losartan-potassium and Premature-Birth

Despite improvements in viability, the long-term neurodevelopmental outcomes of preterm babies remain serious concern as a significant percentage of these infants develop neurological and/or intellectual impairment, and they are also at increased risk of psychiatric illnesses later in life. The current challenge is to develop neuroprotective approaches to improve adverse outcomes in preterm survivors. The purpose of this review was to provide an overview of the current evidence on pharmacological agents targeting the neuroprotection of the preterm brain. Among them, magnesium sulfate, given antenatally to pregnant women with imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine administered to preterm infants after birth, exhibited neuroprotective effects for human preterm brain. Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions. Further studies are also required to assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be implemented as neuroprotectants in clinical practice. Furthermore, other pharmacological agents showing promising signs of neuroprotective efficacy in preclinical studies (growth factors, hyaluronidase inhibitors or treatment, antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as well as stem cell- or exosomal-based therapies and nanomedicine, may prove useful in the future as potential neuroprotective approaches for human preterm brain. KEY POINTS: · Magnesium and caffeine have neuroprotective effects for the preterm brain.. · Follow-up of infants treated with erythropoietin is needed.. · Neuroprotective efficacy of several drugs in animals needs to be shown in humans..

Topics: Brain; Caffeine; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Neuroprotection; Neuroprotective Agents; Pregnancy; Premature Birth

Cerebral palsy occurs more often in preterm than in term deliveries and is one of the major neurologic injuries seen in preterm infants. Magnesium sulfate has been found to reduce the risk of cerebral palsy in patients at risk of delivery before 32 weeks' gestational age. Multiple large clinical trials have shown this effect. The authors recommend magnesium sulfate bolus followed by continuous dosing of magnesium sulfate in those at risk of delivery before 32 weeks' gestation until delivery occurs or is no longer imminent. This article also discusses novel and emerging therapies for the prevention of cerebral palsy.

Topics: Cerebral Palsy; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Hypothermia, Induced; Infant, Newborn; Infant, Premature; Ischemic Preconditioning; Magnesium Sulfate; Maternal-Fetal Exchange; Mesenchymal Stem Cell Transplantation; Neuroprotection; Neuroprotective Agents; Obstetric Labor, Premature; Pregnancy; Premature Birth

Many controversial questions regarding the practice of neonatal red blood cell (RBC) transfusions exist, so that practices and policies vary widely. This article will critically assess information pertaining to two of these controversies, namely, the transfusion of RBCs stored for up to 42 days after collection vs the transfusion of fresh RBCs stored 7 days or less after donation and the use of recombinant human erythropoietin (rHuEPO) in attempts to either diminish the severity of or to treat the anemia of prematurity. Based on both theoretical considerations and several published clinical trials, RBCs from one donor stored up to 42 days in extended storage preservative solutions can safely provide all RBCs needed by most infants for small-volume transfusions. Based on a large number of clinical trials and a meta-analysis of these trials, it is impossible to provide firm guidelines for the use of rHuEPO in the treatment of the anemia of prematurity. Clearly, rHuEPO has efficacy in stimulating erythropoiesis in preterm infants, but success in the elimination or marked reduction in the need for RBC transfusions has not been definitively demonstrated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Animals; Blood Preservation; Child; Child, Preschool; Clinical Trials as Topic; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Middle Aged; Pregnancy; Premature Birth; Recombinant Proteins

Cerebral palsy (CP) is the most common cause of physical disability for children worldwide. Many infants and toddlers are not diagnosed with CP until they fail to achieve obvious motor milestones. Currently, there are no effective pharmacologic interventions available for infants and toddlers to substantially improve their trajectory of neurodevelopment. Because children with CP from preterm birth also exhibit a sustained immune system hyper-reactivity, we hypothesized that neuro-immunomodulation with a regimen of repurposed endogenous neurorestorative medications, erythropoietin (EPO) and melatonin (MLT), could improve this trajectory. Thus, we administered EPO + MLT to rats with CP during human infant-toddler equivalency to determine whether we could influence gait patterns in mature animals. After a prenatal injury on embryonic day 18 (E18) that mimics chorioamnionitis at ∼25 weeks human gestation, rat pups were born and raised with their dam. Beginning on postnatal day 15 (P15), equivalent to human infant ∼1 year, rats were randomized to receive either a regimen of EPO + MLT or vehicle (sterile saline) through P20. Gait was assessed in young adult rats at P30 using computerized digital gait analyses including videography on a treadmill. Results indicate that gait metrics of young adult rats treated with an infantile cocktail of EPO + MLT were restored compared to vehicle-treated rats (p < 0.05) and similar to sham controls. These results provide reassuring evidence that pharmacological interventions may be beneficial to infants and toddlers who are diagnosed with CP well after the traditional neonatal window of intervention.

