Genetic variants of the vitamin K dependent coagulation system and intraventricular hemorrhage in preterm infants.
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ABSTRACT: Background
Pathogenesis of intraventricular hemorrhage (IVH) in premature infants is multifactorial. Little is known about the impact of genetic variants in the vitamin K-dependent coagulation system on the development of IVH.Methods
Polymorphisms in the genes encoding vitamin K epoxide reductase complex 1 (VKORC1 -1639G>A) and coagulation factor 7 (F7 -323Ins10) were examined prospectively in 90 preterm infants <32 weeks gestational age with respect to coagulation profile and IVH risk.Results
F7-323Ins10 was associated with lower factor VII levels, but not with individual IVH risk. In VKORC1-wildtype infants, logistic regression analysis revealed a higher IVH risk compared to carriers of the -1639A allele. Levels of the vitamin K-dependent coagulation parameters assessed in the first hour after birth did not differ between VKORC1-wildtype infants and those carrying -1639A alleles.Conclusions
Our data support the assumption that genetic variants in the vitamin K-dependent coagulation system influence the coagulation profile and the IVH risk in preterm infants. Further studies focussing on short-term changes in vitamin K-kinetics and the coagulation profile during the first days of life are required to further understand a possible link between development of IVH and genetic variants affecting the vitamin K-metabolism.
SUBMITTER: Schreiner C
PROVIDER: S-EPMC4236669 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
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Project description:ImportanceNo trials to date have demonstrated the benefits of tocolysis on death and/or neonatal morbidity in preterm infants; tocolytics may affect the fetal blood-brain barrier.ObjectivesTo assess the risks associated with tocolysis in women delivering prematurely as measured by death and/or intraventricular hemorrhage (IVH) in preterm infants and to compare the association of calcium channel blockers (CCBs) nifedipine and nicardipine hydrochloride vs atosiban used for tocolysis with death and/or IVH.Design, settings, and participantsThe French 2011 EPIPAGE-2 (Enquête Épidémiologique sur les Petits Âges Gestationnels) cohort was limited to mothers admitted for preterm labor without fever, who delivered from 24 to 31 weeks of gestation from April 1 through December 31, 2011. Groups of preterm infants with vs without tocolytic exposure and groups with atosiban vs CCB exposure were compared. Data analysis was performed from June 7, 2014, through September 3, 2017.ExposuresTocolytics.Main outcomes and measuresThe primary outcome was a composite of death and/or IVH in preterm infants. Secondary outcomes included death, IVH, and a composite of death and/or grades III to IV IVH.ResultsA total of 1127 mothers (mean [SD] age, 25.5 [6.0] years) experienced preterm labor and gave birth to 1343 preterm infants with a male to female ratio of 1.23 and mean (SD) gestational age of 27?(2.5) weeks. Of these, 789 mothers (70.0%) received tocolytics; 314 (39.8%) received only atosiban, and 118 (15.0%) received only a CCB. In the first analysis, the primary outcome (death and/or IVH) was not significantly different in preterm infants with vs without tocolytic exposure (183 of 363 [50.4%] vs 207 of 363 [57.0%]; relative risk [RR], 0.88; 95% CI, 0.77-1.01; P?=?.07). The secondary outcome (death and/or grades III-IV IVH) was significantly lower in preterm infants with vs without tocolytic exposure (92 of 363 [25.3%] vs 118 of 363 [32.5%]; RR, 0.78; 95% CI, 0.62-0.98; P?=?.03). Other outcomes did not differ significantly. In the secondary analysis, death and/or IVH was not significantly different in preterm infants with atosiban vs CCB exposure (96 of 214 [44.9%] vs 62 of 121 [51.2%]; RR, 0.88; 95% CI, 0.70-1.10; P?=?.26), nor was IVH (77 of 197 [39.1%] vs 48 of 106 [45.3%]; RR, 0.86; 95% CI, 0.66-1.13; P?=?.29).Conclusions and relevanceIn this population-based study, findings suggest that tocolytics were associated with a reduction of death and severe IVH. Other studies are necessary to compare perinatal outcomes after use of atosiban vs CCBs.
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Project description:Preterm infants with periventricular-intraventricular hemorrhage (PV-IVH) have a high risk of neurological sequelae, with severity depending on the severity of the PV-IVH. Previous studies on the pathogenesis of PV-IVH have focused mainly on comparisons of perinatal risk factors between patients with and without PV-IVH. Notably, most cases of PV-IVH occur within the first 3 days after birth, and the condition may worsen within 1 week following the initial diagnosis. However, the risk factors that contribute to the deterioration of PV-IVH have not been investigated. In this cohort study, 514 PV-IVH infants with a gestational age (GA) < 32 weeks were enrolled. The dependent variable was initially diagnosed as mild PV-IVH (grade I or II) that subsequently progressed to severe PV-IVH (grade III or IV) within 1 week. A stepwise forward multivariate logistic regression model was adopted to select potential or related factors that affected the deterioration of PV-IVH in preterm infants. Overall, 42 of the 514 infants with PV-IVH (8.2%) showed deterioration within 1 week. The results showed that maternal lower genital tract infection (OR 3.73, 95% CI 1.75-7.95) was an independent risk factor for PV-IVH deterioration. Higher GA (OR 0.62, 95% CI 0.48-0.80) was a protective factor. Our results suggest that maternal lower genital tract infection and a lower GA may contribute to PV-IVH deterioration in preterm infants.
