Early development of the human placenta and pregnancy complications.

An adequately sized placenta at a suitable site with appropriate depth and centripetal progression of implantation are the major factors for optimal fetal development. The cytotrophoblasts surround the blastocyst fuses at the site of the uterine attachment. This forms a second layer of multinucleated syncytiotrophoblasts that constitutes the inner epithelial boundary of the chorionic villous against the intervillous space. In a normal pregnancy, extravillous cytotrophoblasts (EVT) invade and obstruct the spiral arteries and remodel them. Vacuoles in the syncytial cell layer fuse and develop the intervillous space. The inner cell mass (embryoblast) gives rise to the umbilical cord and the mesenchyme in the chorionic villi. Vasculogenesis starts with the formation of hemangioblastic cords in this mesenchyme. The trophoblastic cell columns anchor the placenta. A variety of molecular pathways participate in the placentation process. Placental morphogenesis occurs mainly through complex cellular interactions between the chorionic villous and the extravillous cytotrophoblasts. The formation of the normal structure of the chorionic villi, syncytiotrophoblast layer and vasculature is essential for placental function, hormone production, and regulation of fetal growth. At each stage of placental development, genetic variants, exposure to infection, poor vascular function, oxidative stress, or failure of normal development can all lead to abnormal formation resulting in the clinical complications of pregnancy such as fetal growth disorders, neonatal neurologic abnormalities, placental adhesions, and inflammatory problems as well as maternal disease such as preeclampsia.

The Role of Oxidative Stress, Adhesion Molecules and Antioxidants in Preeclampsia.

Oxidative stress is a consequence of reduction in the antioxidant capacity and excessive production of reactive oxygen and nitrogen species (ROS). Oxidative agents, which are overproduced due to ischemic-reperfusion injury in the placenta, may overwhelm the normal antioxidant activity. This imbalance is a key feature in the pathogenesis of preeclampsia. A decrease in glutathione peroxidase (GPX) activity is associated with the synthesis of vasoconstrictive eicosanoids such as F2-isoprostanes and thromboxane, which are known to be upregulated in preeclampsia. Biochemical markers of lipid peroxidation, such as malondialdehyde and F2-isoprostane in the placenta, are also increased. Adhesion molecules participate in the pathophysiology of preeclampsia by contributing to a reduced invasion by the trophoblast and increased vascular endothelial damage. Superoxide dismutase (SOD), catalase (CAT) and GPX play important roles counteracting oxidative stress. Other antioxidant factors participate in the etiology of preeclampsia. Levels of antioxidants such as Lycopene, Coenzyme 10, as well as some vitamins, are reduced in preeclamptic gestations.

Use of antenatal corticosteroids in special circumstances: a comprehensive review.

The aim of this study was to determine, in pregnancies complicated by preterm premature rupture of membranes (PPROM), hypertension, intrauterine growth restriction, multi-fetal gestations and pregnancies 23-26 weeks and ≥34 weeks' gestation, whether antenatal corticosteroids benefit the fetus. Literature review using PubMed, Web of Science, Clinical trials.gov, Cochrane Database of Systematic Reviews (1990-2015). Search terms linked special circumstances with corticosteroids. Randomized clinical trials, retrospective and prospective cohort studies, and case control studies were reviewed. In all, 468 abstracts were identified and 84 added from selected article bibliographies; of these, 503 abstracts were excluded, leaving 49 articles as the basis of review. The literature supports corticosteroids for PPROM up to 32-34 weeks without chorioamnionitis. Antenatal corticosteroids are beneficial for preterm infants of women with HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome/severe preeclampsia. Postpartum corticosteroid treatment of HELLP patients results in more rapid correction of liver enzymes, platelet counts, and urinary output, which can reduce maternal morbidity. Corticosteroids in twin pregnancies decrease respiratory distress syndrome but the effect is less than in singleton pregnancies. Corticosteroid effects on intrauterine growth restriction pregnancies are conflicting and steroid use should be individualized. Corticosteroid use for 23-26 weeks reduces neonatal mortality but not morbidity. In pregnancies of 34 weeks to 366/7  weeks, corticosteroids reduce respiratory distress syndrome, but follow-up studies are unavailable. No long-term adverse child developmental effects have been observed with one or two courses of corticosteroids, but three or more steroid courses lowers birthweight and organ weight, and there may be an increase in neurodevelopmental abnormalities. Longer follow up of corticosteroid-treated fetuses is required.

