PEDIATRICS Vol. 118 No. 2 August 2006, pp. 683-689 (doi:10.1542/10.1542/peds.2005-2670)
ARTICLE |
Genetic Polymorphisms of Hemostasis Genes and Primary Outcome of Very Low Birth Weight Infants
a Department of Pediatrics
b Institute of Biometry and Statistics, University at Lübeck, Lübeck, Germany
c Kinderklinik auf der Bult, Hannover, Germany
d Olgahospital, Stuttgart, Germany
e Department of Pediatrics, University of Greifswald, Greifswald, Germany
f Children's Hospital Saarbrücken, Saarbrücken, Germany
g Children's Hospital Kassel, Kassel, Germany
h University of Cologne, Cologne, Germany
i Kinderklinik St Hedwig, Regensburg, Germany
j University of Aschaffenburg, Aschaffenburg, Germany
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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BACKGROUND. Recent investigations have reported an influence of thrombophilic mutations and antithrombotic risk factors with development of intraventricular hemorrhage. It was our objective for this study to investigate the impact of genetic polymorphisms of hemostasis genes on the primary outcome measures of sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia in a large cohort of very low birth weight infants.
METHODS. There were 586 very low birth weight infants enrolled prospectively in a multicenter trial between September 2003 and July 2005, and an additional 595 very low birth weight infants, who had been recruited in a previous prospective trial, were studied. DNA samples were taken by buccal swab, and genotypes of factor V Leiden mutation, prothrombin G20210A mutation, the factor VII-323 del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion.
RESULTS. In contrast to data published previously, the frequency of intraventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate and a longer period of hospital care compared with noncarriers. The factor VII-323 del/ins polymorphism was found to be a potential protective factor against bronchopulmonary dysplasia.
CONCLUSIONS. We could not confirm previously reported associations of hemostasis gene variants and development of intraventricular hemorrhage in very low birth weight infants. To better understand gene-disease associations in very low birth weight infants, the prospective development of large-scale cohorts with well-defined phenotypes and corresponding DNA samples is essential.
Key Words: VLBW • outcome • hemostasis genes • polymorphism
Abbreviations: VLBW—very low birth weight • IVH—intraventricular hemorrhage • PVL—periventricular leukomalacia • BPD—bronchopulmonary dysplasia • ROP—retinopathy of prematurity
Genetic association studies have been applied to a wide range of complex diseases to identify populations who are at an increased risk. For example, substantial progress has been made in the identification of inherited hypercoagulable disorders and their association to cerebrovascular diseases in adulthood.1,2 These thrombophilic disorders include the factor V Leiden mutation, which renders factor V resistant to cleavage by activated protein C, and the prothrombin G20210A mutation, which was found to be associated with raised plasma concentrations of prothrombin.3
To achieve a balanced hemostasis, fibrin clot structure is highly dependent on the activity of factor XIII. Factor XIII catalyzes the formation of bonds between fibrin monomers and incorporates various adhesive and antifibrinolytic proteins into the final fibrin clot thereby increasing mechanical strength. Several studies have investigated the functional relevance of factor XIII gene polymorphisms on fibrin clot structure and risk of hemostatic imbalance (reviewed by Kobbervig and Williams4). The factor XIII-Val34Leu polymorphism is the most studied genetic variant, because carriage of the factor XIII-Leu34 allele is biochemically associated with the formation of a fibrin meshwork having thinner fibers, smaller pores, and altered permeation characteristics compared with fibrin clots formed by individuals with factor XIII-Val34 homozygosity.5 The effects of prothrombin concentrations on clot structure have suggested that thinner clots are more resistant to fibrinolysis and are associated with increased risk for thrombosis. Most clinical studies, however, have demonstrated that the factor XIII-Leu34 allele may have a protective effect against thrombosis and infarction in various clinical entities.6–9 Regarding coagulation factor VII, many polymorphisms have been described to be associated with alterations in factor VII levels.10–12 Two polymorphisms were demonstrated to correlate with increased factor VII levels and a higher risk for cerebrovascular disease (factor VII-C122T)13 and myocardial infarction (factor VII-G402A).14 Other genetic variants of factor VII, including polymorphisms of intron 7 and the R353Q polymorphism, are associated with decreased factor VII levels, which may have a highly variable influence on the hemostatic balance (reviewed by Mariani et al10). The factor VII-323del/ins (323 A1/A2) promoter polymorphism results in an 
20% decrease of factor VII coagulant activity.14–17 Both the 353Q allele and the 323ins allele (A2) were demonstrated to have a protective effect against myocardial infarction.18 The case-control study by Corral et al2 with 201 patients and 201 healthy adult controls, however, revealed that carriers of the –323ins allele, had a 1.54-fold risk for intracranial hemorrhage (95% confidence interval: 1.03–2.72) indicating different influences of polymorphisms in various clinical states.
