Low molecular weight heparin for the prevention of severe preeclampsia: where next?

Low molecular weight heparin has been extensively evaluated for the prevention of preeclampsia in high-risk pregnant women; however, the results from these trials have been conflicting. This review discusses the potential mechanisms of action of low molecular weight heparin for the prevention of severe preeclampsia, how to optimize the selection of high-risk women for participation in future trials, and the importance of trial standardization.

Clinical Validation of Non-Invasive Cardiac Output Monitoring in Healthy Pregnant Women.

OBJECTIVE: Non-invasive hemodynamic monitoring has the potential to be a valuable clinical tool for the screening and management of hypertensive disorders of pregnancy. The objective of this study was to validate the clinical utility of the non-invasive cardiac output monitoring (NICOM) system in pregnant women. METHODS: Twenty healthy pregnant women with a singleton pregnancy at 22 to 26 weeks' gestation were enrolled in this study. Measures of heart rate, stroke volume, and cardiac output were obtained through NICOM and compared with Doppler echocardiography. RESULTS: NICOM significantly overestimated measures of both stroke volume and cardiac output compared with Doppler echocardiography (95 ± 4 vs. 73 ± 4 mL, P < 0.0001; and 7.4 ± 0.2 vs. 5.6 ± 0.2 L/min, P < 0.0001; respectively). CONCLUSIONS: There is no gold standard for the measurement of cardiac output in the setting of pregnancy. However, once normal values have been established, NICOM has the potential to be a useful clinical tool for monitoring maternal hemodynamics in pregnant women. Further investigation regarding the validity of NICOM is required in larger populations of healthy and hypertensive pregnant women to determine whether this device is appropriate for maternal hemodynamic assessment during pregnancy.

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.

Identification of a novel neutrophil population: proangiogenic granulocytes in second-trimester human decidua.

The maternal leukocytes of the first-trimester decidua play a fundamental role in implantation and early development of the fetus and placenta, yet little is known regarding the second-trimester decidual environment. Our multicolor flow cytometric analyses of human decidual leukocytes detected an elevation in tissue resident neutrophils in the second trimester. These cells in both human and murine samples were spatially restricted to decidua basalis. In comparison with peripheral blood neutrophils (PMNs), the decidual neutrophils expressed high levels of neutrophil activation markers and the angiogenesis-related proteins: vascular endothelial growth factor-A, Arginase-1, and CCL2, similarly shown in tumor-associated neutrophils. Functional in vitro assays showed that second-trimester human decidua conditioned medium stimulated transendothelial PMN invasion, upregulated VEGFA, ARG1, CCL2, and ICAM1 mRNA levels, and increased PMN-driven in vitro angiogenesis in a CXCL8-dependent manner. This study identified a novel neutrophil population with a physiological, angiogenic role in human decidua.

Is heparin a placental anticoagulant in high-risk pregnancies?

Randomized control trials show beneficial effects of heparin in high-risk pregnancies to prevent preeclampsia and intrauterine growth restriction. However, the lack of placental pathology data in these trials challenges the assumption that heparin is a placental anticoagulant. Recent data show that placental infarction is probably associated with abnormalities in development of the placenta, characterized by poor maternal perfusion and an abnormal villous trophoblast compartment in contact with maternal blood, than with maternal thrombophilia. At-risk pregnancies may therefore be predicted by noninvasive prenatal testing of placental function in mid-pregnancy. Heparin has diverse cellular functions that include direct actions on the trophoblast. Dissecting the non-anticoagulant actions of heparin may indicate novel and safer therapeutic targets to prevent the major placental complications of pregnancy.

Web-based education for placental complications of pregnancy.

