Uteroplacental Vascular Insufficiency Research Articles

A review of infant growth and psychomotor developmental outcomes after intrauterine exposure to preeclampsia

Preeclampsia is a hypertensive disorder of pregnancy with serious health implications for mother and their offspring. The uteroplacental vascular insufficiency caused by preeclampsia is associated with epigenetic and pathological changes in the mother and fetus. However, the impact of preeclampsia in infancy (birth to 2 years), a time of rapid development influenced by pre- and postnatal factors that can predict future health outcomes, remains inconclusive. This narrative review of 23 epidemiological and basic science studies assessed the measurement and impact of preeclampsia exposure on infant growth and psychomotor developmental outcomes from birth to 2 years. Studies assessing infant growth report that preeclampsia-exposed infants have lower weight, length and BMI at 2 years than their normotensive controls, or that they instead experience accelerated weight gain to catch up in growth by 2 years, which may have long-term implications for their cardiometabolic health. In contrast, clear discrepancies remain as to whether preeclampsia exposure impairs infant motor and cognitive development, or instead has no impact. It is additionally unknown whether any impacts of preeclampsia are independent of confounders including shared genetic factors that predispose to both preeclampsia and childhood morbidity, perinatal factors including small for gestational age or preterm birth and their sequelae, and postnatal environmental factors such childhood nutrition. Further research is required to account for these variables in larger cohorts born at term, to help elucidate the independent pathophysiological impact of this clinically heterogenous and dangerous disease.

Fetal Cardiac Lipid Sensing Triggers an Early and Sex-related Metabolic Energy Switch in Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR) is an immediate outcome of an adverse womb environment, exposing newborns to developing cardiometabolic disorders later in life. This study investigates the cardiac metabolic consequences and underlying mechanism of energy expenditure in developing fetuses under conditions of IUGR. Using an animal model of IUGR characterized by uteroplacental vascular insufficiency, mitochondrial function, gene profiling, lipidomic analysis, and transcriptional assay were determined in fetal cardiac tissue and cardiomyocytes. IUGR fetuses exhibited an upregulation of key genes associated with fatty acid breakdown and β-oxidation (Acadvl, Acadl, Acaa2), and mitochondrial carnitine shuttle (Cpt1a, Cpt2), instigating a metabolic gene reprogramming in the heart. Induction of Ech1, Acox1, Acox3, Acsl1, and Pex11a indicated a coordinated interplay with peroxisomal β-oxidation and biogenesis mainly observed in females, suggesting sexual dimorphism in peroxisomal activation. Concurring with the sex-related changes, mitochondrial respiration rates were stronger in IUGR female fetal cardiomyocytes, accounting for enhanced adenosine 5'-triphosphate production. Mitochondrial biogenesis was induced in fetal hearts with elevated expression of Ppargc1a transcript specifically in IUGR females. Lipidomic analysis identified the accumulation of arachidonic, eicosapentaenoic, and docosapentaenoic polyunsaturated long-chain fatty acids (LCFAs) in IUGR fetal hearts, which leads to nuclear receptor peroxisome proliferator-activated receptor α (PPARα) transcriptional activation in cardiomyocytes. Also, the enrichment of H3K27ac chromatin marks to PPARα-responsive metabolic genes in IUGR fetal hearts outlines an epigenetic control in the early metabolic energy switch. This study describes a premature and sex-related remodeling of cardiac metabolism in response to an unfavorable intrauterine environment, with specific LCFAs that may serve as predictive effectors leading to IUGR.