Premature very low birth weight (VLBW) infants are known to be a population with high morbidity and mortality; however, the investigation of neonatal primary outcome measures with regard to genetic background is still at an early stage.19 Given the apparent differences in vulnerability of different VLBW infants and the paucity of reliable prenatal predictors of adverse primary outcome, for example, development of intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), bronchopulmonary dysplasia (BPD), and sepsis, we considered the possibility that genetic variants of coagulation factors might play a role in certain disease states of VLBW infants. Recent investigations have reported an influence of thrombophilic risk factors, such as factor V Leiden and prothrombin G20210A mutation, on the development of intracranial hemorrhage in preterm infants.20,21 In contrast, genetically based lower levels of coagulation factors, such as factor VII-323del/ins promoter polymorphism, may not only increase the risk for intracerebral bleeding (as demonstrated in adult cohorts2) but may also impact on cerebrovascular complications in preterm infants, for example, development of cerebral palsy.22 Regarding the effect of the factor XIII-Val34Leu polymorphism on neurologic short-term outcome in VLBW infants, we reported previously our observations that VLBW infants carrying the factor XIII-Val34Leu polymorphism had a decreased risk for white matter disorders.23 Furthermore, factor XIII-Leu 34 allele may be a protective factor against preterm delivery.24
To confirm previous genetic association studies on cerebrovascular disorders, we investigated the effect of genetic variants biochemically relevant for hemostasis (factor V Leiden, prothrombin G20210A, factor VII-323del/ins, and factor XIII-Val34Leu) in a large prospectively enrolled cohort of VLBW infants. Furthermore, we analyzed the effect of these genotypes on other primary outcome parameters, such as BPD, sepsis, and necessity of medical interventions/operations during the hospital stay.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Population
We prospectively studied the influence of gene variants involved in hemostasis on the primary outcome of 586 VLBW infants in a multicenter trial at 9 NICUs in Germany from September 2003 until July 2005 (inclusion criteria: birth weight <1500 g and gestational age 24 + 0 to 36 + 6 weeks; exclusion criteria: lethal malformations, eg, trisomy 13 and trisomy 18). Preterm infants who were born with a gestational age of
23 + 6 weeks were not included in our study, because the mortality rate in this group is very high. Multiple siblings have an identical genetic background of 
50% up to 100% in homozygotic individuals. This large genetic influence will have a significant confounding impact on clinical outcome data of siblings, that is, genotype/phenotype associations are more likely to be notified in siblings than in a cohort of nonrelated individuals. Those associations, however, might be because of other genetic factors, which were not subject to this investigation. Therefore, we randomly selected 1 infant of each group of multiples and excluded their siblings. After written informed consent was given by the parents, a DNA sample of the mother and infant was obtained by buccal swab and transferred to the study center (University of Lübeck). Antenatal and postnatal treatment and outcome data were recorded by according data sheets at the participating centers. After discharge, data sheets were sent to the study center. A physician trained in neonatology evaluated the data quality by on-site monitoring of completed data sets every 6 months. After the monitoring, data were coded and linked to the according maternal and infant DNA sample by a number. We additionally studied 595 VLBW infants from a previous prospective study (2000–2003) who met the above-mentioned inclusion criteria.