OBJECTIVE: The objective of this study was to determine whether a web-based education strategy could improve maternal knowledge of placental complications of pregnancy and reduce maternal anxiety in high risk-pregnancies. METHODS: Prospective study in the Placenta Clinic at Mount Sinai Hospital, Toronto, Ontario. Maternal demographics and Internet usage were recorded at the patient's baseline appointment. Placental knowledge was determined using structured verbal and illustrative assessments. The six-item State-Trait Anxiety Inventory (STAI) was administered to assess baseline maternal anxiety. Women were asked to visit the Placenta Clinic website for a minimum of 15 minutes before their follow-up appointment, at which time their placental knowledge and STAI assessments were repeated. RESULTS: Eighteen women were included in the study. Patient knowledge at the baseline appointment was generally poor (median score 10.5 out of a maximum score of 27, range 1 to 22), with major deficits in basic placental knowledge, placenta previa/increta, and preeclampsia. At the follow-up appointment, placental knowledge was significantly improved (median score 23, range 10 to 27; P < 0.001). Educational status (high school or less vs. college or more) had no effect on either baseline knowledge or knowledge improvement. Maternal anxiety at baseline (median score 12 out of a maximum score of 24, range 6 to 23) was significantly reduced at the follow-up appointment (median score 8.5, range 6 to 20; P = 0.005). CONCLUSION: Deficits in maternal knowledge of placental complications of pregnancy in high-risk pregnant women were substantial but easily rectified with a disease-targeted web-based educational resource. This intervention significantly improved patient knowledge and significantly reduced maternal anxiety.

Objectif : Cette étude avait pour objectif de déterminer si une stratégie pédagogique sur le Web pouvait améliorer les connaissances maternelles en matière de complications placentaires de la grossesse et atténuer l'anxiété maternelle dans le cadre des grossesses exposées à des risques élevés. Méthodes : Tenue d'une étude prospective au sein de la Placenta Clinic du Mount Sinai Hospital à Toronto, en Ontario. Les habitudes d'utilisation d'Internet et les caractéristiques démographiques maternelles ont été consignées au cours de la consultation de départ avec la patiente. Les connaissances quant au placenta ont été déterminées au moyen d'évaluations illustrées et verbales structurées. Le six-item State-Trait Anxiety Inventory (STAI) a été administré pour évaluer l'anxiété maternelle de départ. Nous avons demandé aux femmes de consulter le site Web de la Placenta Clinic pendant un minimum de 15 minutes avant leur consultation de suivi; au cours de celle-ci, leurs connaissances quant au placenta ont été évaluées à nouveau et les évaluations STAI ont été menées une fois de plus. Résultats : Dix-huit femmes ont participé à l'étude. Au moment de la consultation de départ, les connaissances des patientes étaient généralement faibles (score médian de 10,5 sur un score maximal de 27, plage de 1 à 22), des déficits majeurs ayant été constatés en matière de connaissances de base quant au placenta, au placenta prævia/increta et à la prééclampsie. Au moment de la consultation de suivi, les connaissances quant au placenta présentaient une amélioration considérablement accrue (score médian de 23, plage de 10 à 27; P < 0,001). Le niveau de scolarité (études secondaires ou moins vs études postsecondaires ou plus) n'a exercé aucun effet sur l'état des connaissances au départ ni sur l'amélioration des connaissances. L'anxiété maternelle au départ (score médian de 12 sur un score maximal de 24, plage de 6 à 23) avait connu une baisse considérable au moment de la consultation de suivi (score médian de 8,5, plage de 6 à 20; P = 0,005). Conclusion : Les déficits en matière de connaissances maternelles quant aux complications placentaires de la grossesse chez les femmes enceintes exposées à des risques élevés étaient substantiels, mais facilement corrigeables au moyen d'une ressource pédagogique sur le Web axée sur la maladie. Cette intervention a mené à une amélioration significative des connaissances des patientes et à une baisse considérable de l'anxiété maternelle.

Multidisciplinary management of invasive placenta previa.

