Article

Frühe Hirnschäden verhindern

Authors:
  • Marienhausklinikum Neuwied
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Frühchen, die vor der 30. Schwangerschaftswoche zur Welt kommen, sind in besonderem Maße von perinatalen Hirnschäden betroffen. Viele dieser Kinder sind schwerbehindert. Dies gilt es zu vermeiden.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Fetal or neonatal brain injury can result in lifelong neurologic disability. The most significant risk factor for perinatal brain injury is prematurity; however, in absolute numbers, full-term infants represent the majority of affected children. Research on strategies to prevent or mitigate the impact of perinatal brain injury ("perinatal neuroprotection") has established the mitigating roles of magnesium sulfate administration for preterm infants and therapeutic hypothermia for term infants with suspected perinatal brain injury. Banked umbilical cord blood, erythropoietin, and a number of other agents that may improve neuronal repair show promise for improving outcomes following perinatal brain injury in animal models. Other preventative strategies include delayed umbilical cord clamping in preterm infants and progesterone in women with prior preterm birth or short cervix and avoidance of infections. Despite these advances, we have not successfully decreased the rate of preterm birth, nor are we able to predict term infants at risk of hypoxic brain injury in order to intervene prior to the hypoxic event. Further, we lack the ability to modulate the sequelae of neuronal cell insults or the ability to repair brain injury after it has been sustained. As a consequence, despite exciting advances in the field of perinatal neuroprotection, perinatal brain injury still impacts thousands of newborns each year with significant long-term morbidity and mortality.
Article
Full-text available
Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6) MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.
Article
Full-text available
Context Chorioamnionitis has been implicated in the pathogenesis of cerebral palsy, but most studies have not reported a significant association. Cystic periventricular leukomalacia (cPVL) is believed to be a precursor of cerebral palsy in preterm infants.Objectives To determine whether chorioamnionitis is associated with cerebral palsy or cPVL and to examine factors that may explain differences in study results.Data Sources Searches of MEDLINE (1966-1999), Index Medicus (1960-1965), Doctoral Dissertation Abstracts On-Line (1861-1999), bibliographies, and online conference proceedings (1999) were performed for English-language studies with titles or abstracts that discussed prenatal risk factors for cerebral palsy or cPVL.Study Selection Of 229 initially identified publications, meta-analyses were performed on studies that addressed the association between clinical (n = 19) or histologic (n = 7) chorioamnionitis and cerebral palsy or cPVL in both preterm and full-term infants. Inclusion criteria were: presence of appropriate exposure and outcome measures, case-control or cohort study design, and provision of sufficient data to calculate relative risks (RRs) or odds ratios with 95% confidence intervals (CIs). Studies evaluating risk of cerebral palsy following maternal fever, urinary tract infection, or other maternal infection were collected, but not included in the meta-analysis.Data Extraction Information from individual studies was abstracted using standardized forms by 2 independent observers blinded to authors' names, journal titles, and funding sources.Data Synthesis Using a random effects model, clinical chorioamnionitis was significantly associated with both cerebral palsy (RR, 1.9; 95% CI, 1.4-2.5) and cPVL (RR, 3.0; 95% CI, 2.2-4.0) in preterm infants. The RR of histologic chorioamnionitis and cerebral palsy was 1.6 (95% CI, 0.9-2.7) in preterm infants, and histologic chorioamnionitis was significantly associated with cPVL (RR, 2.1; 95% CI, 1.5-2.9). Among full-term infants, a positive association was found between clinical chorioamnionitis and cerebral palsy (RR, 4.7; 95% CI, 1.3-16.2). Factors explaining differences in study results included varying definitions of clinical chorioamnionitis, extent of blinding in determining exposure status, and whether individual studies adjusted for potential confounders.Conclusion Our meta-analysis indicates that chorioamnionitis is a risk factor for both cerebral palsy and cPVL. Figures in this Article Despite improvements in perinatal medicine, the prevalence of cerebral palsy has increased over the last 2 decades,1 and the etiology of cerebral palsy remains poorly understood. Evidence suggests that 70% to 80% of cases of cerebral palsy are due to prenatal factors,2 and that birth asphyxia plays a relatively minor role.3 Chorioamnionitis, or intrauterine infection, has been implicated as a potential cause of cerebral palsy.4- 6 Chorioamnionitis is common and often subclinical. Histologic signs of chorioamnionitis can be detected in more than 50% of women who deliver prematurely,7 and most patients have no clinical signs of infection.8 It is postulated that both subclinical and clinical chorioamnionitis can lead to a fetal inflammatory response, and that this inflammation contributes to neonatal brain injury and subsequent cerebral palsy.5,9- 10 Recent reports of elevated neonatal blood11 and amniotic fluid12 cytokine levels in children with cerebral palsy support the notion that cerebral palsy is preceded by a perinatal inflammatory condition. A number of studies have assessed the relationship between chorioamnionitis and cerebral palsy in premature infants,12- 20 but most have not reported a significant association. In full-term infants, the existing literature supports a relationship between chorioamnionitis and cerebral palsy,6,21 but few studies are available. We conducted a meta-analysis to evaluate the potential association between chorioamnionitis and cerebral palsy in both full-term and preterm infants. In addition to cerebral palsy, we were interested in the outcome of cystic periventricular leukomalacia (cPVL), a powerful predictor of cerebral palsy in preterm infants. An estimated 60% to 100% of patients with cPVL go on to develop cerebral palsy.22 We performed a systematic review of the existing literature addressing all forms of chorioamnionitis as a potential risk factor for cerebral palsy or cPVL.
