsible for the inhibition of trophoblast invasion in complicated pregnancies.

Conclusions: Various new techniques have led to a better insight of trophoblast invasion and its regulation. It is important that these should be interpreted in the context of histological reality as observed in the placental bed.     

Extracellular ATP decreases trophoblast invasion,spiral artery remodeling and immune cells in the mesometrial triangle in pregnant rats

Introduction

Preeclampsia is characterized by deficient trophoblast invasion and spiral artery remodeling, a process governed by inflammatory cells. High levels of the danger signal extracellular adenosine triphosphate (ATP) have been found in women with preeclampsia and infusion of ATP in pregnant rats induced preeclampsia-like symptoms such as albuminuria and placental ischemia. We hypothesized that ATP inhibits trophoblast invasion and spiral artery remodeling and affects macrophages and natural killer (NK) cells present in the rat mesometrial triangle.

Methods

Pregnant rats were infused with ATP or saline (control) on day 14 of pregnancy. Rats were sacrificed on day 15, 17 or 20 of pregnancy and placentas with mesometrial triangle were collected. Sections were stained for trophoblast cells, α-smooth muscle actin (spiral artery remodeling), NK cells and various macrophage populations. Expression of various cytokines in the mesometrial triangle was analyzed using real-time RT-PCR.

Results

ATP infusion decreased interstitial trophoblast invasion on day 17 and spiral artery remodeling on day 17 and 20, increased activated tartrate resistant acid phosphatase (TRAP)-positive macrophages on day 15, decreased NK cells on day 17 and 20, and decreased inducible nitric oxide synthase (iNOS)-positive and CD206-positive macrophages and TNF-α and IL-33 expression at the end of pregnancy (day 20).

Discussion

Interstitial trophoblast invasion and spiral artery remodeling in the rat mesometrial triangle were decreased by infusion of ATP. These ATP-induced modifications were preceded by an increase in activated TRAP-positive macrophages and coincided with NK cell numbers, suggesting that they are involved.

Conclusion

Trophoblast invasion and spiral artery remodeling may be inhibited by ATP-induced activated macrophages and decreased NK cells in the mesometrial triangle in rat pregnancy.     

Galectin-8 is expressed by villous and extravillous trophoblast of the human placenta

Galectins (gals) as multifunctional animal lectins are of great potential significance for establishment and function of the placenta, due to their capacity to modulate cellular functions including proliferation, adhesion, and invasion. Human trophoblast is known to express gal-1, gal-3 and gal-13 proteins, as well as mRNAs for gal-14, -16 and -17. This study was undertaken to establish cellular distribution of gal-8, not previously associated with trophoblast, since we have recently detected gal-8 RNA and protein in cytotrophoblast cell material. Results of immunolocalization showed that gal-8 was expressed by villous and extravillous cytotrophoblast.     

The risk of placental abruption and placenta previa in pregnant women with chronic hepatitis B viral infection: A systematic review and meta-analysis

Introduction

Several epidemiological studies have found a positive association between chronic hepatitis B virus (CHB) infection and the risk of placental abruption and placenta previa, but various studies have reported conflicting findings. The objective was to systematically review the literature to determine a possible association between CHB infection and these two placental complications.

Methods

We conducted a computerized search in electronic database through March 1, 2014, supplemented with a manual search of reference lists, to identify original published research on placental abruption and placenta previa rates in women with CHB infection. Data were independently extracted, and relative risks were calculated. The meta-analysis was performed using Stata version 10.0 software.

Results

Five studies involving 9088 placenta previa cases were identified. No significant association between CHB infection and placenta previa was identified (OR = 0.98, 95% CI = 0.60–1.62). Five studies involving 15571 placental abruption cases were identified. No significant association between CHB infection and placental abruption was identified (OR = 1.42, 95% CI, 0.93–2.15).

Discussion

The immune response against the virus represents a key factor in determining infection outcomes. No observation of significant increased risk of the placental complications could be partially explained by the complex immune response during CHB infection.

Conclusions

Our meta-analysis found no evidence of significant associations between CHB infection and increased risk of placental abruption as well as placenta previa. Further well-designed studies were warranted to assess any potential association between CHB infection and increased risk of placental abruption as well as placenta previa.     