OBJECTIVE: To assess the effectiveness of a multidisciplinary team approach to reduce severe maternal morbidity in women with invasive placenta previa. METHODS: We conducted a prospective study of 33 women with placenta previa and increta-percreta (diagnosed by ultrasound and/or magnetic resonance imaging) delivering at Mount Sinai Hospital, Toronto, following the introduction in January 2008 of a team-based approach to women with this condition. We included women who delivered by June 2012. We reviewed antenatal outpatient and inpatient records for use of six pre-defined team components by the attending staff obstetrician: (1) antenatal maternal-fetal medicine consultation, (2) surgical gynaecology consultation, (3) antenatal MRI, (4) interventional radiology consultation and preoperative placement of balloon catheters in the anterior divisions of the internal iliac arteries, (5) pre-planned surgical date, and (6) surgery performed by members of the invasive placenta surgical team. Antenatal course, delivery, and postpartum details were recorded to derive a five-point composite severe maternal morbidity score based on the presence or absence of: (1) ICU admission following delivery, (2) transfusion > 2 units of blood, (3) general anaesthesia start or conversion, (4) operating time in highest quartile (> 125 minutes), and (5) significant postoperative complications (readmission, prolonged postpartum stay, and/or pulmonary embolism). RESULTS: All 33 women survived during this time period. Two thirds (22/33) had either five or six of the six components of multidisciplinary care. Increasing use of multidisciplinary team components was associated with a significant reduction in composite morbidity (R2 = 0.228, P = 0.005). CONCLUSION: Team-based assessment and management of women with invasive placenta previa is likely to improve maternal outcomes and should be encouraged on a regional basis.

Objectif : Évaluer l'efficacité d'une approche d'équipe multidisciplinaire visant l'atténuation de la morbidité maternelle grave chez les femmes qui présentent un placenta prævia invasif. Méthodes : Nous avons mené une étude prospective auprès de 33 femmes qui présentaient un placenta prævia et increta-percreta (diagnostiqué par échographie et/ou imagerie par résonance magnétique) et qui accouchaient au Mount Sinai Hospital de Toronto, à la suite du lancement (en janvier 2008) d'une approche d'équipe visant les femmes qui présentaient une telle placentation. Nous avons inclus les accouchements chez les femmes visées jusqu'en juin 2012. Nous avons analysé les dossiers prénataux (services externes et services hospitaliers) en vue d'y repérer l'utilisation par l'obstétricien titulaire de six composantes d'équipe prédéfinies : (1) consultation prénatale en médecine fœto-maternelle; (2) consultation en chirurgie gynécologique; (3) IRM prénatale; (4) consultation en radiologie interventionnelle et mise en place préopératoire de sondes à ballonnet dans les divisions antérieures des artères iliaques internes; (5) planification à l'avance de la date de chirurgie; et (6) chirurgie menée par des membres de l'équipe chirurgicale vouée aux cas de placenta invasif. Les détails de l'évolution prénatale, de l'accouchement et de la période postpartum ont été consignés afin d'établir un score composite de morbidité maternelle grave en cinq points fondé sur la présence ou l'absence de ce qui suit : (1) admission à l'USI à la suite de l'accouchement; (2) transfusion de plus de deux unités de sang; (3) anesthésie générale (administration ou conversion); (4) temps opératoire se situant dans le quartile le plus élevé (> 125 minutes); et (5) complications postopératoires significatives (réhospitalisation, hospitalisation postpartum prolongée et/ou embolie pulmonaire). Résultats : Les 33 participantes ont survécu au cours de cette période. Les deux tiers (22/33) d'entre elles présentaient cinq ou six des six composantes des soins multidisciplinaires. L'utilisation croissante des composantes des soins multidisciplinaires a été associée à une baisse significative de la morbidité composite (R2 = 0,228, P = 0,005). Conclusion : L'évaluation et la prise en charge en équipe des femmes qui présentent un placenta prævia invasif sont susceptibles d'améliorer les issues maternelles et devraient être favorisées sur une base régionale.

The molecular role of connexin 43 in human trophoblast cell fusion.