Article
Full-text available
Mesenchymal stem cell (MSC)-based therapies have been proven effective in experimental models of numerous disorders. Treatment of ischemic brain injury by transplantation of MSCs in neonatal animal models has been shown to be effective in reducing lesion volume and improving functional outcome. The beneficial effect of MSC transplantation to treat neonatal brain injury might be explained by the great plasticity of the neonatal brain. The neonatal brain is still in a developmentally active phase, leading to a better efficiency of MSC transplantation than that observed in experiments using adult models of stroke. Enhanced neurogenesis and axonal remodeling likely underlie the improved functional outcome following MSC treatment after neonatal hypoxic-ischemic (HI) brain injury. With respect to the mechanism of repair by MSCs, MSCs do not survive long term and replace damaged tissue themselves. We propose that MSCs react to the needs of the ischemic cerebral environment by secretion of several growth factors, cytokines, and other bioactive molecules to regulate damage and repair processes. Parenchymal cells react to the secretome of the MSCs and contribute to stimulate repair processes. These intrinsic adaptive properties of MSCs make them excellent candidates for a novel therapy to treat the devastating effects of HI encephalopathy in the human neonate.
Article
Full-text available
The fetal inflammatory response syndrome (FIRS) is associated with impending onset of preterm labor/delivery, microbial invasion of the amniotic cavity and increased perinatal morbidity. FIRS has been defined by an elevated fetal plasma interleukin (IL)-6, a cytokine with potent effects on the differentiation and proliferation of hematopoietic precursors. The objective of this study was to characterize the hematologic profile of fetuses with FIRS. Fetal blood sampling was performed in patients with preterm prelabor rupture of membranes and preterm labor with intact membranes (n=152). A fetal plasma IL-6 concentration ≥ 11 pg/mL was used to define FIRS. Hemoglobin concentration, platelet count, total white blood cell (WBC) count, differential count, and nucleated red blood cell (NRBC) count were obtained. Since blood cell count varies with gestational age, the observed values were corrected for fetal age by calculating a ratio between the observed and expected mean value for gestational age. 1) The prevalence of FIRS was 28.9% (44/152); 2) fetuses with FIRS had a higher median corrected WBC and corrected neutrophil count than those without FIRS (WBC: median 1.4, range 0.3-5.6, vs. median 1.1, range 0.4-2.9, P=0.001; neutrophils: median 3.6, range 0.1-57.5, vs. median 1.8, range 0.2-13.9, P<0.001); 3) neutrophilia (defined as a neutrophil count >95th centile of gestational age) was significantly more common in fetuses with FIRS than in those without FIRS (71%, 30/42, vs. 35%, 37/105; P<0.001); 4) more than two-thirds of fetuses with FIRS had neutrophilia, whereas neutropenia was present in only 4.8% (2/42); 5) FIRS was not associated with detectable changes in hemoglobin concentration, platelet, lymphocyte, monocyte, basophil or eosinophil counts; and 6) fetuses with FIRS had a median corrected NRBC count higher than those without FIRS. However, the difference did not reach statistical significance (NRBC median 0.07, range 0-1.3, vs. median 0.04, range 0-2.3, P=0.06). The hematologic profile of the human fetus with FIRS is characterized by significant changes in the total WBC and neutrophil counts. The NRBC count in fetuses with FIRS tends to be higher than fetuses without FIRS.
Article
Full-text available
Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy. In this multicenter, placebo-controlled, double-blind trial, we randomly assigned women at imminent risk for delivery between 24 and 31 weeks of gestation to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2 g per hour, or matching placebo. The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age. A total of 2241 women underwent randomization. The baseline characteristics were similar in the two groups. Follow-up was achieved for 95.6% of the children. The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (11.3% and 11.7%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23). However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55; 95% CI, 0.32 to 0.95). The risk of death did not differ significantly between the groups (9.5% vs. 8.5%; relative risk, 1.12; 95% CI, 0.85 to 1.47). No woman had a life-threatening event. Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors. (ClinicalTrials.gov number, NCT00014989.)
Article
Full-text available
The timing of umbilical cord clamping in 38 women with preterm labour was randomly assigned. Ultrasonographic evidence of periventricular/intraventricular haemorrhage (PVH/IVH), assessed blindly, was found in 77% of the group clamped early compared with 35% of those in whom clamping of the cord was delayed for 1 minute. A hypothesis to explain the possible contribution of the haemodynamic events which accompany cord clamping to the development of PVH/IVH is presented.
Article
Full-text available
A randomized controlled pilot study was performed with a sample of extremely preterm infants to evaluate the impact of postnatal estradiol and progesterone replacement on postnatal bone mineral accretion. Twenty-five of 30 infants in the pilot study survived, and of these, 24 infants were available for the follow-up examination at a median chronological age of 18.1 months (minimum-maximum, 17.0--20.6) corresponding to a corrected age of 14.8 months (minimum-maximum, 12.9--17.4). Somatic growth data and bone mineralization showed no differences between the hormone-treated and control group infants. The deviation of the skeletal age from the corrected age was 0.0 months (minimum-maximum, -7.7 to 7.4) for hormone-treated infants compared with -1.7 months (minimum-maximum, -7.5 to 5.9) for the control group. The Bayley scales mental and psychomotor developmental indexes were 89 (minimum-maximum, 71--107) and 101 (minimum-maximum, 49--121) for the hormone-treated infants and 93 (minimum-maximum, 49--111) and 71 (minimum-maximum, 49--121) for the control group infants, respectively (mental developmental index, P = 1.0; psychomotor developmental index, P = 0.14). The normal psychomotor development in the hormone-treated infants compared with the below average development in the control group infants is encouraging and indicates the potentially important integrative role of sex steroids for the developing brain. Larger studies on the effects of the postnatal replacement of estradiol and progesterone in extremely preterm infants are warranted.