The role of placental breast cancer resistance protein in the efflux of glyburide across the human placenta

Gestational diabetes mellitus is a common medical complication in pregnancy. Recent findings demonstrate that glyburide is effluxed against a concentration gradient from the fetal to the maternal circulation. However, the transport systems involved in the active efflux of glyburide in the human placenta have not yet been identified. The ATP-binding cassette transporter, breast cancer resistance protein (BCRP), is highly expressed in placental syncytiotrophoblast suggesting it may play a role in protecting the fetus from drug toxicity. The objective of the present study was to determine whether BCRP participates in the transport of glyburide across the human placenta. The placental transfer of glyburide in the presence of specific BCRP inhibitor, nicardipine, was investigated using the ex vivo dual perfusion system of isolated human placental lobules. In a closed experiment, glyburide was added (200ng/mL) to the maternal and fetal circulations and the BCRP inhibitor (20muM) was added to the maternal circulation. Samples were taken during pre-control, experimental, and post-control periods for measurement of glyburide and markers of tissue viability. Results obtained from perfusions (n=4) in the presence of the BCRP inhibitor show a significant increase in the mean fetal-to-maternal concentration ratio of glyburide determined at 180min, 0.56+/-0.06, when compared to the mean ratio obtained in the absence of inhibitor, 0.32+/-0.06 (p=0.04). These data indicate that nicardipine partially blocked the transfer of glyburide across the whole placenta through its inhibition of BCRP. This is the first ex vivo evidence that BCRP actively transports glyburide.     

The role of Hofbauer cells on the pathogenesis of early pregnancy loss

Introduction

Hofbauer cells (HC) are the placental macrophages that play a significant role in many important placental events. The aim of this retrospective study is to investigate the role of HC in the pathogenesis of early pregnancy loss (EPL).

Methods

The slides were obtained from archival blocks of missed abortion (MA, n = 15) and blighted ovum (BO, n = 15) cases. Unwanted pregnancies materials constituted the control group (n = 15). HC and endothelial cells were identified using immunohistochemical methods. HC were counted under light microscope. The extent of villous vasculature was evaluated using two methods; the Chalkey method and microvessel scoring.

Results

The mean number of villous HC was found to be significantly higher in both MA and BO groups in contrast to the control group. MA group also showed a higher number of HC in comparison with the BO group. Higher microvessel scoring was also found in MA group in contrast to other two groups. Chalkey method revealed no significant difference in the extent of villous vasculature for the control group in comparison with MA and BO.

Discussion

As we identified relatively low quantity of HC in BO associated with defective vasculature, we hypothesize that an inadequate microvessel formation after hypoxic insult can explain the pathogenesis of BO. We believe that HC are increased in MA due to their divergent roles on immunity and inflammation.

Conclusion

We therefore conclude that HC may be of biological importance in the pathogenesis of EPL.     

Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes

OBJECTIVE: The purpose of this study was to determine whether abnormal placentation (defined as the failure of physiologic transformation of spiral arteries) is present in patients with preterm labor and intact membranes who delivered a preterm neonate. STUDY DESIGN: A cross-sectional study was conducted to examine the histopathologic findings in the placental bed and placenta of patients with preterm labor and intact membranes (n=27), preeclampsia (n=43), and healthy pregnant women at term (n=103). Immunohistochemistry studies with cytokeratin 7 and periodic acid-Schiff were used to detect trophoblast and fibrinoid, respectively, and diagnose the failure of physiologic transformation of the spiral arteries. RESULTS: The mean percentage of spiral arteries with failure of physiologic transformation in the myometrium was significantly higher in patients with preterm labor and preeclampsia than in normal pregnant women at term (P=.0004 and P<.0001, respectively). Similar findings were observed in the decidual segment of spiral arteries within the placental bed (P=.001 and P<.0001). In contrast, the mean percentage of the spiral arteries with failure of physiologic transformation in the decidua of the basal plate was not significantly different between patients with preterm labor and normal pregnant women (P=.17). CONCLUSION: Failure of physiologic transformation of the spiral arteries in the myometrial and decidual segments of the placental bed is frequent in patients with preterm labor and intact membranes.     

Wnt2在植入胎盘组织中的表达及其对滋养细胞迁移和侵袭功能的影响

目的检测Wnt2在植入胎盘组织中的表达,分析Wnt2对滋养细胞凋亡、迁移和侵袭功能的影响。方法收集2020年7月至2021年1月于武汉大学中南医院妇产科行剖宫产的胎盘植入孕产妇胎盘组织15例(植入组)和正常孕产妇胎盘组织15例(对照组)。RT-PCR法和Western blot法检测胎盘组织中Wnt2表达水平,采用siRNA敲低HTR-8/Svneo细胞中Wnt2表达水平,流式细胞学法检测细胞凋亡,Transwell侵袭和迁移实验评估细胞的迁移和侵袭能力,RT-PCR法和Western blot法检测β-catenin、Bcl-2、Caspase-3、MMP-2和MMP-9表达水平。结果与对照组相比,植入组胎盘组织中Wnt2、MMP-2和MMP-9 mRNA和蛋白表达量均显著升高(均P<0.05)。转染敲低HTR-8/Svneo细胞Wnt2水平后,细胞凋亡率显著增加(P<0.05),细胞迁移和侵袭能力显著抑制(P<0.01),β-catenin、Bcl-2、MMP-2和MMP-9表达显著下降(均P<0.05),而Caspase-3表达显著升高(P<0.05)。结论植入胎盘组织中Wnt2蛋白表达显著升高,且Wnt2可能通过wnt/β-catenin信号通路参与了胎盘滋养细胞的凋亡、迁移和侵袭。     