Connexin expression and gap junctional intercellular communication (GJIC) mediated by connexin 43 (Cx43)/gap junction A1 (GJA1) are required for cytotrophoblast fusion into the syncytium, the outer functional layer of the human placenta. Cx43 also impacts intracellular signaling through protein-protein interactions. The transcription factor GCM1 and its downstream target ERVW-1/SYNCYTIN-1 are key players in trophoblast fusion and exert their actions through the ERVW-1 receptor SLC1A5/ASCT-2/RDR/ATB(0). To investigate the molecular role of the Cx43 protein and its interaction with this fusogenic pathway, we utilized stable Cx43-transfected cell lines established from the choriocarcinoma cell line Jeg3: wild-type Jeg3, alphahCG/Cx43 (constitutive Cx43 expression), JpUHD/Cx43 (doxycyclin-inducible Cx43 expression), or JpUHD/trCx43 (doxycyclin-inducible Cx43 carboxyterminal deleted). We hypothesized that truncation of Cx43 at its C-terminus would inhibit trophoblast fusion and protein interaction with either ERVW-1 or SLC1A5. In the alphahCG/Cx43 and JpUHD/Cx43 lines, stimulation with cAMP caused 1) increase in GJA1 mRNA levels, 2) increase in percentage of fused cells, and 3) downregulation of SLC1A5 expression. Cell fusion was inhibited by GJIC blockade using carbenoxylone. Neither Jeg3, which express low levels of Cx43, nor the JpUHD/trCx43 cell line demonstrated cell fusion or downregulation of SLC1A5. However, GCM1 and ERVW-1 mRNAs were upregulated by cAMP treatment in both Jeg3 and all Cx43 cell lines. Silencing of GCM1 prevented the induction of GJA1 mRNA by forskolin in BeWo choriocarcinoma cells, demonstrating that GCM1 is upstream of Cx43. All cell lines and first-trimester villous explants also demonstrated coimmunoprecipitation of SLC1A5 and phosphorylated Cx43. Importantly, SLC1A5 and Cx43 gap junction plaques colocalized in situ to areas of fusing cytotrophoblast, as demonstrated by the loss of E-cadherin staining in the plasma membrane in first-trimester placenta. We conclude that Cx43-mediated GJIC and SLC1A5 interaction play important functional roles in trophoblast cell fusion.

Safer outcomes for placenta accreta spectrum disorders: A decade of quality improvement.

OBJECTIVE: To describe the evolution and evaluation of protocol-based multidisciplinary quality improvement (QI) in women undergoing cesarean hysterectomy for radiologically suspected and pathologically confirmed placenta accreta spectrum (PAS) disorders. METHODS: A single-center, retrospective cohort study was conducted of all patients undergoing cesarean hysterectomy for PAS disorders between March 2009 and June 2018. Two distinct periods were defined to compare outcomes: 2009-2011 (initial period) and 2017-2018 (current period). Primary outcomes included blood loss and administration of blood products. Secondary outcomes included perioperative levels of hemoglobin, adverse events and complications, time to mobilization, and length of hospitalization. RESULTS: Among the 105 consecutive patients identified, there were 26 in the initial period and 32 in the current period. With the implementation of all QI care bundles, median estimated surgical blood loss halved from 2000 ml in the initial period to 1000 ml in the current period, and fewer patients required allogenic blood transfusion (61.5% vs 25%). Patients in the current period demonstrated improved postoperative levels of hemoglobin compared to those in the initial period (101 g/L vs 89 g/L) and had a shorter median postoperative hospital stay (3 days vs 5 days). CONCLUSION: These results support the implementation of a multifaceted QI and patient care initiative for women with PAS disorders.

Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk.