Topics: Animals; Brain Injuries; Erythropoietin; Female; Gait; Humans; Infant; Melatonin; Pregnancy; Premature Birth; Rats

Antenatal iron and multiple micronutrient supplementation has been shown in randomized trials to improve birthweight, although mechanisms are unknown. We examined late pregnancy serum erythropoietin (EPO) and cortisol concentrations in relation to maternal micronutrient supplementation and iron status indicators (haemoglobin, serum ferritin, soluble transferrin receptor) in 737 rural Nepalese women to explore evidence of stress or anaemia-associated hypoxia. A double-masked randomized control trial was conducted from December 1998 to April 2001 in Sarlahi, Nepal, in which women received vitamin A alone (as control), or with folic acid (FA), FA + iron, FA + iron + zinc and a multiple micronutrient supplement. In a substudy, we collected maternal blood in the first and third trimester for biochemical assessments. Generalized estimating equations linear regression analysis was used to examine treatment group differences. EPO was ∼ 14-17 mIU mL(-1) lower (P < 0.0001) in late pregnancy in groups receiving iron vs. the control group, with no difference in the FA-only group. Cortisol was 1.3 μg dL(-1) lower (P = 0.04) only in the micronutrient supplement group compared with the control group. EPO was most strongly associated with iron status indicators in groups that did not receive iron, and in the non-iron groups cortisol was positively correlated with EPO (r = 0.15, P < 0.01) and soluble transferrin receptor (sTfR, r = 0.19, P < 0.001). In adjusted analyses, third trimester EPO was associated with a reduction in low birthweight, whereas cortisol was negatively associated with length of gestation and higher risk of preterm birth. Iron and multiple micronutrient supplementation may enhance birth outcomes by reducing mediators of maternal stress and impaired erythropoiesis.

Topics: Adult; Anemia, Iron-Deficiency; Biomarkers; Deficiency Diseases; Developing Countries; Dietary Supplements; Double-Blind Method; Erythropoietin; Female; Humans; Hydrocortisone; Iron, Dietary; Maternal Nutritional Physiological Phenomena; Micronutrients; Nepal; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Third; Premature Birth; Risk; Rural Health; Young Adult

Darbepoetin can be administered either intravenously (i.v.) or subcutaneously (s.c.). However, no information is available regarding pharmacokinetics and pharmacodynamics following its i.v. administration to neonates.. We administered a single i.v. dose (4 microg/kg) of darbepoetin to 10 neonates who had a hemoglobin < or =10.5 g/dl. Blood was obtained for immature reticulocyte fraction (IRF) and absolute reticulocyte count (ARC), before and 48 h following the dose. Blood was also drawn for pharmacokinetic analysis once before and at four pre-set intervals after dosing.. The study subjects ranged from 704 to 3025 g (median, 1128 g) birth weight, and were 26.0-40.0 weeks (median, 29.2 weeks) gestation at delivery. When the darbepoetin dose was given, ages ranged from 3 to 28 days (median, 8.5 days) with a hemoglobin of 9.8 +/- 0.7 g/dl (mean +/- s.d.). Doses were administered by i.v. infusion over 4 h. No adverse effects of the infusions were detected. The half-life of darbepoetin (t (1/2)) was 10.1 h (range 9.0-22.7 h), the volume of distribution was 0.77 l/kg (range 0.18-3.05 l/kg) and the clearance was 52.8 ml/h/kg (range 22.4-158.0 ml/h/kg). In the preterm neonates, there was no significant correlation between gestational age, or age at darbepoetin administration, and pharmacokinetic parameters. However, in the term and near-term neonates, volume of distribution correlated significantly with both gestational and age at darbepoetin administration (P < 0.05). Forty-eight hours after dosing, the IRFs and ARCs were elevated in six subjects and not in four. Those with predosing reticulocyte counts >200,000/microl did not have an increase in reticulocytes by 48 h (P < 0.05).. Darbepoetin administered i.v. to neonates had a shorter t (1/2), a larger volume of distribution and more rapid clearance than reported in children. We observed a significantly shorter t (1/2) and a less consistent rise in IRF and ARC after i.v. dosing than we previously reported following 4 microg/kg administered SC.