Новые возможности для профилактики преэклампсии

The analysis of literature data on the role of placenta disorders in the development of preeclampsia (PE) was performed according to Pubmed and eLibrary updates. Although a complete understanding of the pathogenesis of PE remains unclear, the placenta theory was found as one of the principal ones. The appropriateness of prescribing progestogens for the prevention of PE is the subject of an actual debate. Based on the results of our own research, there was demonstrated the efficacy in the preventative prescription of dydrogesterone (at a dose of 30 mg/day) from early periods to 20 weeks of gestation in pregnant women with high-risk factors. The rescription of dydrogesterone contributed to a statistically significant reduction in this pregnancy complication (13.1 and 71/4%, p < 0,001).It was found that women taking dydrogesterone significantly less developed such disorders as arterial hypertension (3.2 and 71.2%, p < 0.001), proteinuria (0 and 66.18%, p < 0.001), fetal growth restriction (2.2 and 21.58%, p < 0.001), uteroplacental vascular insufficiency (3.2 and 21.58%, p < 0.001), and preterm birth (8.6 and 53.95%, p < 0.001). Conclusion. The importance of the placental factor in the pathogenesis of PE, the prescription of progestogens corresponds to the main principle of pathogenetic prevention of this complication. Administration of dydrogesterone in the first and second trimesters (6 to 20 weeks of pregnancy) significantly reduces the incidence of PE in high-risk pregnant women. Key words: preeclampsia, prevention, high-risk groups, progestogens, dydrogesterone

An Objective Histopathological Scoring System for Placental Pathology in Pre-Eclampsia and Eclampsia.

Background and objectivePre-eclampsia and eclampsia are common complications in pregnancy, and they lead to uteroplacental vascular insufficiency. More than 38% of pregnant women succumb to seizures without meeting the clinical criteria for pre-eclampsia or eclampsia. This highlights the importance of a confirmatory diagnosis of pre-eclampsia or eclampsia using the histopathological changes seen in the placenta. Hence, the present study aimed to validate an objective histopathological scoring system of the placenta for an appropriate diagnosis of pre-eclampsia or eclampsia.Material and methodsIn this prospective study spanning two years, 50 cases of pre-eclampsia/eclampsia and 50 control subjects with normal placenta were included. The histomorphological changes in the placenta were examined for both groups and a scoring system was formulated to assess the severity of pre-eclampsia/eclampsia syndrome. A maximum score of 2 and a minimum score of 0 was assigned for maternal floor infarcts, calcification, villous basement membrane thickening, and fibrin deposition. Syncytial knots were assigned a minimum score of 0 and a maximum score of 1. The association of various placental histopathological variables with a clinical diagnosis of pre-eclampsia, eclampsia, and control was analyzed using the chi-squared/Fisher’s exact test. A one-way analysis of variance (ANOVA) test was used for comparing objective histopathological scores between pre-eclampsia, eclampsia, and control groups. A p-value of less than 0.05 was considered to be statistically significant.ResultsWe found a significant association between each histopathological parameters of the placenta, including fibrin deposition, maternal floor infarction, calcification, villous basement membrane thickening, and syncytial knots, and clinical diagnosis of pre-eclampsia, eclampsia, and control groups. A median score of 2 significantly correlated with the normal group, while median scores of 4 and 6 correlated with pre-eclampsia and eclampsia respectively.ConclusionThis comprehensive scoring system can be a basis for validating reporting patterns of the placenta in pre-eclampsia and eclampsia patients, as well as other disorders related to maternal uteroplacental insufficiency.

Placental insufficiency and fetal growth restriction: etiology, prevention, and treatment

The review presents modern aspects of the etiology of placental insufficiency (uteroplacental vascular insufficiency), fetal growth restriction and preeclampsia, which arises primarily due to deficient remodeling of the uterine spiral arteries supplying the placenta during early pregnancy. The embryonic, maternal and placental factors of the occurrence of placental insufficiency and placental-related pathology considered. The issues of prevention and treatment of placental insufficiency are considered taking into account the common pathogenesis of this pathological condition.

Role of L-Arginine In Uteroplacental Vascular Insufficiency

Role of L-Arginine In Uteroplacental Vascular Insufficiency

Parental ethnicity and placental maternal vascular malperfusion pathology in healthy nulliparous women