BACKGROUND: Women with a history of placental disease are at increased risk for the future development of vascular disease. It is unknown whether preexisting endothelial dysfunction underlies both the predisposition to placental disease and the later development of vascular disease. The aim of this study was to assess vascular function in postpartum women and to determine whether differences emerged depending on the presentation of placental disease. METHODS AND RESULTS: Women with a history of early-onset preeclampsia (n=15), late-onset preeclampsia (n=9), intrauterine growth restriction without preeclampsia (n=9), and prior normal pregnancy (n=16) were studied 6 to 24 months postpartum. Flow-mediated vasodilatation and flow-independent (glyceryl trinitrate-induced) vasodilatation were studied through the use of high-resolution vascular ultrasound examination of the brachial artery. Arterial stiffness was assessed by pulse-wave analysis (augmentation index). Laboratory assessment included circulating angiogenic factors (vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin). Flow-mediated vasodilatation was significantly reduced in women with previous early-onset preeclampsia and intrauterine growth restriction compared with women with previous late-onset preeclampsia and control subjects (3.2±2.7% and 2.1±1.2% versus 7.9±3.8% and 9.1±3.5%, respectively; P<0.0001). Flow-independent vasodilatation was similar among all groups. Similarly, the radial augmentation index was significantly increased among women with previous early-onset preeclampsia and intrauterine growth restriction, but not among late preeclamptic women and control subjects (P=0.0105). Circulating angiogenic factors were similar in all groups. CONCLUSION: Only women with a history of early-onset preeclampsia or intrauterine growth restriction without preeclampsia exhibit impaired vascular function, which might explain their predisposition to placental disease and their higher risk of future vascular disease.

Sonographic findings and clinical outcomes in women with massive subchorionic hematoma detected in the second trimester.

BACKGROUND: Small hematomas on the placental surface, termed subamniotic hemorrhage, are a common finding either at the routine 18- to 20-week anatomy ultrasound or at subsequent assessments of fetal growth and well-being. Hemorrhage beneath or at the edge of the placenta, or behind an isolated area of the fetal membranes, is of greater concern. THE CASES: We describe the ultrasound findings and clinical outcomes in two women with a diagnosis of massive intrauterine hematoma arising from the fetal membranes. Both required blood transfusion because of the extent of concealed and revealed bleeding. In each case the initial placental appearances and uterine artery Doppler studies were normal. Both hematomas resolved with growth of the fetus and amniotic sac. Each neonate survived the perinatal period favourably. One was born vaginally at 32 weeks' gestation following premature preterm rupture of the membranes, and the second was born by emergency Caesarean section at 37 weeks because of a recurrence of antepartum hemorrhage. CONCLUSION: Large intrauterine hematomas may be acutely detrimental to maternal health in the second trimester. Ultrasound assessment of the placenta is useful to define the perinatal prognosis and may demonstrate gradual resolution. Despite a dramatic initial presentation, this finding may be compatible with a favourable outcome.

Planned caesarean hysterectomy versus "conserving" caesarean section in patients with placenta accreta.

OBJECTIVES: Invasive placentation (placenta accreta, increta, or percreta) presents significant challenges at Caesarean section. Caesarean hysterectomy in such circumstances may result in massive blood loss despite surgical expertise. We reviewed two divergent surgical approaches: planned Caesarean hysterectomy versus a "conserving surgery" in which the placenta is left in situ after Caesarean section. METHODS: We conducted a single-centre retrospective review of all patients who delivered with invasive placentation between 2000 and 2009. We included only patients with antenatally diagnosed invasive placentation and planned mode of delivery. RESULTS: Twenty-six patients met the inclusion criteria. Caesarean hysterectomy was planned in 16 patients and conserving surgery in 10. Intraoperative and postoperative complications were comparable in the two groups. Four of 10 patients initially treated by conservative surgery required a subsequent hysterectomy for severe vaginal bleeding, coagulopathy, or sepsis. No pregnancies were subsequently reported in the conserving surgery group. CONCLUSION: An initial conserving surgical procedure is an option in patients with extensive invasive placentation, but it requires further monitoring for potential complications and carries a high subsequent hysterectomy rate.

Utility of head/abdomen circumference ratio in the evaluation of severe early-onset intrauterine growth restriction.