Article
Full-text available
The purpose of the present study was to determine whether endotoxins (lipopolysaccharides, LPS) affect the fetal cardiovascular system in a way likely to cause brain damage. Thirteen fetal sheep were chronically instrumented at a mean gestational age of 107 +/- 1 days. After control measurements of organ blood flow (microsphere method), blood gases, and acid base balance were obtained, seven of 13 fetuses received LPS (53 +/- 3 microg/kg fetal weight) intravenously. Sixty minutes later, asphyxia was induced by occlusion of the maternal aorta for 2 minutes. Measurements of organ blood flows were made at -60, -1, +2, +4, +30, and +60 minutes. Unlike in the control group, after LPS infusion there was a significant decrease in arterial oxygen saturation (-46%; P <.001) and pH (P <.001). In LPS-treated fetuses the portion of combined ventricular output directed to the placenta decreased significantly (-76%; P <.001), whereas output to the fetal body (+60%; P <.001), heart (+167%; P <.05), and adrenals (+229%; P <.01) increased. Furthermore, during asphyxia circulatory centralization was impaired considerably in LPS-treated fetuses, and there was clear evidence of circulatory decentralization. This decentralization caused a severe decrease in cerebral oxygen delivery by 70%. Within 30 minutes after induction of asphyxia five of seven LPS-treated fetuses died, whereas all control fetuses recovered completely. Endotoxemia severely impaired fetal cardiovascular control during normoxia and asphyxia, resulting in a considerable decrease in cerebral oxygen delivery. These effects might have important effects in the development of fetal brain damage associated with intrauterine infection.
Article
Full-text available
This study compared the effects of immediate (ICC) and delayed (DCC) cord clamping on very low birth weight (VLBW) infants on 2 primary variables: bronchopulmonary dysplasia (BPD) and suspected necrotizing enterocolitis (SNEC). Other outcome variables were late-onset sepsis (LOS) and intraventricular hemorrhage (IVH). This was a randomized, controlled unmasked trial in which women in labor with singleton fetuses <32 weeks' gestation were randomly assigned to ICC (cord clamped at 5-10 seconds) or DCC (30-45 seconds) groups. Women were excluded for the following reasons: their obstetrician refused to participate, major congenital anomalies, multiple gestations, intent to withhold care, severe maternal illnesses, placenta abruption or previa, or rapid delivery after admission. Seventy-two mother/infant pairs were randomized. Infants in the ICC and DCC groups weighed 1151 and 1175 g, and mean gestational ages were 28.2 and 28.3 weeks, respectively. Analyses revealed no difference in maternal and infant demographic, clinical, and safety variables. There were no differences in the incidence of our primary outcomes (BPD and suspected NEC). However, significant differences were found between the ICC and DCC groups in the rates of IVH and LOS. Two of the 23 male infants in the DCC group had IVH versus 8 of the 19 in the ICC group. No cases of sepsis occurred in the 23 boys in the DCC group, whereas 6 of the 19 boys in the ICC group had confirmed sepsis. There was a trend toward higher initial hematocrit in the infants in the DCC group. Delayed cord clamping seems to protect VLBW infants from IVH and LOS, especially for male infants.
Article
The optimal timing for clamping the umbilical cord after birth has been a subject of controversy and debate. Although many randomized controlled trials in term and preterm infants have evaluated the benefits of delayed umbilical cord clamping versus immediate umbilical cord clamping, the ideal timing for cord clamping has yet to be established. Several systematic reviews have suggested that clamping the umbilical cord in all births should be delayed for at least 30-60 seconds, with the infant maintained at or below the level of the placenta because of the associated neonatal benefits, including increased blood volume, reduced need for blood transfusion, decreased incidence of intracranial hemorrhage in preterm infants, and lower frequency of iron deficiency anemia in term infants. Evidence exists to support delayed umbilical cord clamping in preterm infants, when feasible. The single most important clinical benefit for preterm infants is the possibility for a nearly 50% reduction in intraventricular hemorrhage. However, currently, evidence is insufficient to confirm or refute the potential for benefits from delayed umbilical cord clamping in term infants, especially in settings with rich resources.
Article
The U.S. Food and Drug Administration advises against the use of magnesium sulfate injections for more than 5–7 days to stop preterm labor in pregnant women. Based on this, the drug classification was changed from Category A to Category D, and the labeling was changed to include this new warning information. However, the U.S. Food and Drug Administration's change in classification addresses an unindicated and nonstan-dard use of magnesium sulfate in obstetric care. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine continue to support the short-term (usually less than 48 hours) use of magnesium sulfate in obstetric care for appropriate conditions and for appropriate durations of treatment, which includes the prevention and treatment of seizures in women with preeclampsia or eclampsia, fetal neuroprotection before anticipated early preterm (less than 32 weeks of gestation) delivery, and short-term prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal corticosteroids in pregnant women between 24 weeks of gestation and 34 weeks of gestation who are at risk of preterm delivery within 7 days.
Article
Objective: We sought to provide evidence-based guidelines for using progestogens for the prevention of preterm birth (PTB). Methods: Relevant documents, in particular randomized trials, were identified using PubMed (US National Library of Medicine, 1983 through February 2012) publications, written in English, which evaluate the effectiveness of progestogens for prevention of PTB. Progestogens evaluated were, in particular, vaginal progesterone and 17-alpha-hydroxy-progesterone caproate. Additionally, the Cochrane Library, organizational guidelines, and studies identified through review of the above were utilized to identify relevant articles. Data were evaluated according to population studied, with separate analyses for singleton vs multiple gestations, prior PTB, or short transvaginal ultrasound cervical length (CL), and combinations of these factors. Consistent with US Preventive Task Force suggestions, references were evaluated for quality based on the highest level of evidence, and recommendations were graded. Results and recommendations: Summary of randomized studies indicates that in women with singleton gestations, no prior PTB, and short CL ≤ 20 mm at ≤ 24 weeks, vaginal progesterone, either 90-mg gel or 200-mg suppository, is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases. The issue of universal CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as reasonable, and can be considered by individual practitioners, following strict guidelines. In singleton gestations with prior PTB 20-36 6/7 weeks, 17-alpha-hydroxy-progesterone caproate 250 mg intramuscularly weekly, preferably starting at 16-20 weeks until 36 weeks, is recommended. In these women with prior PTB, if the transvaginal ultrasound CL shortens to < 25 mm at < 24 weeks, cervical cerclage may be offered. Progestogens have not been associated with prevention of PTB in women who have in the current pregnancy multiple gestations, preterm labor, or preterm premature rupture of membranes. There is insufficient evidence to recommend the use of progestogens in women with any of these risk factors, with or without a short CL.