Assessment of Outcome Parameters
BPD was defined as chronic lung disease with required oxygen supplement for >36 + 0 weeks of corrected gestational age. Sepsis was defined as clinical and laboratory signs of sepsis confirmed by a positive blood culture at any time during the stay in the hospital. All kinds of antibiotic treatment because of suspected infection was recorded. Antibiotic treatment without suspected infection (prophylactic treatment) was recorded separately. IVH grade I was defined as blood within the germinal matrix regions, grade II as blood within the ventricular system without distension and 50% of the ventricular volume, grade III as blood within the ventricular system >50% of the ventricular volume or ventricular distention, and grade IV as blood within the ventricular system and parenchymal involvement with subsequent parenchymal destruction. PVL was defined as 1 echodense lesions, which eventually cavitate to become a porencephalic cyst.
Genotyping
DNA samples were extracted from buccal swabs with a commercially available kit (Qiagen, Hilden, Germany). All of the polymorphisms were detected by polymerase chain reaction and restriction enzyme digestion. Primer and DNA sequences were selected from reports published previously. Polymerase chain reaction for factor V Leiden-mutation1 and prothrombin G20210A mutation25 were performed as described previously. Primer pairs for the detection of the factor XIII-Val34Leu polymorphism were 5'-CAT GCC TTT TCT GTT GTC TTC-3' and 5'-TAC CTT GCA GGT TGA CGC CCC GGG GCA CTA-3' (DdeI-digest26) and 5'-GGC CTG GTC TGG AGG CTC TCT TC-3' and 5'-GAG CGG ACG GTT TTG TTG CCA GCG-3' (HindIII digest) for the factor VII-323del/ins mutation.16
The expected carrier frequencies for white populations for the homozygous or heterozygous factor V Leiden, prothrombin G20210A, factor VII-121ins/del, and homozygous factor XIII-Val34Leu polymorphism were 4.9%, 3.0%, 19.9%, and 3%.2 Based on these expected frequencies, an 
error < .05 (2-sided equivalence test of proportions) and a power of 0.8, our sample size would be sufficient to detect total differences of carrier frequencies between VLBW infants with or without investigated diseases of 5% (prothrombin G20210A and factor XIII-Val34Leu) to 9% (factor VII ins/del).
Statistical Analysis
Data analysis was performed by using the SPSS 13.0 data-analysis package (Munich, Germany). Hypotheses were evaluated with Fisher's exact test (2-sided) and multivariate logistic-regression models. P < .05 was considered statistically significant.
Ethics
All parts of the study were approved by the local committee on research in human subjects of the University of Lübeck.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Clinical Data
In our multicenter trial, 785 VLBW infants fulfilled the inclusion criteria within the study period between September 2003 and July 2005. Causes of nonparticipation included early death of the infant (n = 50), no consent given (n = 14), no inquiry for participation in the study (n = 122), and others (n = 11). Primary outcome data were not different between nonincluded VLBW infants and the remaining 586 prospectively enrolled VLBW infants except for the higher frequency of death in nonincluded VLBW infants (25.3% vs 2.1%; P < .001). An additional 595 VLBW infants, who had been recruited in a previous prospective trial (2000–2003), were studied (total n = 1179, data of all infants are given in Supplementary Tables 2, 4, 6, and 8, which are published as supporting information on www.pediatrics.org/content/full/118/2/FirstPageNo). After exclusion of siblings, 1009 VLBW infants remained. In this population, genotyping was successful in 1003 (factor V Leiden), 1006 (prothrombin G20210A mutation), 1004 (factor VII-323del/ins polymorphism), and 1008 (factor XIII-Val34Leu polymorphism; 98%–99%) VLBW infants. Distribution of polymorphisms of hemostasis genes in VLBW infants was in Hardy-Weinberg equilibrium.