OBJECTIVE: To determine whether the predominant phenotype of intrauterine growth restriction (IUGR) is symmetric or asymmetric in severe, early-onset disease due to placental insufficiency. METHODS: We conducted a retrospective chart review of high-risk pregnant women with severe, early-onset IUGR who were delivering at < 33+0 weeks' gestation at Mount Sinai Hospital from 2001 to 2010. Ultrasound images were reviewed for fetal biometry, amniotic fluid volume, and uterine and umbilical Doppler flow studies within seven days of delivery, and the frequency of head circumference/abdominal circumference ratio ≥ 95th percentile for gestation was determined. RESULTS: Sixty-two of 107 pregnancies (58%) with early-onset IUGR had an elevated HC/AC ratio (≥ 95th percentile), which was more than 10-fold greater than the expected proportion (P < 0.001). High rates of severe preeclampsia (53%), abnormal amniotic fluid (70%), and abnormal uterine artery Doppler studies (78%) indicated placental insufficiency. CONCLUSION: Fetuses with severe placental IUGR in the second trimester are more likely to have an asymmetric phenotype. This is in contrast to the current belief that asymmetric IUGR is confined to third trimester IUGR.

Hypospadias in males with intrauterine growth restriction due to placental insufficiency: the placental role in the embryogenesis of male external genitalia.

Our aim was to define the association between early onset intra-uterine growth restriction (IUGR) due to placental insufficiency and hypospadias in males. We prospectively studied a cohort of small-for-gestational age (SGA) male infants with hypospadias managed by a multidisciplinary team over a 5-year period. Thirty SGA male infants were diagnosed with hypospadias/abnormal genitalia after birth, and four of them were diagnosed antenatally. Five cases occurred in the smaller pair of discordant IUGR twins, where the larger co-twin had normal male genitalia. Serial ultrasounds demonstrated features of early-onset IUGR in all cases at a median gestational age of 21 weeks (range 14-31weeks). Twenty-one (70%) pregnancies were subsequently complicated by absent/reversed end-diastolic flow in the umbilical arteries indicating severe IUGR, and 17 (57%) women developed severe pre-eclampsia. There were 27 (90%) live births at a median gestational age of 31 weeks (range 27-37); 23 (77%) of the neonates had birth weights <3rd centile. All newborns had normal male karyotypes. In 62% (18/29) the hypospadias was severe. A correlation was found between the severity of the IUGR and the severity of hypospadias as significantly more infants with severe hypospadias were less than the 3rd centile compared to the mild-moderate hypospadias group: 94% (17/18) versus 55% (6/11), respectively (P = 0.02). In conclusion, SGA male newborns with hypospadias exhibit a high rate of early-onset severe IUGR due to placental insufficiency. Early placental development likely influences male external genitalia formation. Careful sonographic evaluation of the genitalia is advised when early-onset placentally mediated IUGR is found.

Sonographic maturation of the placenta at 30 to 34 weeks is not associated with second trimester markers of placental insufficiency in low-risk pregnancies.

OBJECTIVE: Advanced placental maturation (Grannum [G] grade 3) before term is associated with adverse perinatal outcomes associated with placental insufficiency. The nature and timing of the underlying pathology of this process is presently unclear. We hypothesized that advanced placental maturation at 30 to 34 weeks' gestation is not associated with established second trimester markers of severe placental dysfunction. METHODS: In a cohort study of 1238 low-risk Caucasian women with singleton pregnancies who had sonographic assessment of placental maturation and fetal growth at 34 weeks, the results of maternal serum screening (MSS) and uterine artery Doppler (UtAD) flow studies at 16 weeks were related to adverse perinatal outcomes associated with placental insufficiency: antepartum hemorrhage, preeclampsia, preterm birth < 37 weeks, small for gestational age (< 10th percentile), or postnatal evidence of intrauterine growth restriction (IUGR; ponderal index < 5th percentile). RESULTS: G1 was found in 127 women (10.3%), G2 was found in 18 women (1.5%), and no cases of G3 were observed. Advanced Grannum grading was significantly associated with IUGR (48 [4.4%] in G0, 9 [7.1%] in G1, 5 [27.8%] in G2; P < 0.001), but was dependent on smoking status. IUGR was not predicted by abnormal MSS or abnormal UtAD findings at either the second or third trimester ultrasounds. CONCLUSION: G2 maturation at 30 to 34 weeks' gestation is associated with mild IUGR at delivery in low-risk women and with smoking. IUGR was not predicted by either second or third trimester markers of severe placental dysfunction. Future studies directly observing the placenta in the late third trimester may aid the elusive diagnosis of "late-onset" mild IUGR.