Article
The sex hormone Progesterone has been shown to improve outcomes in animal models of a number of neurologic diseases, including traumatic brain injury, ischemia, spinal cord injury, peripheral nerve injury, demyelinating disease, neuromuscular disorders, and seizures. Evidence suggests it exerts its neuroprotective effects through several pathways, including reducing edema, improving neuronal survive, and modulating inflammation and apoptosis. In this review, we summarize the functional outcomes and pathophysiologic mechanisms attributed to Progesterone treatment in neurologic disease. We then comment on the breadth of evidence for the use of Progesterone in each neurologic disease family. Finally, we provide support for further human studies using Progesterone to treat several neurologic diseases.
Chapter
There is a growing body of evidence from clinical and epidemiologic studies that in utero exposure to infection plays an important role in the genesis of fetal or neonatal injury leading to cerebral palsy and chronic lung disease. Thus, after chorioamnionitis the incidence of immature neonates with periventricular white matter damage and periventricular or intraventricular hemorrhage is significantly elevated. Recent clinical and experimental data support the hypothesis that a fetal inflammatory response links antenatal infection with brain white matter damage and subsequent motor handicap. A variety of studies support the view that cytokines released during intrauterine infection directly cause injury to the immature brain. In this review, we provide evidence that in utero exposure to bacterial infection can severely alter fetal cardiovascular function, resulting in dysregulation of cerebral blood flow and subsequent hypoxic-ischemic brain injury. ( J Soc Gynecol Investig 2003;10:450 -9) Copyright © 2003 by the Society for Gynecologic Investigation.
Article
Objective: To test a possible neuroprotective activity of 17β-estradiol in the neonatal rat brain exposed to hypoxic-ischemia (controlled hypoxia after unilateral carotid artery ligation). Methods: Seven-day-old Wistar rats underwent ligation of the left common carotid artery followed by 80 minutes hypoxia in 8% oxygen inducing an ipsilateral brain damage. Seven days later (d14), brains were analyzed quantitatively using a macroscopic and microscopic score for structural damage, hemisphere volumes were calculated, and immunohistochemistry for cleaved-caspase-3 (marker for apoptotic cells) was performed. Animals from the study group (n = 19) received 17β-estradiol (0.05 µg/g body weight intraperitoneally) before (-64, -40, and -16 hours) and after (+3 hours) the hypoxia (hour 0: start of the hypoxia) and the control group (n = 21) received mock treatment. Results: Of the 21 pups, 13 in the NaCl group had macroscopically a severe brain damage and 7 of 19 animals in the study group encountered only discrete to mild lesions. Microscopic brain damage in the study group was significantly lower (score 1.5 ± 0.7 vs 2.8 ± 0.8, P < .05). The determined volumes of the affected hemisphere were significantly lower in the NaCl group than in the treatment group. The numbers of apoptotic cells in both hemispheres was equal in the estradiol group, but in the control group, there were significantly more apoptotic cells in the affected hemisphere (control group: ipsilateral: 1435 ± 653 vs contralateral: 143 ± 57 cells, P < .05). Discussion: 17β-Estradiol protects newborn rat brains from hypoxic-ischemic injury, in terms of both microscopic cell injury and apoptosis.
Article
It is important to establish whether research recommendations regarding magnesium sulphate for neuroprotection can be readily translated into clinical practice and achieve the dual objectives of good coverage of the target group, while minimising unnecessary or prolonged exposure to treatment. This retrospective cohort study included all women admitted to a tertiary obstetric centre at 23-32 weeks gestation in the first 12 months following implementation of the guideline 'Magnesium sulphate for the prevention of cerebral palsy'. We determined the number triaged to receive magnesium sulphate, the proportion of infants who received magnesium sulphate prior to delivery and the total number of doses administered. A total of 330 women were admitted at a mean gestational age of 28.2 weeks, and 132/330 (40%) were prescribed magnesium sulphate, of whom 123/132 (93%) delivered. 142/191 (74%) infants born at <32 weeks' gestation received magnesium sulphate prior to delivery, with no significant differences seen by plurality or gestational age. Of the 145 doses administered, only 13 women received more than one dose, and only nine of 145 (7%) doses proved to be unnecessary. The median treatment duration was 3 h 58 min. The infusion was discontinued as result of side effects in 2% of women. Research recommendations regarding administration of magnesium sulphate with neuroprotective intent can be successfully translated into clinical practice. Appropriate triaging of women at high risk of imminent preterm birth is feasible, enabling a high level of magnesium sulphate coverage for infants that deliver prior to 32 weeks gestation, with minimal toxicity and a low rate of unnecessary maternal exposure.
Article
To compare two strategies to enhance placento-fetal blood transfusion in preterm neonates before 33 weeks of gestation. We recruited women at risk for singleton preterm deliveries. All delivered before 33 completed weeks of gestation. In this single-center trial, women were randomized to either standard treatment (clamping the cord for 30 seconds after delivery) or repeated (four times) milking of the cord toward the neonate. Exclusion criteria included inadequate time to obtain consent before delivery, known congenital abnormalities of the fetus, Rhesus sensitization, or fetal hydrops. Of 58 neonates included the trial, 31 were randomized to cord clamping and 27 were randomized to repeated milking of the cord. Mean birth weight was 1,263±428 g in the clamping group and 1,235±468 g in the milking group, with mean gestational age of 29.2±2.3 weeks and 29.5±2.7 weeks, respectively. Mean hemoglobin values for each group at 1 hour after birth were 17.3 g/L for clamping and 17.5 g/L for milking (P=.71). There was no significant difference in number of neonates undergoing transfusion (clamping group, 15; milking group, 17; P=.40) or the median number of transfusions within the first 42 days of life (median [range]: clamping group 0 [0-7]; milking group 0 [0-20]; P=.76). Milking the cord four times achieved a similar amount of placento-fetal blood transfusion compared with delaying clamping the cord for 30 seconds. National Research Register UK, www.nihr.ac.uk/Pages/default.aspx, N0051177741. I.