Disseminated intravascular coagulation in the HELLP syndrome: how much do we really know?

The rate of disseminated intravascular coagulation (DIC) during pregnancy varies among nations from 0.03% to 0.35%. The existing reports suggest dissimilarity in the underlying mechanisms leading to DIC during gestation. While in developing countries preeclampsia and the HELLP syndrome are prevalent causes of DIC, the leading causes in the developed countries are placental abruption and postpartum hemorrhage. In different cohort studies, DIC is reported in about 12-14% of women with preeclampsia. Nevertheless, it has been suggested that in most cases these women also had a HELLP syndrome and that the occurrence of DIC in women who had only preeclampsia without manifestations of the HELLP syndrome is rare. The aims of this review are to: (1) highlight the mechanisms leading to DIC; (2) describe the changes in the coagulation system during this complication; and; (3) discuss the diagnostic tool and treatment modalities of DIC, in women who develop a HELLP syndrome.

Antenatal corticosteroid treatment: factors other than lung maturation.

Antenatal corticosteroid (CS) therapy improves both fetal lung mechanism and gas exchange due to accelerated morphologic development of type one and two pneumocytes. This therapy also enhances the production of surfactant binding proteins and fetal lung antioxidant enzymes. In women with threatening preterm delivery, a single course is advocated between 24 and 34 weeks' gestation with either betamethasone (two doses of 12 mg 24 h apart) or dexamethasone (four doses of 6 mg at 12-h intervals). Such treatment reduces the rate of respiratory distress syndrome, comorbidity, and mortality in neonates in the first 48 h of life. The optimal time interval between CS administration and delivery is reported to be 1-7 days. Weekly repeat courses reduce the occurrences and severity of respiratory diseases but are associated with reduce fetal growth. Multiple courses should be avoided. However, a repeat course should be considered in women at risk of preterm birth 7 or more days after an initial course in women who remain at risk of preterm birth <34 weeks' gestation. CS may be harmful in growth restricted fetuses associated with an absent or reversed end-diastolic UA flow since they are at increased risk of acidosis and perinatal death. The purpose of this publication is to update and highlight antenatal CS therapy.

Tocolysis for acute preterm labor: does anything work.

The central rationale of tocolysis for preterm labor (PTL) is to delay delivery for at least 48 h to allow for transfer of the mother to a tertiary facility and for corticosteroids to induce surfactant production in fetal lungs. Beta-mimetics decrease the number of women in preterm labor giving birth within 48 h without reducing adverse neonatal outcomes. Calcium channel blockers inclusive of nifedipine decrease the adverse neonatal outcomes by significantly delaying delivery. Atosiban has the best maternal and fetal safety profile but does not seem to reduce neonatal complications. Magnesium sulfate is controversial as a tocolytic, but is valuable as a neuroprotective agent and for treatment of eclamptic seizures. Indomethacin may be a reasonable first choice for acute tocolytsis in gestational ages less than 32 weeks' gestation. Prolonged use (>48 h) should be avoided. Transdermal nitroglycerin can reduce neonatal morbidity and mortality as a result of decreased risk of birth before 28 weeks' gestation. Nifedipine may be a reasonable first choice because it is easy to administer and also of limited side effects relative to ß2-mimetics. Tocolysis does not appear to significantly lengthen the gestational age beyond seven days.

Genetic aspects of preeclampsia and the HELLP syndrome.