IntroductionRates of some placental-associated pregnancy complications vary by ethnicity, though the strength of association with underlying placental pathology is presently unknown. Our objective was to determine whether an association between ethnicity and placental pathology occurs in low-risk pregnancies. Methods829 low-risk nulliparous pregnant women were prospectively studied. Data were obtained from standardized obstetrical appointments (clinical history, serum biomarkers, placental ultrasound) and hospital delivery records (pregnancy complications, delivery details and perinatal outcomes). Placental pathology was performed in all subjects using standard criteria. ResultsIn our cohort, 72% of women were Caucasian, 14% East Asian, 8% South Asian, 4% Afro-Caribbean and 3% Hispanic women. 81% of couples were concordant (same ethnic background) and 19% discordant (mixed ethnicities). South Asian women had the highest rate of small for gestational age (SGA) birth (customized birthweight <10th percentile) (24.2%), which was associated with the placental features of uteroplacental vascular insufficiency (placental weight <10th percentile with decidual vasculopathy, focal infarction, and/or syncytial knot formation) (p = 0.05). Placental efficiency varied significantly by ethnicity; Caucasian women had the highest efficiency (7.1 ± 1.2) and Afro-Caribbean women the lowest (6.5 ± 0.9) (p < 0.003). Afro-Caribbean women had the highest rate of marginal cord insertion. Placental efficiency, was higher in concordant vs. discordant couples (7.0 ± 1.2 vs. 6.8 ± 1.1; p < 0.05). Placental histopathology was not affected by parental ethnic discordance. DiscussionMaternal ethnicity influences placental efficiency and relationship between uteroplacental vascular insufficiency and SGA birth, but was not associated with other placental pathologies. Discordant parental ethnicity did not affect the development of placental pathologies or adverse pregnancy outcomes.

Placental Pathology in Relation to Uterine Artery Doppler Findings in Pregnancies with Severe Intrauterine Growth Restriction and Abnormal Umbilical Artery Doppler Changes.

Objectives Current guidelines for diagnosis and management of early-onset intrauterine growth restriction (IUGR) rely on umbilical artery Doppler (UAD), without including uterine artery Doppler (UtAD). We hypothesized that IUGR cases with abnormal UAD but normal UtAD has a different spectrum of placental pathology compared with those with abnormal UtAD. Study Design Retrospective review of pregnancies with sonographic evidence of IUGR and abnormal UAD prior to delivery. Cases with ≥ 1 UtAD record(s) after 18+0 weeks' gestation and placental pathology were included. Cases were stratified according to initial UtAD pulsatility index (PI) values (n = 196): normal (n = 19; PI < 95th centile for gestational age/no notching), intermediate (n = 69; PI ≥ 95th centile/no/unilateral notching) and abnormal (n = 108; PI ≥ 95th centile/bilateral notching). Pregnancy outcomes and placental pathology were compared between groups. Results Women in the normal group delivered later than those in the abnormal group (30.1 ± 3.5 vs. 28.0 ± 3.5 weeks; mean ± standard deviation; p = 0.03). Their placentas exhibited higher rates of chronic intervillositis (15.8 vs. 0.9%; p = 0.01), chorangiosis (15.8 vs. 0.9%; p < 0.0001), and massive perivillous fibrin deposition (21.1 vs. 7.4%; p = 0.05), but had lower rates of uteroplacental vascular insufficiency (26.3 vs. 79.6%; p < 0.0001). Conclusion Approximately 10% of pregnancies with early-onset IUGR and abnormal UAD exhibited normal UtAD waveforms. They delivered later, and their placentas exhibited unusual placental pathologies.

Intrauterine growth restriction: impact on cardiovascular development and function throughout infancy.

Intrauterine growth restriction (IUGR) refers to the situation where a fetus does not grow according to its genetic growth potential. One of the main causes of IUGR is uteroplacental vascular insufficiency. Under these circumstances of chronic oxygen and nutrient deprivation, the growth-restricted fetus often displays typical circulatory changes, which in part represent adaptations to the suboptimal intrauterine environment. These fetal adaptations aim to preserve oxygen and nutrient supply to vital organs such as the brain, the heart, and the adrenals. These prenatal circulatory adaptations are thought to lead to an altered development of the cardiovascular system and "program" the fetus for life long cardiovascular morbidities. In this review, we discuss the alterations to cardiovascular structure, function, and control that have been observed in growth-restricted fetuses, neonates, and infants following uteroplacental vascular insufficiency. We also discuss the current knowledge on early life surveillance and interventions to prevent progression into chronic disease.