Article
To examine the relationships between clinical or histological chorioamnionitis and cerebral palsy using a meta-analysis approach. A systematic review of the literature appeared in PubMed between 2000 and 2009 was conducted using the search terms "cerebral palsy" and "infection," with broad-scope variations in terminology of "white matter damage," "periventricular leukomalacia," "cystic periventricular leukomalacia," "chorioamnionitis," "intrauterine infection," "intraventricular hemorrhage," "funisitis," "fetal inflammatory response," "early neonatal sepsis," "neurological impairment," "virus," "bacteria," "fungi," and "protozoa," with variations of suffixes (eg, "viral," "bacterial," "fungal," "protozoan," etc), and "urinary tract infection," "bacterial vaginosis," "bacteriuria," and "cytokines." The related key words "gestational age," "small for gestational age," "preterm," and "low birth weight" also were added to the search terms. Only studies published in English were included. Three hundred eight articles were retrieved and systematically reviewed independently by two authors. Application of four inclusion criteria led to 15 studies being considered for data abstraction. An exposure was considered relevant if it met the established criteria for clinical or histological chorioamnionitis. The outcome was a diagnosis of cerebral palsy in accordance with established criteria. The data were abstracted onto standard forms, correlated according to eight characteristics, and tabulated. Twelve of the 15 studies contained information on the association between clinical chorioamnionitis and cerebral palsy, and eight studies included information on the association between histological chorioamnionitis and cerebral palsy. The results indicated that there were significant associations between clinical chorioamnionitis or histological chorioamnionitis and cerebral palsy, for clinical chorioamnionitis (chi1=13.91; P<.001) with a pooled odds ratio of 2.42 (95% confidence interval 1.52-3.84), and for histological chorioamnionitis (chi1=6.86; P=.009) with a pooled odds ratio of 1.83 (95% confidence interval, 1.17-2.89). The data suggested increased risks of 140% and 80% for neonates exposed to clinical chorioamnionitis or histological chorioamnionitis, respectively. The significant association of clinical or histological chorioamnionitis with cerebral palsy suggested that clinical strategies to prevent or reduce chorioamnionitis would lead to a reduction in cerebral palsy. The culture techniques currently used to diagnose the presence of pathogenic microorganisms during pregnancy need to improve, both in their methodology and in the length of time they require.
Article
Human ESC-derived mesenchymal stem cell (MSC)-conditioned medium (CM) was previously shown to mediate cardioprotection during myocardial ischemia/reperfusion injury through large complexes of 50-100 nm. Here we show that these MSCs secreted 50- to 100-nm particles. These particles could be visualized by electron microscopy and were shown to be phospholipid vesicles consisting of cholesterol, sphingomyelin, and phosphatidylcholine. They contained coimmunoprecipitating exosome-associated proteins, e.g., CD81, CD9, and Alix. These particles were purified as a homogeneous population of particles with a hydrodynamic radius of 55-65 nm by size-exclusion fractionation on a HPLC. Together these observations indicated that these particles are exosomes. These purified exosomes reduced infarct size in a mouse model of myocardial ischemia/reperfusion injury. Therefore, MSC mediated its cardioprotective paracrine effect by secreting exosomes. This novel role of exosomes highlights a new perspective into intercellular mediation of tissue injury and repair, and engenders novel approaches to the development of biologics for tissue repair.
Article
We conducted a systematic review and metaanalysis of randomized controlled trials to determine whether magnesium sulfate administered to women at risk of preterm delivery before 34 weeks of gestation may reduce the risk of cerebral palsy in their children. Six trials involving 4796 women and 5357 infants were included. Antenatal magnesium sulfate was associated with a significant reduction in the risk of cerebral palsy (relative risk [RR], 0.69; 95% confidence interval [CI], 0.55-0.88), moderate or severe cerebral palsy (RR, 0.64; 95% CI, 0.44-0.92), and substantial gross motor dysfunction (RR, 0.60; 95% CI, 0.43-0.83). There was no overall difference in the risk of total pediatric mortality (RR, 1.01; 95% CI, 0.89-1.14). Minor side effects were more frequent among women receiving magnesium sulfate. In conclusion, magnesium sulfate administered to women at risk of delivery before 34 weeks of gestation reduces the risk of cerebral palsy.
Article
The use of magnesium for prevention of cerebral palsy in preterm infants has been a pressing clinical question for some time. This issue was recently brought to the forefront again after the completion of a large trial conducted by the Maternal-Fetal Medicine Units Network and published by Rouse et al in August, 2008 in the New England Journal of Medicine. After review of the complex body of literature on this topic, and the recent addition of this important piece of evidence, we discussed the "pros" and "cons" of the evidence-based use of magnesium for prevention of cerebral palsy at the annual meeting for the Society of Maternal-Fetal Medicine as a luncheon roundtable. The evidence currently available does not make the clinical decision of whether or not to use magnesium for the prevention of cerebral palsy as clear as we would hope. It appears that despite well-designed and executed studies on this critically important topic in obstetrics, the answer to the question of whether evidence-based medicine supports the use of magnesium for neuroprophylaxis in preterm infants remains unclear.