Both preeclampsia and the HELLP syndrome have their origin in the placenta. The aim of this study is to review genetic factors involved in development of preeclampsia and the HELLP syndrome using literature search in PubMed. A familial cohort links chromosomes 2q, 5q, and 13q to preeclampsia. The chromosome 12q is coupled with the HELLP syndrome. The STOX1 gene, the ERAP1 and 2 genes, the syncytin envelope gene, and the -670 Fas receptor polymorphisms are involved in the development of preeclampsia. The ACVR2A gene on chromosome 2q22 is also implicated. The toll-like receptor-4 (TLR-4) and factor V Leiden mutation participate both in development of preeclampsia and the HELLP syndrome. Carriers of the TT and the CC genotype of the MTHFR C677T polymorphism seem to have an increased risk of the HELLP syndrome. The placental levels of VEGF mRNA are reduced both in women with preeclampsia and in women with the HELLP syndrome. The BclI polymorphism is engaged in development of the HELLP syndrome but not in development of severe preeclampsia. The ACE I/D polymorphism affects uteroplacental and umbilical artery blood flows in women with preeclampsia. In women with preeclampsia and the HELLP syndrome several genes in the placenta are deregulated. Preeclampsia and the HELLP syndrome are multiplex genetic diseases.

Cerclage, progesterone and α-hydroxyprogeterone caproate treatment in women at risk for preterm delivery.

The most significant action of progesterone appears to be on the cervix and in prevention rather than on treatment of preterm delivery. In women with singleton gestations, no prior PTB, and CL <20 mm at <24 weeks, vaginal progesterone, either 90 mg gel or 200 mg suppository, is associated with reduction of both preterm birth (PTB) and perinatal morbidity/mortality. Cerclage is as effective as vaginal progesterone in women with CL <25 mm. Treatment of women with previous PTB with 17OHP-C from 16 to 20 weeks' gestation until 36 weeks could reduce significantly both the risk of delivery at <37, <35 and <32 weeks' gestation, as well as the rates of NEC, the need for supplemental oxygen and IVH. In women successfully treated with tocolytics progesterone combined with corticosteroid therapy lengthens pregnancy, reduces occurrence of respiratory distress syndrome and low birth weight. However, there is currently insufficient evidence on the role of progesterone after arrested preterm labor. It is reasonable to support an approach with CL screening of women with prior PTB starting at 16 to 19 weeks and administration of progesterone to women with a short cervix. Cerclage may be offered to those with a CL<25 mm. A combination of traditional tocolytics, corticosteroids and progesterone might be beneficial.

Intrauterine growth restriction: effects of physiological fetal growth determinants on diagnosis.

The growth of the fetus, which is strongly associated with the outcome of pregnancy, reflects interplay of several physiological and pathological factors. The assessment of fetal growth is based on comparison of birthweight (BW) or estimated fetal weight (EFW) to standards which define reference ranges at a spectrum of gestational ages. Most birthweight standards do not take into account effects of physiological determinants of fetal growth. Additionally, gestational age in many standards is based on the menstrual history and is often inaccurate. Fetal growth norms should be based on an early ultrasound estimate of gestational age. Customized standards, which have included only ultrasound-dated pregnancies, seem to be superior to population-based birthweight norms in predicting perinatal mortality and morbidity. Adjustment for individual variation in customized growth curves reduces false-positive diagnosis of IUGR and may lead to a very significant reduction in intervention for suspected IUGR. Customized growth potential identifies better the risk for adverse outcome than the currently used national standards, but customized charts may fail in detecting growth-restricted stillbirth. An individual's birthweight is the sum of physiological and pathological influences operating during pregnancy. Growth potential norms are a better discriminator of aberrations of fetal growth than population, ultrasound, and customized norms.

Influence of mineral and vitamin supplements on pregnancy outcome.