Anatomie pathologique de l’insuffisance vasculaire utéroplacentaire

The indications of the pathological examination of the placenta are mainly represented by uteroplacental vascular deficiency. The clinical context is often evocative, but it can sometimes be solely an intra-uterine growth retardation or an unexplained in utero fetal death. So, the pathological lesions of this uteroplacental vascular deficiency must be well-known to be correctly interpreted, for none of these lesions is truly specific. The pathological diagnosis is based on a group of macroscopic and microscopic arguments. Various physiopathological mechanisms, often imperfectly known, can be at the origin of an uteroplacental vascular insufficiency, but in the current position, the pathological examination does not allow etiopathogenic orientation. The development of the trophoblastic biopsies gives us access to a new material which, in parallel with the cytogenetic analysis, often allows us, in front of an unexplained intra-uterine growth retardation, to direct the diagnosis towards uteroplacental vascular insufficiency. The histological analysis of the chorionic villous sampling taken precociously during pathological pregnancies is thus a major diagnostic contribution. But especially, this analysis gives access to new information which, in the near future, will enable us to better define the pathological evolution of the lesions of hypoxic chorionic villous and to contribute to a better knowledge of this pathology which, under many aspects, still conceals many mysteries.

Fetal concentrations of the growth factors TGF-α and TGF-β1 in relation to normal and restricted fetal growth at term

Transforming growth factor-α (TGF-α) and TGF-β1 are major anti-inflammatory cytokines and substantially contribute to normal pregnancy outcome. TGF-α stimulates placental mitosis, whereas TGF-β1 is a critical regulator of trophoblast invasion and fetal growth. We aimed to study cord blood TGF-α and TGF-β1 concentrations in intrauterine-growth-restricted (IUGR, usually associated with abnormal trophoblast invasion, uteroplacental vascular insufficiency and enhanced inflammation) and appropriate-for-gestational-age-(AGA) pregnancies, and investigate possible correlations of the above concentrations with several demographic parameters of infants at birth. Plasma TGF-α and TGF-β1 concentrations were determined by ELISA in 154 mixed arterio-venous cord blood samples from IUGR (n=50) and AGA (n=104) singleton full-term infants. After controlling for possible confounding factors (gender, birth-weight, gestational age, maternal age and parity), cord blood TGF-α and TGF-β1 concentrations were significantly higher in IUGR than AGA group (b=0.402, SE=0.179, p=0.027 and b=0.152, SE=0.061, p=0.014, respectively). Delivery mode had an effect on cord blood TGF-α and TGF-β1 concentrations, both being elevated in cases of vaginal delivery (b=−0.282, SE=0.117, p=0.018 and b=−0.123, SE=0.059, p=0.038, respectively). In conclusion, higher cord blood TGF-α and TGF-β1 concentrations may represent a compensatory response to the inflammatory process characterizing the IUGR state. Additionally, higher cord blood TGF-β1 concentrations in IUGRs could be attributed to increased shear stress, resulting from abnormal blood flow in IUGR fetal blood vessels. Finally, vaginal delivery-associated cytokine release may account for elevated TGF-α and TGF-β1 concentrations.

Cord Blood H- and L-Ficolin Concentrations in Term Pregnancies with Normal and Restricted Fetal Growth

Background and Aims: Ficolins H and L are serum defence proteins, mainly expressed in the liver and differing in ligand specificity. They initiate the lectin pathway of complement activation through association with mannose-binding-protein- associated proteases (MASPs). Ficolins are implicated in the pathogenesis of infectious and autoimmune diseases, apoptosis and preeclampsia. H-ficolin is a powerful direct opsonin binding to late apoptotic cells. This study aimed to determine H- and L-ficolin cord blood concentrations in appropriate-for-gestational-age (AGA) and intrauterine-growth-restricted pregnancies (IUGR), associated with excessive apoptosis, uteroplacental vascular insufficiency and activation of the innate immune system. Furthermore to investigate possible correlations of H- and L-ficolin concentrations with several demographic parameters of infants at birth. Methods: Serum H- and L-ficolin concentrations were determined by ELISA in 160 mixed arteriovenous cord blood samples from 50 IUGR and 110 AGA singleton full-term pregnancies. Results: No significant differences in cord blood H- and L-ficolin concentrations were observed between IUGR and AGA groups. The effect of customized centile, birthweight, gender, gestational age, parity and maternal age on cord blood H- and L-ficolin concentrations was not significant in both groups. Conclusions: Lack of differences in cord blood H- and L- ficolin concentrations at term between IUGR and AGA groups possibly suggests that they are not directly implicated in the pathophysiological processes of IUGR. Possibly this happens because the lectin pathway of complement activation, as far as ficolins are concerned, may not be fully functional at birth.