Article
Background: Epidemiological and basic science evidence suggests that magnesium sulphate before birth may be neuroprotective for the fetus. Objectives: To assess the effects of magnesium sulphate as a neuroprotective agent when given to women considered at risk of preterm birth. Search strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2008). Selection criteria: Randomised controlled trials of antenatal magnesium sulphate therapy in women threatening or likely to give birth at less than 37 weeks' gestational age. For one subgroup analysis, studies were broadly categorised by the primary intent of the study into "neuroprotective intent", or "other intent (maternal neuroprotective - pre-eclampsia)", or "other intent (tocolytic)". Data collection and analysis: At least two authors assessed trial eligibility and quality, and extracted data. Main results: Five trials (6145 babies) were eligible for this review. Antenatal magnesium sulphate therapy given to women at risk of preterm birth substantially reduced the risk of cerebral palsy in their child (Relative Risk (RR) 0.68; 95% Confidence interval (CI) 0.54 to 0.87; five trials; 6145 infants). There was also a significant reduction in the rate of substantial gross motor dysfunction (RR 0.61; 95% CI 0.44 to 0.85; four trials; 5980 infants). No statistically significant effect of antenatal magnesium sulphate therapy was detected on paediatric mortality (RR 1.04; 95% CI 0.92 to 1.17; five trials; 6145 infants), or on other neurological impairments or disabilities in the first few years of life. Overall there were no significant effects of antenatal magnesium therapy on combined rates of mortality with cerebral palsy, although there were significant reductions for the neuroprotective groups RR 0.85; 95% CI 0.74 to 0.98; four trials; 4446 infants, but not for the other intent subgroups. There were higher rates of minor maternal side effects in the magnesium groups, but no significant effects on major maternal complications. Authors' conclusions: The neuroprotective role for antenatal magnesium sulphate therapy given to women at risk of preterm birth for the preterm fetus is now established. The number of women needed to be treated to benefit one baby by avoiding cerebral palsy is 63 (95% confidence interval 43 to 87). Given the beneficial effects of magnesium sulphate on substantial gross motor function in early childhood, outcomes later in childhood should be evaluated to determine the presence or absence of later potentially important neurological effects, particularly on motor or cognitive function.
Article
To evaluate the hypothesis that the proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor-alpha might be the link between prenatal intrauterine infection (IUI) and neonatal brain damage, the authors review the relevant epidemiologic and cytokine literature. Maternal IUI appears to increase the risk of preterm delivery, which in turn is associated with an increased risk of intraventricular hemorrhage, neonatal white matter damage, and subsequent cerebral palsy. IL-1, IL-6, and TNF-alpha have been found associated with IUI, preterm birth, neonatal infections. and neonatal brain damage. Unifying models not only postulate the presence of cytokines in the three relevant maternal/fetal compartments (uterus, fetal circulation, and fetal brain) and the ability of the cytokines to cross boundaries (placenta and blood-brain barrier) between these compartments, but also postulate how proinflammatory cytokines might lead to IVH and neonatal white matter damage during prenatal maternal infection. Interrupting the proinflammatory cytokine cascade might prevent later disability in those born near the end of the second trimester.
Article
Perinatal brain damage in the mature fetus is usually brought about by severe intrauterine asphyxia following an acute reduction of the uterine or umbilical circulation. The areas most heavily affected are the parasagittal region of the cerebral cortex and the basal ganglia. The fetus reacts to a severe lack of oxygen with activation of the sympathetic-adrenergic nervous system and a redistribution of cardiac output in favour of the central organs (brain, heart and adrenals). If the asphyxic insult persists, the fetus is unable to maintain circulatory centralisation, and the cardiac output and extent of cerebral perfusion fall. Owing to the acute reduction in oxygen supply, oxidative phosphorylation in the brain comes to a standstill. The Na(+)/K(+) pump at the cell membrane has no more energy to maintain the ionic gradients. In the absence of a membrane potential, large amounts of calcium ions flow through the voltage-dependent ion channel, down an extreme extra-/intracellular concentration gradient, into the cell. Current research suggests that the excessive increase in levels of intracellular calcium, so-called calcium overload, leads to cell damage through the activation of proteases, lipases and endonucleases. During ischemia, besides the influx of calcium ions into the cells via voltage-dependent calcium channels, more calcium enters the cells through glutamate-regulated ion channels. Glutamate, an excitatory neurotransmitter, is released from presynaptic vesicles during ischemia following anoxic cell depolarisation. The acute lack of cellular energy arising during ischemia induces almost complete inhibition of cerebral protein biosynthesis. Once the ischemic period is over, protein biosynthesis returns to pre-ischemic levels in non-vulnerable regions of the brain, while in more vulnerable areas it remains inhibited. The inhibition of protein synthesis, therefore, appears to be an early indicator of subsequent neuronal cell death. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the post-ischemic release of oxygen radicals, synthesis of nitric oxide (NO), inflammatory reactions and an imbalance between the excitatory and inhibitory neurotransmitter systems. Part of the secondary neuronal cell damage may be caused by induction of a kind of cellular suicide programme known as apoptosis. Knowledge of these pathophysiological mechanisms has enabled scientists to develop new therapeutic strategies with successful results in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of i.v. administration of magnesium or post-ischemic induction of cerebral hypothermia.
Article
In addition to its role as a sex hormone, oestrogen affects the structure and function of the nervous system. Oestrogen receptors are expressed in brain regions that are involved in sex differentiation and maturation. But in addition to its well-known effects, oestrogen also has important neuroprotective actions that are both dependent and independent of a nuclear oestrogen-receptor activity. Furthermore, oestrogen can interact with neuroprotective intracellular signalling pathways and is itself a neuroprotective antioxidant. Understanding the mechanisms of oestrogen action will be crucial to determine its potential as a therapeutic agent, particularly in the elderly.