The literature was searched for publications on minerals and vitamins during pregnancy and the possible influence of supplements on pregnancy outcome. Maternal iron (Fe) deficiency has a direct impact on neonatal Fe stores and birth weight, and may cause cognitive and behavioural problems in childhood. Fe supplementation is recommended to low-income pregnant women, to pregnant women in developing countries, and in documented deficiency, but overtreatment should be avoided. Calcium (Ca) deficiency is associated with pre-eclampsia and intra-uterine growth restriction. Supplementation may reduce both the risk of low birth weight and the severity of pre-eclampsia. Gestational magnesium (Mg) deficiency may cause hematological and teratogenic damage. A Cochrane review showed a significant low birth weight risk reduction in Mg supplemented individuals. Intake of cereal-based diets rich in phytate, high intakes of supplemental Fe, or any gastrointestinal disease, may interfere with zinc (Zn) absorption. Zn deficiency in pregnant animals may limit fetal growth. Supplemental Zn may be prudent for women with poor gastrointestinal function, and in Zn deficient women, increasing birth weight and head circumference, but no evidence was found for beneficial effects of general Zn supplementation during pregnancy. Selenium (Se) is an antioxidant supporting humoral and cell-mediated immunity. Low Se status is associated with recurrent abortion, pre-eclampsia and IUGR, and although beneficial effects are suggested there is no evidence-based recommendation for supplementation. An average of 20-30% of pregnant women suffer from any vitamin deficiency, and without prophylaxis, about 75% of these would show a deficit of at least one vitamin. Vitamin B6 deficiency is associated with pre-eclampsia, gestational carbohydrate intolerance, hyperemesis gravidarum, and neurologic disease of infants. About 25% of pregnant women in India are folate deficient. Folate deficiency may lead to congenital malformations (neural tube damage, orofacial clefts, cardiac anomalies), anaemia and spontaneous abortions, and pre-eclampsia, IUGR and abruption placentae. Pregestational supplementation of folate prevents neural tube defects. A daily supplemental dose of 400 µg/day of folate is recommended when planning pregnancy. In developing countries diets are generally low in animal products and consequently in vitamin B12 content. An insufficient supply may cause reduced fetal growth. In vegetarian women, supplementation of vitamin B12 may be needed. Vitamin A deficiency is prevalent in the developing world, impairing Fe status and resistance to infections. The recommended upper limit for retinol supplements is 3000 IU/day. Vitamin A supplementation enhances birth weight and growth in infants born to HIV-infected women. Overdosing should be avoided. Low concentrations of vitamin C seem to increase the development of pre-eclampsia, and supplementation may be beneficial. Supplementation with vitamin D in the third trimester in vitamin D deficient women seems to be beneficial. The use of vitamins E, although generally considered "healthy", may be harmful to the pregnancy outcome by disrupting a physiologic oxidative gestational state and is consequently not recommended to prevent pre-eclampsia. Further studies on specific substances are needed as the basis for stratified, placebo-controlled analyses.

The HELLP syndrome: clinical issues and management. A Review.

BACKGROUND: The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10-20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence. METHODS: Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases. RESULTS AND CONCLUSION: About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH (> 600 U/L), AST (>or= 70 U/L), and platelets < 100 x 10(9)/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment (>or= 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.

[Foetal growth retardation]. / Vekstretardasjon hos fosteret.

BACKGROUND: Intrauterine growth : restriction (IUGR) occurs in 3-10% of all pregnancies : The condition has different adverse effects on the foetus, during childhood and even in adult life. MATERIAL AND METHODS: Literature was retrieved from the Pub Med and Cochrane databases. RESULTS AND INTERPRETATION: The most common limit for IUGR and severe growth restriction is a neonatal weight < 10th percentile. Placental failure, infections or foetal anomalies may cause IUGR before the 32 nd gestational week (early IUGR). Chromosome abnormalities may be the cause of up to 20% of all growth-restricted infants. About 20% of early-onset preeclampsia may cause low birth weight. Up to 10% of infections may also cause IUGR (e.g. HIV, cytomegalovirus, toxoplasmosis, peridontitis, malaria). Monochorial twin pregnancy carries a risk for twin-to-twin transfusion with uneven foetal growth. Systemic vessel diseases (diabetes mellitus with nephropathy and retinopathy, Crohn's disease, systemic lupus erythematosus disseminatus, and antiphospholipid syndrome) may cause growth restriction. The anamnesis and a low symphysis to fundus increment may give suspicion of growth restriction. The diagnosis is verified by ultrasound examination. Preterm delivery carries a risk for neonatal respiratory distress and cerebral haemorrhage. Therefore, two doses of corticosteroid should be given to the mothers in risk of preterm delivery before the 34 th gestational week. Growth restriction between 34 to 37 weeks gestation, associated with serious preeclampsia, is an indication for delivery. Other indications are arrest of foetal growth, pathological cardiotocography or Doppler findings, oligohydramnion or worsening of the maternal condition.