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Project description:BackgroundPrevious studies describe a short-term decrease in cerebral oxygen saturation (StO2) after intraventricular hemorrhage (IVH) in premature infants; little is known about long-term implications.MethodsInfants born <30 weeks gestational age (GA) were included. Clinical characteristics, hemoglobin measurements, the highest grade of IVH, and white matter injury (WMI) were noted. NIRS monitoring occurred daily or every other day for 4 weeks; weekly through 36 weeks GA. Recordings were error-corrected before calculation of mean StO2 and fractional tissue oxygen extraction (FTOE). Mean StO2 and FTOE were plotted by postnatal age and injury group (IVH/no IVH; WMI/no WMI). Non-linear regression by locally estimated scatterplot smoothing was used to generate the best-fit line and CI.ResultsA total of 1237 recordings from 185 infants were included; mean length = 6.5 h; mean GA = 26.3 w; mean BW = 951 g; overall/severe IVH incidence was 29/8%, WMI incidence was 16%. IVH was independently associated with an acute drop in StO2, which remained lower for 68 d. Severe IVH was associated with lower StO2 values than mild IVH. WMI was associated with early and persistent elevation of FTOE.ConclusionIVH of any grade is associated with a prolonged cerebral desaturation and WMI is associated with prolonged elevation of FTOE. This finding is exacerbated for infants with severe IVH.ImpactThe longitudinal impact of IVH on cerebral oxygenation has not been previously studied. IVH is associated with persistent cerebral desaturation, months in length, and is independent of anemia. More severe IVH is associated with worsened cerebral hypoxia. Infants later diagnosed with white matter injury have an early and persistent elevation of cerebral oxygen extraction (cFTOE). This cerebral desaturation, below previously identified normative ranges, may provide insight into the mechanistic link between IVH and white matter injury.
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Project description:We previously demonstrated that transplanting mesenchymal stem cells (MSCs) improved recovery from brain injury induced by severe intraventricular hemorrhage (IVH) in newborn rats. To assess the safety and feasibility of MSCs in preterm infants with severe IVH, we performed a phase I dose-escalation clinical trial. The first three patients received a low dose of MSCs (5 × 106 cells/kg), and the next six received a high dose (1 × 107 cells/kg). We assessed adverse outcomes, including mortality and the progress of posthemorrhagic hydrocephalus. Intraventricular transplantation of MSCs was performed in nine premature infants with mean gestational age of 26.1 ± 0.7 weeks and birth weight of 808 ± 85 g at 11.6 ± 0.9 postnatal days. Treatment with MSCs was well tolerated, and no patients showed serious adverse effects or dose-limiting toxicities attributable to MSC transplantation. There was no mortality in IVH patients receiving MSCs. Infants who underwent shunt surgery showed a higher level of interleukin (IL)-6 in cerebrospinal fluid (CSF) obtained before MSC transplantation in comparison with infants who did not receive a shunt. Levels of IL-6 and tumor necrosis factor-α in initially obtained CSF correlated significantly with baseline ventricular index. Intraventricular transplantation of allogeneic human UCB-derived MSCs into preterm infants with severe IVH is safe and feasible, and warrants a larger, and controlled, phase II study. Stem Cells Translational Medicine 2018;7:847-856.
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Project description:Although chorioamnionitis (CA) is a well-known risk factor for white matter disease of prematurity, the association with intraventricular hemorrhage (IVH) is controversial and has not been yet systematically reviewed. We performed a systematic review and meta-analysis of studies exploring the association between CA and IVH. A comprehensive literature search was conducted using PubMed/MEDLINE and EMBASE, from their inception to 1 July 2017. Studies were included if they examined preterm infants and reported primary data that could be used to measure the association between exposure to CA and the presence of IVH. A random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). We found 1,284 potentially relevant studies, of which 85 met the inclusion criteria (46,244 infants, 13,432 CA cases). Meta-analysis showed that CA exposure was significantly associated with all grades IVH (OR 1.88, 95% CI 1.61-2.19), with grades 1-2 IVH (OR 1.69, 95% CI 1.22-2.34), and with grades 3-4 IVH (OR 1.62, 95% CI 1.42-1.85). Both clinical and histological CA were associated with an increased risk for developing IVH in very preterm infants. In contrast, the presence of funisitis did not increase IVH risk when compared to CA in the absence of funisitis (OR 1.22, 95% CI 0.89-1.67). Further meta-analyses confirmed earlier findings that CA-exposed infants have significantly lower gestational age (GA; mean difference [MD] -1.20 weeks) and lower birth weight (BW; MD -55 g) than the infants not exposed to CA. However, meta-regression and subgroup analysis could not demonstrate an association between the lower GA and BW and the risk of IVH in the CA-exposed infants. In conclusion, our data show that CA is a risk factor for IVH, but also a risk factor for greater prematurity and more clinical instability. In contrast to other complications of prematurity, such as patent ductus arteriosus, retinopathy of prematurity, or bronchopulmonary dysplasia, the effect of CA on IVH appears to be independent of CA as causative factor for very preterm birth.
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