Article
Perinatal brain damage is associated not only with hypoxic-ischemic insults but also with intrauterine inflammation. A combination of antenatal inflammation and asphyxia increases the risk of cerebral palsy >70 times. The aim of the present study was to determine the effect of intracisternal (i.c.) administration of endotoxin [lipopolysaccharides (LPS)] on subsequent hypoxic-ischemic brain damage in neonatal rats. Seven-day-old Wistar rats were subjected to i.c. application of NaCl or LPS (5 microg/pup). One hour later, the left common carotid artery was exposed through a midline neck incision and ligated with 6-0 surgical silk. After another hour of recovery, the pups were subjected to a hypoxic gas mixture (8% oxygen/92% nitrogen) for 60 min. The animals were randomized to four experimental groups: 1) sham control group, left common carotid artery exposed but not ligated (n = 5); 2) LPS group, subjected to i.c. application of LPS (n = 7); 3) hypoxic-ischemic study group, i.c. injection of NaCl and exposure to hypoxia after ligation of the left carotid artery (n = 17); or 4) hypoxic-ischemic/LPS study group, i.c. injection of LPS and exposure to hypoxia after ligation of the left carotid artery (n = 19). Seven days later, neonatal brains were assessed for neuronal cell damage. In a second set of experiments, rat pups received an i.c. injection of LPS (5 microg/pup) and were evaluated for tumor necrosis factor-alpha expression by immunohistochemistry. Neuronal cell damage could not be observed in the sham control or in the LPS group. In the hypoxic-ischemic/LPS group, neuronal injury in the cerebral cortex was significantly higher than in animals that were subjected to hypoxia/ischemia after i.c. application of NaCl. Injecting LPS intracisternally caused a marked expression of tumor necrosis factor-alpha in the leptomeninges. Applying LPS intracisternally sensitizes the immature rat brain to a subsequent hypoxic-ischemic insult.
Article
This study was undertaken to determine whether progestational agents can prevent inflammation-induced preterm parturition and fetal demise. The activation of contractile and inflammatory pathways in response to localized intrauterine inflammation was investigated by using quantitative polymerase chain reaction (PCR). Serum progesterone (P4) levels and alterations in progesterone receptor-B (PR-B) were determined with radioimmunoassay and quantitative PCR, respectively. With our in vivo model of intrauterine inflammation, animals were randomly assigned to pretreatment with P4 or medroxyprogesterone acetate (MPA) before intrauterine lipopolysaccharide (LPS). Animals were observed for preterm delivery. The number of live pups 48 hours after intrauterine LPS was recorded for each treatment group. The ability of MPA to alter signal transduction pathways leading to preterm parturition were investigated by quantitative PCR and histochemical studies. Intrauterine inflammation is associated with decreased serum progesterone levels and decreased transcription of PR-B. Preterm delivery rates were 100% for LPS alone, 63% for LPS+P4, and 0% for LPS+MPA. No live pups remained at 48 hours in the LPS or LPS+P4 groups. Pretreatment with MPA significantly preserved fetal viability. MPA suppressed activation of contraction-associated genes and inflammatory mediators and prevented cervical ripening in response to intrauterine inflammation. MPA, with its progestational and anti-inflammatory properties, prevented inflammation-induced preterm parturition and significantly preserved fetal viability.
Article
Activation of the innate immune receptors, Toll-like receptors 2 and 4, are critical for a host inflammatory response to both Gram-positive and Gram-negative organisms. These receptors can initiate and modulate the inflammatory response. Differential regulation of Toll-like receptors may be one of the mechanisms by which intrauterine inflammation signals parturition. Likewise, progestational agents may have the ability to modify this effect. These studies were performed to elucidate the effect of intrauterine inflammation and medroxyprogesterone acetate on Toll-like receptor expression in the uterus, cervix, and placenta in a mouse model of intrauterine inflammation. On day 15 of gestation, CD-1 mice were randomized to pretreatment with medroxyprogesterone acetate or vehicle before intrauterine infusion with lipopolysaccharide or sterile saline solution. Six hours after intrauterine infusion, uterine, cervical, and placental tissues were harvested. RNA and protein were extracted. Quantitative polymerase chain reaction was performed for Toll-like receptor 2 and 4 messenger RNA. Western blot analysis was performed with Toll-like receptor 4-specific antibodies. Intrauterine inflammation up-regulated Toll-like receptor 2 and 4 messenger RNA in uterus, cervix, and placenta. Pretreatment with medroxyprogesterone acetate decreased the lipopolysaccharide-induced up-regulation of Toll-like receptor 2 and 4 messenger RNA in the cervix and placenta. Medroxyprogesterone acetate treatment, in the presence of lipopolysaccharide, was unable to prevent the lipopolysaccharide-induced increase in Toll-like receptor 4 messenger RNA and protein in the uterus. Medroxyprogesterone acetate treatment alone in pregnant mice significantly increased Toll-like receptor 4 messenger RNA expression in the uterus. Intrauterine inflammation has a differential effect on Toll-like receptor 2 and 4 expression. The observed up-regulation of Toll-like receptor 2 in the uterus in response to intrauterine lipopolysaccharide may be a mechanism to augment the inflammatory response and may serve to promote parturition in the setting of inflammation. Consequently, the ability of medroxyprogesterone acetate to suppress lipopolysaccharide-induced up-regulation of Toll-like receptor 2 messenger RNA may be one of the mechanisms by which progestins are able to decrease preterm birth.
Article
Early onset cerebral hypoperfusion after birth is highly correlated with neurological injury in premature infants, but the relationship with the evolution of injury remains unclear. We studied changes in cerebral oxygenation, and cytochrome oxidase (CytOx) using near-infrared spectroscopy in preterm fetal sheep (103-104 days of gestation, term is 147 days) during recovery from a profound asphyxial insult (n= 7) that we have shown produces severe subcortical injury, or sham asphyxia (n= 7). From 1 h after asphyxia there was a significant secondary fall in carotid blood flow (P < 0.001), and total cerebral blood volume, as reflected by total haemoglobin (P < 0.005), which only partially recovered after 72 h. Intracerebral oxygenation (difference between oxygenated and deoxygenated haemoglobin concentrations) fell transiently at 3 and 4 h after asphyxia (P < 0.01), followed by a substantial increase to well over sham control levels (P < 0.001). CytOx levels were normal in the first hour after occlusion, was greater than sham control values at 2-3 h (P < 0.05), but then progressively fell, and became significantly suppressed from 10 h onward (P < 0.01). In the early hours after reperfusion the fetal EEG was highly suppressed, with a superimposed mixture of fast and slow epileptiform transients; overt seizures developed from 8 +/- 0.5 h. These data strongly indicate that severe asphyxia leads to delayed, evolving loss of mitochondrial oxidative metabolism, accompanied by late seizures and relative luxury perfusion. In contrast, the combination of relative cerebral deoxygenation with evolving epileptiform transients in the early recovery phase raises the possibility that these early events accelerate or worsen the subsequent mitochondrial failure.