Soluble Fas Antigen and Soluble Fas Ligand in Intrauterine Growth Restriction

Background: The Fas-Fas ligand (FasL) pathway of apoptosis contributes to immune tolerance at the fetomaternal interface and has been ascribed a role in implantation and placental development. Intrauterine growth restriction (IUGR) may be associated with impaired maternal-fetal tolerance, resulting in increased trophoblast apoptosis and uteroplacental vascular insufficiency. Objectives: To investigate soluble Fas (sFas) and FasL (sFasL) concentrations in maternal, fetal and neonatal serum of IUGR and appropriate-for-gestational-age (AGA) pregnancies. Methods: Circulating sFas and sFasL concentrations were determined in 40 mothers and their 20 IUGR (due to several etiologies) and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and 4 (N4). Results: No significant differences in sFas and sFasL concentrations were observed between groups. In both groups, maternal sFas concentrations were increased compared to fetal, N1 and N4 ones (p≤0.005 in AGA and p < 0.001 in IUGR, in all cases). On the other hand, maternal sFasL concentrations were lower compared to fetal, N1 and N4 ones (p < 0.001 in all cases). Fetal sFasL concentrations were increased compared to maternal, but lower compared to N4 sFasL ones (p < 0.001 in AGA and p ≤ 0.020 in IUGR, in all cases). N4 sFasL concentrations were elevated compared to N1 ones (p < 0.001). Conclusions: Circulating maternal, as well as fetal sFas and sFasL concentrations do not differ between AGA controls and IUGR cases, irrespectively of the etiology of the latter. Furthermore, the results of this study imply an acceleration of Fas-FasL-mediated apoptosis during delivery and a respective decrease postpartum in both normal and IUGR pregnancies.

Intrapartum Stillbirths in Hospital Unrelated to Uteroplacental Vascular Insufficiency

The aim of this study was to investigate the causes of intrapartum asphyxia and its relationship to placental abnormalities. Twenty intrapartum fetal death autopsies carried out over a 10-year period in one hospital pathology department associated with a large obstetric unit were reviewed. All the intrapartum fetal deaths occurred in the hospital, while the mothers were being monitored during and after labor. On morphologic grounds, all the fetal deaths were thought to be caused by intrapartum asphyxia. Seven of the intrapartum fetal deaths were associated with intrauterine infection causing funisitis, and in 6 of these cases, chorioamnionitis was present as well. Two cases were caused by placental abruption, and 1 case was caused by cord compression. In 8 of the 10 remaining cases in which the placenta was examined, a minor placental abnormality was detected in only 1 case. Five of the 10 cases had a mild astrocytosis in the intracerebral periventricular white matter, suggestive of intrauterine ischemia at least 12 hours before death. Five of the 10 cases were thought by the delivering obstetrician to have umbilical cord abnormalities. The main conclusions from this study are that, except in cases of intrauterine infection, placental vascular abnormalities are unlikely to be associated with intrapartum asphyxia leading to fetal death during labor. The number of cases with umbilical cord abnormalities raises the possibility that cord accidents may be a significant cause of intrapartum stillbirth.

Intrauterine growth restriction due to uteroplacental vascular insufficiency leads to increased hypoxia-induced cerebral apoptosis in newborn piglets

Uteroplacental vascular insufficiency in humans is a common cause of intrauterine growth restriction (IUGR) and is associated with an increased incidence of perinatal asphyxia and neurodevelopmental disorders compared to normal weight newborns. Experimental models that provide an opportunity to analyze the pathogenesis of these relationships are limited. Here, we used neonatal pigs from large litters in which there were piglets of normal birth weight (for controls) and of low birth weight (for uteroplacental vascular insufficiency). Hypoxia was induced in paired littermates by reducing the fraction of inspired oxygen to 4% for 25 min. Brain tissue was collected 4 h post-hypoxia. Cerebral levels of apoptosis were quantified morphologically and verified with caspase-3 activity and TUNEL. Expression of Bcl-2, Bcl-XL and Bax proteins was investigated using immunohistochemistry. Cellular positivity for Bcl-2 was consistently higher in the non-apoptotic white matter of the hypoxic IUGR animals compared with their littermates and reached significance at P < 0.05 in several pairs of littermates. Alterations in Bax showed a trend towards higher expression in the hypoxic IUGR littermates but rarely reached significance. The IUGR piglets showed a significantly greater amount of apoptosis in response to the hypoxia than the normal weight piglets, suggesting an increased vulnerability to apoptosis in the IUGR piglets.