The role of the loop electrosurgical excision procedure in the diagnosis and management of early invasive cervical cancer

The management of cervical intra-epithelial neoplasia (CIN) has evolved so that excisional techniques are now preferred over ablative procedures. This is in part due to a 1–3% rate of discovering unsuspected early invasive carcinomas that would not have been detected by ablative management of CIN. A review of our initial experience over 20 months with the loop electrosurgical excision procedure (LEEP) in treating CIN found seven out of 237 patients (3%) to have otherwise unsuspected invasive lesions. The management of three additional patients with suspected early invasive lesions has been facilitated by LEEP. The procedure has been found to produce excellent pathologic specimens and has virtually replaced traditional operative cervical conization in the management of both CIN and early invasive cervical cancer.     

Spontaneous uterine rupture at a non-cesarean section scar site caused by placenta percreta in the early second trimester of gestation: A case report

ObjectivesRisk factors for placenta percreta are placenta previa and prior cesarean delivery. Placenta percreta–induced ruptures at non-cesarean sites are very rare, particularly in the early second trimester.Case reportA 30-year-old woman with a prior cesarean delivery was brought to our emergency department at 17 weeks' gestation for sudden-onset consciousness loss and generalized convulsions. Hypovolemic shock was identified. Computed tomography scans suggested uterine rupture and massive ascites, r/o hemoperitoneum. Emergency exploratory laparotomy revealed a ruptured hole over the left uterine fundus with protruding placental tissue; placenta percreta was impressed. An intact intrauterine sac was dissected and removed. The placenta was removed and hysterorrhaphy was completed.ConclusionPlacenta percreta is dangerous and is rarely seen in the early second trimester. Uterine rupture should always be kept in mind in pregnant woman with acute abdomen associated with hypovolemic shock, even in those of early pregnancy without scarred uterus. Routine sonographic examination of placentation, even in early second trimester, should be emphasized.     

Successful use of uterine artery embolisation to treat placenta increta in the first trimester

A 39-year-old Asian woman was admitted to hospital with persistent, heavy vaginal bleeding following an uncomplicated first trimester surgical termination of pregnancy (STOP). Her heavy bleeding continued after the STOP and she had recurrent hospital admissions which included two procedures to evacuate presumed retained products of conception. She eventually had a MRI scan performed which suggested placental tissue in the fundal region, extended into the uterine wall. The findings were consistent with placenta increta and the patient had a bilateral uterine artery embolisation (UAE), following which her symptoms rapidly subsided. We describe the first successfully managed case of persistent vaginal bleeding secondary to abnormal placentation. It would seem to substantiate the efficacy of UAE as a therapeutic modality for the conservative management of invasive placentation in the first trimester of pregnancy.     

Combination of uterine artery Doppler velocimetry and maternal serum placental growth factor estimation in predicting occurrence of pre-eclampsia in early second trimester pregnancy: a prospective cohort study

Objective

To determine the effectiveness of the combined use of uterine artery Doppler velocimetry (UADV) and estimation of maternal serum placental growth factor (PlGF) levels in early second trimester (20–22 weeks of gestation) in identifying pregnant women at risk of developing pre-eclampsia.

Study design

Prospective cohort study on 1104 pregnant women with singleton pregnancies between May 2009 and December 2010. UADV and maternal serum PlGF estimation were done at 20–22 weeks’ gestation. Association between the two variables and the occurrence of pre-eclampsia was analyzed by logistic regression analysis and odds ratio was computed. The results were considered significant when p was <0.05.

Results

Logistic regression analysis showed that both abnormal UADV (odds ratio (OR) 4.1; 95% CI 2.3–7.2; p = 0.000) and serum PlGF < 188 pg/ml (OR 3.6; 95% CI 1.95–6.5; p = 0.000) are independent variables in the occurrence of pre-eclampsia, and the difference between the association of these two variables with pre-eclampsia was statistically insignificant as 95% CI values overlap. Multivariate logistic regression analysis showed that a combination of abnormal UADV and serum PlGF < 188 pg/ml at 20–22 weeks had a very poor association (OR 1.1; 95% CI 0.3–3.8; p = 0.938) with the occurrence of pre-eclampsia, as the 95% CI values encompass 1 and p is >0.05.