Topics: Birth Weight; Darbepoetin alfa; Erythropoietin; Female; Gestational Age; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Infusions, Intravenous; Intensive Care Units, Neonatal; Male; Premature Birth; Reticulocyte Count

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

Topics: Animals; Biomarkers; Cognition; Cognitive Dysfunction; Erythropoietin; Female; Humans; Infant, Newborn; Male; Placenta; Placental Insufficiency; Pregnancy; Premature Birth; Rats

In a two-part process, we assessed elements of the principal hormonal pathway regulating iron homeostasis in human neonates. Part 1: Quantifying erythropoietin (Epo), erythroferrone (ERFE), hepcidin, and relevant serum and erythrocytic iron-related metrics in umbilical cord blood from term (n = 13) and preterm (n = 10) neonates, and from neonates born to mothers with diabetes and obesity (n = 13); Part 2: Quantifying serum Epo, ERFE, and hepcidin before and following darbepoetin administration. Part 1: We measured Epo, ERFE and hepcidin in all cord blood samples. Epo and ERFE levels did not differ between the three groups. Preterm neonates had the lowest hepcidin levels, while neonates born to diabetic women with a very high BMI had the lowest ferritin and RET-He levels. Part 2: Following darbepoetin dosing, ERFE levels generally increased (p < 0.05) and hepcidin levels generally fell (p < 0.05). Our observations suggest that the Epo/ERFE/hepcidin axis is intact in the newborn period.

Topics: Erythropoietin; Female; Fetal Blood; Hepcidins; Humans; Infant, Newborn; Infant, Premature; Male; Obesity; Peptide Hormones; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Premature Birth; Signal Transduction

To investigate the role of stromal cell-derived factor 1 (SDF-1) and C-X-C chemokine receptor type 4 (CXCR-4) in the premature brain with white matter damage (WMD) undergoing treatment with human umbilical cord mesenchymal stem cells (hUC-MSCs) and recombinant human erythropoietin (rhEPO).. Three-day-old Sprague-Dawley (SD) rats were randomly divided into sham operation group, hypoxia-ischemia (HI) group, rhEPO treated HI group, hUC-MSCs treated HI group, and rhEPO + hUC-MSCs treated HI group. WMD was established in all groups except the Sham group. SDF-1 and CXCR-4 levels in each group were detected at postnatal day (P) 5, P7, and P14. Pathological changes were assessed via HE staining at P14 and neuroethological tests were performed at P28.. The rhEPO and hUC-MSCs intervention reduced injury area, increased body weight at P7, and improved neurobehavioral scores at P28. Furthermore, their combined use proved even more beneficial. SDF-1 levels in the rhEPO group were higher than those in the other groups and highest in the hUC-MSCs + rhEPO group (all p < .01). SDF-1 levels in the hUC-MSCs + rhEPO and rhEPO groups were increased at P5 and reached a peak at P7. CXCR-4 levels in the hUC-MSCs group were higher than those in the other groups and highest in the hUC-MSCs + rhEPO group (all p < .01). CXCR-4 levels were also increased at P5 and highest at P14.. hUC-MSCs + rhEPO might reduce nerve cell damage and improve neurobehavioral development, in connection with increased SDF-1 and CXCR-4 expression, in premature rats with WMD due to hypoxic-ischemic injury.