Fetal response to maternal exercise in pregnancies with uteroplacental insufficiency

The purpose of this study was to determine the fetal response to submaximal maternal exercise at 22 to 26 weeks in pregnancies with abnormal uterine artery Doppler. This was a prospective comparison of singleton pregnancies with uteroplacental vascular insufficiency (UPVI) (mean uterine pulsatility index [PI] values >1.45 [n = 12]) and those with normal uterine artery Doppler (n = 23). Maternal and fetal cardiovascular responses to 5 minutes of steady state cycling at 10% and at 15% of predicted work rate maximum were studied. Umbilical artery Doppler deteriorated after exercise in patients with UPVI (pre PI 1.4 [0.35-2.14], post PI 1.64 [0.45-2.18]). Three (25%) had transient absent-end diastolic flow (AEDF) in umbilical artery, 2 of which developed early-onset intrauterine growth restriction (IUGR) with AEDF. Fetal cardiac output studies remained stable during the examinations. Submaximal steady state exercise had a transient deleterious effect in a subset of women with uteroplacental vascular insufficiency destined to develop early-onset IUGR.

Fetal response to maternal exercise in pregnancies with uteroplacental vascular insufficiency

To determine the fetal response to sub-maximal maternal exercise at 22-26 weeks in pregnancies with abnormal uterine artery Doppler. A prospective matched cohort-control study was undertaken. Twelve singleton pregnancies with bilateral uterine artery notching and mean uterine pulsatility index (PI) values >1.45 at 22-26 weeks of gestation were evaluated. Matched controls (n = 23) were clinically normal and had normal uterine artery Doppler. Maternal and fetal cardiovascular responses to 5 minutes of steady state cycling at 10% and at 15% of maximum predicted work rate were evaluated by ultrasound/Doppler. Baseline characteristics were similar between the 2 groups. No differences in either resting or in exercise-induced maternal or fetal cardiac parameters were found between the 2 groups. There was no difference between the basline umbilical artery PI values for cases and controls but the difference became significant post exercise (P = .02 after the 10% load and P = .006 after the 15% load). Of the 12 cases, 6 subsequently developed preeclampsia, 5 had SGA fetuses, 2 of which developed absent end-diastolic flow velocity (AEDF) and early-onset intrauterine growth restriction (IUGR). Mean gestational age at delivery was 33 weeks vs. 40 weeks in the controls (P = .001). 3/12 (25%) cases developed transient (AEDF) in umbilical artery Doppler after the exercise that recovered after cessation of exercise, compared with none of the controls. 2/3 of these subsequently developed AEDF and IUGR. Sub-maximal steady state exercise may have transient deleterious effects in a subset of women with uteroplacental vascular insufficiency. These findings may impact on advice regarding physical activity in this sub-group of women. Dynamic testing such as maternal exercise may be of value in identifying pregnancies that adapt poorly to uteroplacental vascular insufficiency.

Relationship between Uteroplacental Blood Flow snd Thrombophilia in Women eith Late Complicated Pregnancies.