Article
Currently there is not enough evidence to show if magnesium sulphate given to women at risk of preterm birth might help to protect the baby's brain and improve long-term outcomes. Babies born too early (preterm) have a higher risk of dying in the first weeks of life than babies born at term, and those who survive often have damage to their nerves in the form of cerebral palsy, blindness, deafness or physical disabilities. This can cause huge distress for parents. Magnesium is an important element essential for normal body functions. Magnesium sulphate is used to reduce the risk of fits, i.e., it is an anticonvulsant drug, in women with very high blood pressure in pregnancy. So, theoretically, it may help to reduce the effect of damaging events to a preterm baby's brain. However, it has adverse effects in the mother of flushing, sweating, nausea, vomiting, headaches and a rapid heartbeat (palpitations). This review identified four studies involving 3701 infants, but it cannot conclusively confirm if magnesium sulphate therapy protects the unborn baby's brain. Further research (yet to be published) is needed to show if magnesium can provide these benefits.
Article
There is strong evidence from recent clinical studies that ascending intrauterine infection is associated with an increased incidence of periventricular leukomalacia in very premature fetuses. Periventricular leukomalacia is characterized by disrupted myelination from a loss of oligodendrocyte progenitors. We investigated the effects of proinflammatory cytokines on the survival and differentiation of this cell type. Cultures of more than 90% A2B5-positive progenitors were prepared from neonatal rats and kept for 3 days in medium supplemented with factors that stimulate cell proliferation. After 1 day in proliferation medium, cells were treated with interferon-gamma (100 U/mL) and tumor necrosis factor-alpha (100 ng/mL) for 48 hours triggering an increase in apoptotic A2B5 progenitor cells from 3.2 +/- 2.3% to 11.0 +/- 2.6%. After cytokine treatment cultures were transferred to medium containing factors to promote differentiation of progenitors into the myelinating phenotype. In cytokine pretreated cultures, only 2.6 +/- 1.1% of total cells survived after a total of 9 days in vitro, whereas in untreated cultures most cells differentiated as shown by expression of myelin basic protein, myelin-associated glycoprotein, 2,3-cyclic nucleotide 3-phosphodiesterase, and myelin oligodendrocyte-specific protein. Using ten-fold reduced concentrations of combined interferon-gamma (10 U/mL) and tumor necrosis factor-alpha (10 ng/mL) pretreatment resulted in a survival to 11.2 +/- 4.9% of total cells with 36.3 +/- 11.6% A2B5-positive cells at day 9. This indicates a major enrichment of undifferentiated cells compared with untreated controls which harbored only 1.0 +/- 0.3% A2B5-positive cells. Inflammatory cytokines not only induced apoptotic cell death but also prevented the differentiation of immature A2B5 oligodendrocyte progenitors into the myelinating phenotype.
Article
Hypoxia-ischemia is relatively common in human infants. Hypoxia-ischemia can occur as a result of complications associated with prematurity or birth, frequently leading to altered brain development and cognitive and behavioral deficits that persist throughout life. Despite the relative frequency of neonatal hypoxic-ischemic encephalopathy, the immature brain sustains relatively less damage than an adult who experiences a similar crisis of oxygen and nutrient deprivation. Therefore, factors may be present that protect the developing brain. During late gestation, the infant brain encounters high levels of the steroid hormone 17beta-estradiol. This observation, combined with evidence supporting 17beta-estradiol as a neuroprotective agent, led us to hypothesize that increasing the basal level of 17beta-estradiol would reduce the amount of hypoxia-ischemia induced injury to the neonatal brain. To test that hypothesis we administered 17beta-estradiol using either a repeated dosing paradigm or a single dose paradigm to immature male and female rats. Here we show that the repeated dosing paradigm (three doses of 17beta-estradiol) provided approximately 70% protection of the hippocampus, basal ganglia, and amygdala. By contrast, a single administration of 17beta-estradiol 24 h prior to hypoxia-ischemia conferred little protection. The only exception was the pyramidal layer of the female hippocampus, which was modestly protected (16% reduction in damage). The protection afforded by the multiple administrations of 17beta-estradiol was similar for females and males, with the only exception being the male amygdala, which displayed less damage than the female amgydala. We conclude that 17beta-estradiol acts as a potent neuroprotective agent against hypoxia-ischemia induced damage to the developing brain, and that pretreating infants at risk for hypoxic-ischemic injury may be advisable.
Hematologic profile of the fetus with systemic inflammatory response syndrome
  • R Romero
  • Z A Savasan
  • T Chaiworapongsa
  • R. Romero
) 17beta-estradiol protects the neonatal brain from hypoxia-ischemia
  • J Nunez
  • Z Yang
  • Y Jiang
  • J. Nunez
Medicine Publications Committee, with assistance of Vincenzo Berghella (2012) Progesterone and preterm birth prevention: translating clinical trials data into clinical practice
  • Society
Committee Opinion No.543: timing of umbilical cord clamping after birth
  • American College
  • Gynecologists Obstetricians
Perinatal neuroprotection. F1000Prime Rep 6:6
  • K E Salmeen
  • A C Jelin
  • M P Thiet
Infection-related perinatal brain injury: the pathogenic role of impaired fetal cardiovascular control
  • Y Garnier
  • A B Coumans
  • A Jensen
  • Y. Garnier
17β-estradiol protects 7-day old rats from acute brain injury and reduces the number of apoptotic cells
  • M M Muller
  • J Middelanis
  • C Meier
  • M.M. Muller