Topics: Animals; Behavior, Animal; Body Weight; Chemokine CXCL12; Disease Models, Animal; Erythropoietin; Female; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pregnancy; Premature Birth; Rats; Rats, Sprague-Dawley; Receptors, CXCR4; Recombinant Proteins; White Matter

Preterm delivery is the leading cause of neonatal mortality and contributes to delayed physical and cognitive development in children. At present, there is no efficient therapy to prevent preterm labor. A large body of evidence suggests that infections might play a significant and potentially preventable cause of premature birth. This work assessed the effects of erythropoietin (EPO) in a murine model of inflammation-associated preterm delivery, which mimics central features of preterm infections in humans.. BALB/c mice were injected i.p. with 20 000 IU/kg EPO or normal saline twice on gestational day (GD) 15, with a 3 hours time interval between injections. An hour after the first EPO or normal saline injection, all mice received two injections of 50 μg/kg LPS, also given 3 hours apart.. EPO significantly prevented preterm labor and increased offspring survival in an LPS induced preterm delivery model. EPO prevented LPS-induced leukocyte infiltration into the placenta. Moreover, EPO inhibited the expression of pro-inflammatory cytokines, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α) in maternal serum and amniotic fluid. EPO also prevented LPS-induced increase in placental prostaglandin (PG)E2 and uterine inducible nitric oxide synthase (iNOS) production, while decreasing nuclear factor kappa-B (NF-κβ) activity in the myometrium. EPO also increased the gene expression of placental programmed cell death ligand 1 (PD-L1) in LPS-treated mice.. Our results suggest that EPO could be a potential novel therapeutic strategy to tackle infection-related preterm labor.

Topics: Amniotic Fluid; Animals; B7-H1 Antigen; Cytokines; Dinoprostone; Erythropoietin; Female; Leukocytes; Lipopolysaccharides; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide Synthase Type II; Placenta; Pregnancy; Pregnancy Complications, Infectious; Premature Birth

Iron (Fe) status of neonates born to women carrying multiple fetuses might be compromised as a consequence of the high prevalence of maternal Fe deficiency and anemia coupled with an increased risk of preterm birth. This study aimed to characterize and identify determinants of anemia in this neonatal population.. Umbilical cord blood obtained from 183 neonates was utilized to assess hemoglobin (Hb), ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, serum Fe, erythropoietin, folate, vitamin B-12, C-reactive protein, and interleukin-6. Associations with maternal Fe status were explored.. Cord Hb or SF did not change significantly as a function of gestational age at birth (25-38 wks). Neonates born to women who were obese prior to pregnancy or smoked cigarettes during pregnancy had a 4-5-fold greater odds of anemia at birth. Cord sTfR was the strongest indicator of cord Hb (P < 0.0001), and it was significantly associated with maternal sTfR at mid-gestation (P = 0.01) and delivery (P = 0.002). Cord Fe indicators were significantly associated with cord hepcidin, but not maternal hepcidin.. Screening for Fe status in neonates born to women carrying multiple fetuses is warranted, especially for those born to smokers or to women who are obese at entry into pregnancy.

Topics: Adult; Anemia; Anemia, Iron-Deficiency; C-Reactive Protein; Cohort Studies; Erythropoietin; Female; Ferritins; Fetal Blood; Folic Acid; Hemoglobins; Hepcidins; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Infant, Premature, Diseases; Interleukin-6; Iron; Obesity; Pregnancy; Pregnancy Complications; Pregnancy, Multiple; Premature Birth; Receptors, Transferrin; Smoking; Tobacco Use Disorder; Vitamin B 12; Young Adult

Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs.. We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction.. Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

Topics: Adolescent; Angiotensin II Type 1 Receptor Blockers; Antigens, CD34; Apgar Score; Biopsy; Child; Endothelial Cells; Erythropoietin; Female; Fibrosis; Glomerulosclerosis, Focal Segmental; Hemoglobins; Humans; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Kidney Glomerulus; Kidney Tubules; Male; Microvascular Rarefaction; Nephrons; Platelet Endothelial Cell Adhesion Molecule-1; Polycythemia; Pregnancy; Premature Birth; Proteinuria; Valsartan

Topics: Anemia; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Male; Premature Birth