There is a growing body of evidence that thrombophilia is linked to several obstetrical complications, most likely through uteroplacental vascular insufficiency. Very few studies have however evaluated whether alterations of the uteroplacental blood flow, as assessed functionally by Doppler ultrasound analysis, are associated with thrombophilic abnormalities in women with late pregnancy complications. Forty-nine non-smoking women followed during their whole pregnancy in the High Risk Pregnancy Clinic of the Cliniques Universitaires Saint-Luc, Brussels, in 2003 were enrolled in this retrospective study. They all had an unexplained late pregnancy complication (intrauterine growth retardation (IUGR) (n=34), intrauterine fetal death (IUFD) (n=4), preeclampsia (n=11)). They were not treated with anti-thrombotic agents. They all had a complete thrombophilic work-up (functional antithrombin, protein C and S assays, homocystein level, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), activated protein C resistance, G20210A prothrombin gene mutation). Doppler evaluation of the uterine arteries (assessed by the presence of bilateral notches after 26 weeks) and umbilical arteries (assessed by resistance index above 90th percentile) was performed. Thrombophilic abnormalities were identified in 8 of 49 (16%) women (factor V Leiden (FVL) (n=4), G20210A prothrombin gene mutation (n=2) and isolated anticardiolipin antibodies (n=2)). Of the 49 women, 20 had an abnormal Doppler (uterine (n=5) and umbilical (n=15)) including IUGR (n=13), IUFD (n=2) and preeclampsia (n=5). Four women with thrombophilia were found to have Doppler abnormalities (4/20; 20%) while most women with Doppler alterations had no thrombophilia. In conclusion, abnormal uteroplacental Doppler findings are frequently found in women with late pregnancy complications. They do not seem to be correlated with the presence of thrombophilic abnormalities even if thrombophilia seems to be more frequent in obstetrical complications.

Polycystic ovary syndrome, infertility, familial thrombophilia, familial hypofibrinolysis, recurrent loss of in vitro fertilized embryos, and miscarriage

Objective: To study reversible determinants of infertility and recurrent loss of transferred embryos after failure of 7 of 10 embryo transfers, 1 live birth, and 2 miscarriages. Design: Measures of thrombophilia, hypofibrinolysis, reproductive hormones, and androgenic steroids before and after metformin therapy. Setting: Outpatient clinical research center. Patient(s): A 32-year-old amenorrheic, infertile woman with polycystic ovary syndrome (PCOS) who had 7 of 10 embryo transfers fail, 1 premature live birth, and 2 miscarriages at 8 and 17 weeks. Intervention(s): Metformin (2.55 g/d) was given to ameliorate the endocrinopathy of PCOS. Main Outcome Measure(s): Coagulation, insulin, reproductive hormones, and androgenic steroids. Result(s): The propositus had thrombophilia (familial protein S deficiency [free protein S 32%; normal ≥65%]). She also had familial hypofibrinolysis with 4G4G polymorphism of the plasminogen activator inhibitor (PAI-1) gene and high PAI-1 activity (PAI-Fx), 42.5 U/mL, normal <21.1. Polycystic ovary syndrome was characterized by amenorrhea, polycystic ovaries, high fasting serum insulin (39 μU/mL, normal <20), androstenedione (763 ng/dL, normal <250), and testosterone (229 ng/dL, normal <83). After she received metformin for 4 months, PAI-Fx normalized (12.4 U/mL), as did insulin (12 μU/mL), androstenedione (185 ng/dL), and testosterone (39 ng/dL); weight fell from 109 to 91.3 kg (16%). Conclusion(s): Metformin reversed the endocrinopathy of PCOS. Familial thrombophilia and hypofibrinolysis may lead to thrombosis-mediated uteroplacental vascular insufficiency, failure to achieve pregnancy after embryo transfer, and miscarriage.

Morphological findings and value of placental examination at fetal and perinatal autopsy.

The purpose of this study was to report on the morphological findings in placentae from abortions, stillbirths and perinatal deaths, and to assess the value of the results of the placental examinations. The material included 341 placentae and their matched autopsies. Fifty placentae came from abortions induced for medical reasons, 194 from spontaneous abortions, 84 from stillbirths, and 13 from livebirths. Histological slides from all placentae were reviewed and the placental diagnoses were related to the autopsy diagnoses. Frequently observed placental lesions were inflammation of the membranes and/or umbilical cord, placental edema, vascular lesions, single umbilical artery, and degenerative lesions. The placental examination in pregnancies terminating with fetal or perinatal death was of value in half the cases. Some placental lesions provide us with clues when assessing the cause of fetal death, but such lesions are rare. Two important groups of lesions, acute inflammation of the membranes and/or umbilical cord and lesions consistent with uteroplacental vascular insufficiency, seen mainly as infarction and decidual arteriopathy, were observed. Gross examination is informative, though microscopic examination is often necessary.