Conclusion

UADV and maternal serum PlGF estimation at 20–22 weeks of gestation are strong predictors of the occurrence of pre-eclampsia when used individually but in combination their association with pre-eclampsia is not significant.     

First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction

Objective

We test the hypothesis that first-trimester serum analytes, 4-D power Doppler placental vascular indices and uterine artery Doppler (UAD) predicts abnormal placental morphometry in pregnancies with preeclampsia (PE) and fetal growth restriction (FGR).

Study design

Maternal serum analytes (PAPP-A, hCG, ADAM12s, and PP13), bilateral UADs, and placental vascular indices were measured at 11-14 weeks in a nested-case control study within a prospective cohort of women followed from the first-trimester to delivery. Vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were obtained from 4-D power Doppler histograms. Serum analytes were measured using immunofluorometric assays and values converted to multiples of the median (MoM) for gestational age. Morphometric analysis was performed on placentas from pregnancies complicated by PE (n = 13), gestational hypertension (HBP, n = 7) and FGR (defined as fetal weight <10th percentile with abnormal umbilical artery Doppler: n = 7); and 20 uncomplicated pregnancies. Two pregnancies had both FGR and PE. Each placenta was weighed and random samples taken, and fixed in formalin within 1 h of delivery. Hematoxylin & Eosin stained slides were analyzed by design-based stereology to quantify linear dimensions, surface areas and volumes of placental components. Paired t-test and ANOVA with adjustments for multiple comparisons were used.

Results

The surface areas of terminal and intermediate villi as well as the volume of terminal villi were significantly smaller in placentas from pregnancies complicated by FGR and PE. Compared with the control group the mean PAPP-A (MoM) was lower in the pregnancies with abnormal placenta morphometry (1.1 ± 0.5 versus 0.7 ± 0.5, P = 0.03). The morphometric indices were lower in those pregnancies with low PAPP-A and IUGR compared with preeclampsia.

Conclusion

First-trimester PAPP-A levels are associated with abnormal placental morphometry at delivery in pregnancies with PE and IUGR. These findings may explain the association between adverse pregnancy outcomes and first-trimester PAPP-A.     

The role of laparoscopic dissection of the uterine artery in the surgical treatment of fibroid-related menorrhagia: a pilot study

This pilot study assessed the outcome, tissue trauma, clinical improvement and reduction in size of fibroids following laparoscopic dissection of the uterine artery (LDUA) in fibroid-related menorrhagia. Fifty-three patients with complete records were included in the prospective clinical study. Before LDUA, and 3 and 6 months following the procedure, ultrasonography or MRI was done to measure the size of the uterus and dominant fibroid. Blood samples for hemoglobin and assay of marker inflammatory response and tissue trauma were taken preoperatively on the 1st and 3rd postoperative days. All patients underwent successful LDUA using ultrasonically activated shears without intra-operative complications. Fifty (96.2%) laparoscopically treated patients with fibroids who subsequently experienced improvement in menorrhagia and anemia are described. The LDUA procedure can be completed within 30–40 min with only minimal blood loss and a short hospital stay if performed by experienced surgeons. Our study results show that single laparoscopic dissection of the uterine artery performed with ultrasonic technique is associated with an insignificant stress response. The average reductions in the uterine volume and dominant fibroid volume were 36.6 and 57.9% at 6 months after surgery, respectively. Four women conceived within 1 year, and their pregnancies were without complications during gestation.     

A trio of risk factors for the onset of preeclampsia in the second and early third trimesters

ObjectiveWe evaluated the biological interaction among mean blood pressure (MBP), uterine artery Doppler (UAD), and the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio for preeclampsia (PE) risk.Study designA prospective cohort study.Main outcome measuresIn 1239 pregnant women, MBP and UAD were measured at 16–23 weeks of gestation, and plasma levels of the sFlt-1/PlGF ratio at 19–25 weeks and 26–31 weeks. A Cox proportional hazard model was used. Women with a low sFlt-1/PlGF ratio and either low BP or normal UAD were set as controls. The relative excess risk due to biological interaction (RERI) was calculated using the following equation: RERI = hazard ratio (HR) in women with high sFlt-1/PlGF and both high BP and abnormal UAD (group 3) – HR in women with both high BP and abnormal UAD alone (group 1) – HR in women with high sFlt-1/PlGF alone (group 2) + 1. RERI ⩾ 10 was considered to be strong.ResultsAt 19–25 weeks, the HR and 95% confidence intervals (CI) in group 1, group 2, and group 3 were 7.4 (3.1–17.4), 15.3 (4.5–52.2), and 107.0 (41.0–279), respectively, and the RERI for PE was 85.3. At 26–31 weeks, the HR and 95% CI in each group were 8.3 (2.9–23.2), 7.5 (0.97–57.8), and 69.0 (18.5–256), respectively; the RERI for PE was 54.2.ConclusionsWe found a trio of risk factors for the onset of PE in the second and early third trimesters: high BP, abnormal UAD, and high sFlt-1/PlGF ratio.     