Haemoglobin and serum ferritin in pregnancy--correlation with smoking and body mass index.

BACKGROUND: Little is known about factors which may influence haemoglobin (Hb) and ferritin levels in pregnancy. AIM: To analyse if haemoglobin and ferritin levels during pregnancy are influenced by maternal age, body mass index, cigarette smoking, and iron supplementation. METHODS: A random sample of 561 parous pregnant women were recruited from the catchment areas of three Scandinavian university hospitals. The analyses were based on 5024 haemoglobin and 1529 ferritin measures sampled from the first trimester to 42 weeks of gestation. Multilevel modelling was used to construct mean and percentile curves for haemoglobin and ferritin by gestational age. RESULTS: Women aged 25-34 years had significantly higher haemoglobin values than older and younger women. Haemoglobin values were significantly lower for women with body mass index < 19 kg/m(2) than for women with body mass index > or =19. Smokers had significantly lower haemoglobin values throughout pregnancy compared to non-smokers, with the lowest values among women who smoked 1-9 cigarettes per day. There were no similar associations between ferritin and maternal age, body mass index, or smoking. Women with iron supplementation throughout pregnancy had a higher relative increase in haemoglobin concentration toward the end of pregnancy. In non-supplemented women the decline in ferritin concentration was significantly steeper than in those who received iron supplementation. CONCLUSIONS: Haemoglobin levels during pregnancy are significantly associated with maternal age, cigarette smoking, body mass index, and iron supplementation. No such associations were found with ferritin levels, except for iron supplementation.

Paroxysmal nocturnal hemoglobinuria in pregnancy.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which a defect of glycophosphatidylinositol (GPI)-anchored proteins in the cell membrane of bone marrow stem cells leads to increased sensitivity of the red cells to complement, causing intravascular hemolysis and hemoglobinuria. Other clinical features of this disease are cytopenia and an increased frequency of thrombotic events. We report a case of a pregnant woman with PNH on high-dosage anticoagulation therapy, the follow-up during the pregnancy, the delivery and the postpartum period. The obstetric literature on women with PNH is reviewed, the maternal and fetal risks are evaluated and the management of pregnancies and deliveries in such patients are discussed. During the pregnancy our patient was hypertransfused and used anticoagulation treatment. A healthy child was delivered in week 37 by cesarean section because of premature rupture of the membranes, unsuccessful induction and intrauterine infection. Because of bleeding problems a hysterectomy also had to be performed. In the postpartum period the patient developed her second episode of a liver vein thrombosis. She recovered gradually and 18 months after the delivery her disease is now in a stable phase. The literature shows a high maternal morbidity and mortality among pregnant PNH patients. Fetal wastage and prematurity rate are also high. Pregnancy in patients with PNH represents a high-risk situation for both the mother and the child and should not be recommended. A pregnant PNH woman should be followed closely by both obstetricians and hematologists.

[Thrombocytopaenia in pregnancy]. / Trombocytopeni i svangerskapet.