Assisted reproductive technology and placenta-mediated adverse pregnancy outcomes.

OBJECTIVE: To estimate whether the use of specific types of assisted reproductive technology (ART) is associated with an increased risk of placenta-mediated pregnancy complications, which include preeclampsia, stillbirth, small for gestational age at birth, and placental abruption. METHODS: A population-based retrospective cohort study was conducted on singleton pregnancies conceived by different types of ART based on the 2004-2007 Ontario Niday Perinatal Database. Patients with fetal anomalies and maternal health problems were excluded as important confounders. Three exposed groups were created by the subtype of ART, including in vitro fertilization with or without intracytoplasmic sperm injection, intrauterine insemination, and ovulation induction. The nonexposed groups were the singleton pregnancies conceived naturally. For each exposed woman, four women from the nonexposed group were randomly matched by maternal age and parity. RESULTS: There were 2,118 exposed participants and 8,420 matched nonexposed participants in the study. The sample size provided 80% power for a relative risk of 2.0 of placenta-mediated adverse pregnancy outcomes with ART. After adjustment of potential confounders, including smoking, delivery hospital level, initiating time of prenatal care, average neighborhood income, fetal sex, and previous cesarean delivery, there was no association observed between different types of ART groups and the composite of placenta-mediated pregnancy complications. Intrauterine insemination was associated with a significantly increased risk of preeclampsia (12 [2.67%] odds ratio 2.2, 95% confidence interval 1.04-5.04) compared with the corresponding control group (23 [1.29%]). CONCLUSION: Assisted reproductive technology is not associated with an increased risk of the composite outcome of placenta-mediated pregnancy complications among singleton pregnancies. LEVEL OF EVIDENCE: II.

Failure of Decidualization and Maternal Immune Tolerance Underlies Uterovascular Resistance in Intra Uterine Growth Restriction.

Failure of uterine vascular transformation is associated with pregnancy complications including Intra Uterine Growth Restriction (IUGR). The decidua and its immune cell populations play a key role in the earliest stages of this process. Here we investigate the hypothesis that abnormal decidualization and failure of maternal immune tolerance in the second trimester may underlie the uteroplacental pathology of IUGR. Placental bed biopsies were obtained from women undergoing elective caesarian delivery of a healthy term pregnancy, an IUGR pregnancy or a pregnancy complicated by both IUGR and preeclampsia. Decidual tissues were also collected from second trimester terminations from women with either normal or high uterine artery Doppler pulsatile index (PI). Immunohistochemical image analysis and flow cytometry were used to quantify vascular remodeling, decidual leukocytes and decidual status in cases vs. controls. Biopsies from pregnancies complicated by severe IUGR with a high uterine artery pulsatile index (PI) displayed a lack of: myometrial vascular transformation, interstitial, and endovascular extravillous trophoblast (EVT) invasion, and a lower number of maternal leukocytes. Apoptotic mural EVT were observed in association with mature dendritic cells and T cells in the IUGR samples. Second trimester pregnancies with high uterine artery PI displayed a higher incidence of small for gestational age fetuses; a skewed decidual immunology with higher numbers of; CD8 T cells, mature CD83 dendritic cells and lymphatic vessels that were packed with decidual leukocytes. The decidual stromal cells (DSCs) failed to differentiate into the large secretory DSC in these cases, remaining small and cuboidal and expressing lower levels of the nuclear progesterone receptor isoform B, and DSC markers Insulin Growth Factor Binding protein-1 (IGFBP-1) and CD10 as compared to controls. This study shows that defective progesterone mediated decidualization and a hostile maternal immune response against the invading endovascular EVT contribute to the failure of uterovascular remodeling in IUGR pregnancies.

Determinants of adverse perinatal outcome in high-risk women with abnormal uterine artery Doppler images.