Premature infants exhibit neurodevelopmental delay and reduced growth of the cerebral cortex. However, the underlying mechanisms have remained elusive. Therefore, we hypothesized that neurogenesis in the ventricular and subventricular zones of the cerebral cortex would continue in the third trimester of pregnancy and that preterm birth would suppress neurogenesis. To test our hypotheses, we evaluated autopsy materials from human fetuses and preterm infants of 16-35 gestational weeks (gw). We noted that both cycling and noncycling Sox2(+) radial glial cells and Tbr2(+) intermediate progenitors were abundant in human preterm infants until 28 gw. However, their densities consistently decreased from 16 through 28 gw. To determine the effect of premature birth on neurogenesis, we used a rabbit model and compared preterm [embryonic day 29 (E29), 3 d old] and term (E32, <2 h old) pups at an equivalent postconceptional age. Glutamatergic neurogenesis was suppressed in preterm rabbits, as indicated by the reduced number of Tbr2(+) intermediate progenitors and the increased number of Sox2(+) radial glia. Additionally, hypoxia-inducible factor-1α, vascular endothelial growth factor, and erythropoietin were higher in term than preterm pups, reflecting the hypoxic intrauterine environment of just-born term pups. Proneural genes, including Pax6 and Neurogenin-1 and -2, were higher in preterm rabbit pups compared with term pups. Importantly, neurogenesis and associated factors were restored in preterm pups by treatment with dimethyloxallyl glycine, a hypoxia mimetic agent. Hence, glutamatergic neurogenesis continues in the premature infants, preterm birth suppresses neurogenesis, and hypoxia-mimetic agents might restore neurogenesis, enhance cortical growth, and improve neurodevelopmental outcome of premature infants.

Topics: Adult; Animals; beta Catenin; Cell Count; Cerebral Ventricles; Erythropoietin; Female; Gestational Age; Glycine; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Immunohistochemistry; Infant, Newborn; Infant, Premature; Male; Nerve Tissue Proteins; Neural Stem Cells; Neurogenesis; Pregnancy; Pregnancy Trimester, Third; Premature Birth; Rabbits; Signal Transduction; Telencephalon; Vascular Endothelial Growth Factor A; Wnt Proteins

To evaluate cord blood erythropoietin (EPO) and interleukin-6 (IL-6) levels to predict preterm infants at risk of developing intraventricular hemorrhage (IVH).. Levels of umbilical cord EPO, acid-base status and IL-6 were analyzed in 116 consecutive, preterm newborns (GA at delivery: 29 [23-34 ] weeks) born to mothers who had a clinically indicated amniocentesis to rule out infection. Early-onset neonatal sepsis (EONS) was diagnosed using symptoms, hematological criteria and blood cultures.. IVH was diagnosed by cranial ultrasounds. The prevalence of IVH in our population was 25% (29/116). There was a direct relationship between cord blood EPO and cord blood IL-6 concentration (r = 0.225, p = 0.014), independent of GA at birth. Elevated cord blood EPO levels (r = 0.182, p = 0.016) and GA at birth (r =  -0.236, p = 0.004) remained significant independent factors associated with the risk of IVH, when evaluated with stepwise logistic regression analyses. Cord blood IL-6, pH, and EONS were not associated with IVH. These relationships remained following correction for GA at birth (p = 0.027).. Our results suggest that elevation in cord blood EPO may predict newborns at risk for IVH, independent of fetal inflammatory status. Further studies are warranted to confirm this association.

Topics: Adult; Biomarkers; Chorioamnionitis; Erythropoietin; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Premature, Diseases; Interleukin-6; Intracranial Hemorrhages; Pregnancy; Premature Birth; Prospective Studies; Sepsis; Young Adult

This article reports the results of a study on the relationship between cord blood levels of erythropoietin and periventricular leukomalacia. Cord blood was obtained from 19 infants with gestational age between 27 and 32 weeks. Cystic periventricular leukomalacia was seen in 4 of them. Erythropoietin levels were not different between those with and those without periventricular leukomalacia.

Topics: Erythropoietin; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Leukomalacia, Periventricular; Pilot Projects; Premature Birth; Statistics as Topic; Statistics, Nonparametric