The Role of Apoptosis on Trophoblast Cell Invasion in the Placental Bed of Normotensive and Preeclamptic Pregnancies

Background. Placental development depends on careful coordination of trophoblast proliferation and apoptosis; however, the synchrony of its effect on trophoblast invasion is unknown. Objective. To examine the relationship between trophoblast apoptosis and proliferation in placental bed tissue of preeclamptic and normotensive pregnancies. Methods. Serial sections from archived placental bed biopsies of 12 normotensive (group 1) and 12 preeclamptic (group 2) were immunolabeled with a rabbit anti-Ki67 antibody, a mouse anti-cytokeratin 18 and its neo-epitope, and a monoclonal cytodeath M30 antibody. Results. The immunoexpression of Ki67 for all trophoblast cell subpopulations within the myometrium was non-reactive in both study groups. Smooth muscle cells of the microvasculature reflected a moderate degree of proliferation in both groups. Morphometric image analysis of the wall of the spiral artery revealed a mean area of 31,1729?±?51,180?µm² compared to 35,795?±?8045?µm² in groups 1 and 2, respectively. An elevation of intramural trophoblast was evident within the spiral artery of group 1 (13%). Comparative analyses of M30 distribution on corresponding serial sections were 0.06% versus 0% in groups 1 and 2, respectively. The mean field area percentage of interstitial trophoblast invasion was 10.79% versus 2.87% with corresponding areas of apoptosis been 0.8 % versus 1.9 % in groups 1 and 2, respectively. Conclusions. This study demonstrates an increased trophoblast apoptosis in placental bed of preeclamptic compared to normotensive pregnancies with concurrent absence of proliferation at term.     

Uterine artery blood flow volume in pregnant women with an abnormal pulsatility index of the uterine arteries delivering normal or intrauterine growth restricted newborns

The aim of this study was to assess and compare uterine artery (UtA) blood flow volume in pregnant patients with an abnormal uterine Doppler pulsatility index (PI) who delivered fetuses with an appropriate weight for gestational age (AGA) or with intrauterine growth restricted (IUGR).We prospectively recruited singleton pregnancies with abnormal uterine arteries P.I. between 18 and 38 weeks of gestation regardless of estimated fetal weight (EFW). Vessel diameter and blood flow velocity were measured along the UtA upstream to the vessel bifurcation in both the right and left UtAs. Uterine blood flow volumes measured in these pregnancies were compared to historical Control-pregnancies. Forty-three patients delivered at term a normal weight newborn (AGA-pregnancies). Thirty patients delivered growth restricted newborns at 32 weeks (i.r. 29-36w) with a median weight of 1160 gr (i.r. 1000-2065 gr) (IUGR-pregnancies).At mid-gestation (18 + 0 − 25 + 6 weeks + days of gestation) a significantly lower uterine blood flow volume per unit weight was observed between the two study groups and compared to controls: 142 ml/min/kg in IUGR-pregnancies, 217 ml/min/kg in AGA-pregnancies and 538 ml/min/kg in Control-pregnancies. These striking differences in blood flow volume were already present at mid-gestation, at a time when EFW was still normal. In late gestation (27 + 0 − 37 + 6 weeks + days of gestation), pregnancies with an abnormal uterine P.I. showed persistently low UtA flow (<50% of controls) even when corrected for fetal weight: 81 ml/min/kg in IUGR-pregnancies, 105 ml/min/kg in AGA-pregnancies, and 193 ml/min/kg in Control-pregnancies; p < 0.0001.Our findings are consistent with other recent studies regarding the association between reduced uterine blood flow volume and fetal growth restriction. However, the study brings new insight into the finding of abnormal uterine P.I. in normally grown fetuses typically dismissed as “falsely abnormal” or “false positive” findings. Our study suggests that blood flow volume measurement may serve as a new tool to assess this group of patients and possibly those with ischemic placental diseases that may provide some basis for therapeutic interventions.