OBJECTIVE: The purpose of this study was to evaluate the prognostic role of placental ultrasound imaging at 19-23 weeks of gestation in clinically high-risk women with abnormal uterine artery Doppler (UTAD). STUDY DESIGN: Placentas of 60 women with abnormal UTAD were examined at 19-23 weeks of gestation for shape and texture abnormalities. Findings were correlated with clinical outcomes (preterm delivery at <32 weeks of gestation; birth weight <10th percentile [small for gestational age]; preeclampsia/hemolysis, elevated liver enzymes, low platelets; early-onset intrauterine growth restriction with abnormal umbilical artery Doppler; and intrauterine fetal death) and maternal serum screening data. Placental disease was reviewed by 2 perinatal pathologists. RESULTS: Women with abnormal placental shape at 19-23 weeks of gestation (n = 28) had higher odds of intrauterine fetal death (odds ratio, 4.5; 95% CI, 1.3-15.6), delivery at <32 weeks of gestation (odds ratio, 4.7; 95% CI, 1.6-14.1]), and intrauterine growth restriction (odds ratio, 4.7; 95% CI, 1.4-15.1]) than did the women with a normal placental shape. Thirty-two of 41 placentas (74%) weighed <10th percentile, and 36 of 43 placentas (83%) had ischemic-thrombotic pathologic condition. There was no association between abnormal placental shape at 19-23 weeks of gestation and placental weight, but 5 of 6 placentas that were <10 cm long were <10th percentile for weight at delivery. There was a poor correlation between measures of ultrasound texture at 19-23 weeks of gestation and the presence of specific lesions at delivery. CONCLUSION: Combined abnormal UTAD and placental dysmorphologic condition before fetal viability identifies a subset of women who are at risk of adverse outcomes. Placental size is critical in the determination of the outcome in this situation because of the very high prevalence of destructive lesions, although present methods of placental imaging have significant limitations.

Fetal growth pathology score: a novel ultrasound parameter for individualized assessment of third trimester growth abnormalities.

OBJECTIVES: To study fetal growth in pregnancies at risk for growth restriction (GR) using, for the first time, the fetal growth pathology score (FGPS1). METHODS: A retrospective cohort study of GR was carried out in 184 selected SGA singletons using a novel, composite measure of growth abnormalities termed the FGPS1. Serial fetal biometry was used to establish second trimester Rossavik size models and determine FGPS1 values prior to delivery. FGPS1 data were compared to neonatal growth outcomes assessed using growth potential realization index (GPRI) values (average negative pathological GPRI (av - pGPRI)). Growth at the end of pregnancy was evaluated from differences in negative, individual composite prenatal growth assessment scores (-icPGAS) measured at the last two ultrasound scans. The FGPS1 and av - pGPRI values were used to classify fetal growth and neonatal growth outcomes, respectively, as Normal (N) or Abnormal (A). RESULTS: The risk of neonatal GR (based on birth weight (BW)) was moderate (MR: between 5th and10th percentiles (n = 113)) or significant (SR:<5th percentile) (n = 71)). Individual pregnancies were grouped into four categories, two representing agreement (N-N (29%), A-A (40%)) and two representing discordance (N-A (11%), A-N (20%)). In the largest and most variable subgroup (A-A,<5%tile, n = 49), there was a statistically significant correlation (0.63, p < .0001) between the FGPS1 and av - pGPRI. In N-A, all 20 cases (100%) had long last-scan-to-delivery intervals (1.9 weeks or greater), suggesting late development of the growth abnormality. For A-N, in approximately equal proportions, GR was improving, progressing or unclassifiable at the end of pregnancy. CONCLUSIONS: Significant agreement between prenatal and postnatal growth assessments was found using a novel approach for quantifying fetal growth pathology (FGPS1). Discordances appear to be due to lack of appropriate prenatal scans or an inadequate set of neonatal measurements. Evidence for a quantitative relationship between assessment methods was seen in the largest and most variable subgroup. The FGPS1 has the potential for characterizing GR in the third trimester and may provide a means for predicting the severity of corresponding abnormal neonatal growth outcomes.