BACKGROUND, MATERIAL AND METHODS: This paper provides a short review of thrombocytopaenia in pregnancy based on a search in PubMed as well as clinical experience. RESULTS AND INTERPRETATION: Normal platelet count in pregnancy is 250-290 x 10(9)/l, Thrombocytopaenia in pregnancy may be defined as platelet counts below 150 x 10(9)/l. Benign gestational thrombocytopaenia (platelet count 70-150 x 10(9)/l without clinical findings or any maternal or fetal risk) develops in 5%-12% of all pregnancies in the third trimester. Immune thrombocytopaenia (ITP) occurs in about one or two out of 1000 pregnancies and may be complicated by fetal alloimmune thrombocytopaenia. Thrombocytopaenia is present in nearly half of the cases with preeclampsia. The HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelet count) is classified according to platelet counts. Thrombotic thrombocytopenic purpura (TTP), haemolytic uremic syndrome (HUS) and fatty liver may imply low platelet counts. Infections, folate deficiency, leukaemia, congenital conditions, drugs or concurrent autoimmune disease may cause thrombocytopaenia. Platelet counts during pregnancy should be based on clinical indications.

Preterm delivery: an overview.

Preterm delivery is the leading factor causing neonatal mortality and morbidity. We have conducted a PubMed literature search to obtain an update on the etiology, diagnostic problems and therapeutic considerations of preterm delivery. Approximately 5-10% of all births are premature. Preterm labor is associated with preterm rupture of membranes, cervical incompetence, polyhydramnion, fetal and uterine anomalies, infections, social factors, stress, smoking, heavy work and other risk factors. The diagnosis is made on the patients presenting symptoms, clinical findings and of progressive effacement and dilatation of the cervix. Biochemical markers of preterm delivery are of minor importance in daily clinical work. Measurement of the cervix, however, is a practical and valuable tool to predict preterm delivery. Cervical cerclage can be useful in selected cases. Antibiotics may help to prevent preterm labor in cases of known etiologic agents (e.g. preterm rupture of membranes and urinary infection). The use of tocolytic agents such as beta-sympathetic receptor stimulators can be advocated for a few days. There is evidence that their long-term use is not beneficial and could even be harmful to the fetus. Calcium channel blockers (nifedipine) and a new selective oxytocin receptor antagonist, atosiban, appear to be as effective as beta-sympathomimetic drugs on uterine contractions with fewer side-effects. Prostaglandin synthetase inhibitors such as indomethacin may prevent uterine contractions and can be used prior to the 32nd week of pregnancy. A single course of corticosteroid treatment in two doses of 12 mg betamethasone or 6 mg of dexamethasone is important for the prevention of respiratory distress between the 24th and 34th weeks of pregnancy. Multiple doses may be harmful and should be avoided. In these cases management should depend on gestation age (fetal maturity). Uterine contractions after 34 weeks' gestation are not an indication for tocolytic treatment.

[HIV infection in pregnant women--clinical findings and treatment]. / HIV-infeksjon hos gravide--klinikk og behandling.

BACKGROUND AND METHODS: The paper reviews HIV infection in pregnancy. We have mainly used PubMed for literature searches with focus on risk factors for vertical infection and measures to prevent mother-to-child transmission. RESULTS: The risk of vertical HIV-transmission is greatest when the mother has high levels of viraemia. Antiviral treatment decreases the fetal risk. When the viral load is low, i.e. HIV-RNA below 1000 copies/ml, the risk of infection of the fetus is small; individually adapted antiviral treatment is indicated to obtain this goal. Increased risk of infection of the fetus may occur as a result of vaginal bleeding, amniocentesis, vaginal delivery, the use of scalp electrodes and fetal scalp pH measurement. The use of vacuum extraction and forceps delivery should be avoided if possible. An important factor associated with increased fetal risk is long lasting rupture of the membranes (> 4 hours). INTERPRETATION: Elective delivery by Caesarean section at 38th week, before labour and rupture of the membranes, is advocated. A Caesarean section may, however, cause complications, and vaginal delivery at term may be considered when the viraemia is low (HIV-RNA < 1000 copies/ml). Amniotomy and long-standing rupture of the membranes should be avoided, as should breastfeeding.