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The clinical data of VLBW infants stratified to their genotype of hemostasis genes are given in Table 1. Clinical data were comparable between VLBW infants carrying factor V Leiden mutation, prothrombin G20210 mutation, factor VII-323del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms and VLBW infants without the respective genetic variant except for the observation that antenatal antibiotics were less given to mothers of VLBW with factor V Leiden mutation (24.4% vs 41.8%; P = .025). Regarding the cause of preterm delivery, a lower frequency of factor V Leiden mutation in VLBW infants born because of preeclampsia of their mothers (8.2% vs 19.5%; P = .018) was noted as single difference between carriers and noncarriers of gene variants (Table 2).
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Primary Outcome
In contrast to data published previously, the frequency of IVH or PVL was not significantly influenced by all of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate (30.5% vs 18.7%; P = .04) and a longer period of hospital care (83 ± 39 vs 71 ± 38 days; P = .014) compared with noncarriers. In line with this, a trend to higher frequencies of both Gram-positive and Gram-negative sepsis (20.3% vs 12.5% and 6.8 vs 3.6%) was noted in carriers of the factor XIII-Val34Leu polymorphism compared with noncarriers (Table 3). The factor VII-323del/ins polymorphism was found to be a potential protective factor against BPD (8.3% in carriers vs 14.6% in noncarriers; P = .011; Table 3).
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Medical Interventions and Operations
With regard to frequencies of medical interventions (eg, mechanical ventilation and intravenous long-line catheterization) and essential operations because of patent ductus arteriosus (surgical closure), retinopathy of prematurity ([ROP] cryotherapy and laser therapy), posthemorrhagic hydrocephalus (ventriculoperitoneal shunting and external cerebrospinal fluid drainage), necrotizing enterocolitis, and focal intestinal perforation (laparotomy and surgical revision), carriers of factor V Leiden mutation had a higher risk for surgical closure of patent ductus arteriosus (11.1% vs 3.3%; P = .027), and the frequency of operative ROP therapy was higher in VLBW infants with prothrombin G20210A mutation compared with noncarriers (11.8% vs 3.1%; P = .01; Table 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The major complications after preterm birth, for example, IVH, PVL, sepsis, and BPD, are suggested to be disease states that are influenced by coagulation abnormalities.27 Therefore, polymorphic variations of hemostasis genes could be reasonable candidates for altered susceptibility to adverse outcomes in VLBW infants. To our best knowledge, this is the first study aimed at evaluating the impact of genetic variants of hemostasis genes on primary outcome measures in a large-scale cohort of VLBW infants.
The association of thrombophilic risk factors with IVH in preterm infants has been reported previously with conflicting results. In a prospective case-control design, Petäjä et al20 studied 51 VLBW infants, 22 infants with IVH grades II–IV, and 29 control VLBW infants. The factor V Leiden mutation was significantly more frequent in VLBW infants with IVH. These data were supported by Komlosi et al,21 who noted an increased prevalence of factor V Leiden mutation in preterm infants (birth weight <2500 g) with IVH I° (n = 60) compared with control preterm infants (n = 63). Our group previously studied a population-based cohort of 305 VLBW infants and found, in contrast, a reduced risk of developing extension of IVH to grade II or more in VLBW infants with factor V Leiden or prothrombin G20210A mutation.28 Kenet et al,29 however, concluded from a study of 116 preterm infants that thrombophilia does not increase the risk for vascular or other neonatal complications, other than venous thromboembolism.
In this prospective study, we were not able to confirm an association between hemostasis gene variants and IVH. Possible explanations for the apparent differences between our current report and data published previously include incidental associations of IVH and hemostasis genotypes in previous trials. Furthermore, differences in the study design (prospective population-based cohort versus case-control study), population size and ethnicity, and definitions of clinical phenotypes may account for conflicting results.
With regard to the decreased prevalence of white matter disease in VLBW infants carrying the factor XIII-Val34Leu polymorphism, we could not confirm a significant association as has been reported previously.23 Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate with a tendency to more Gram-positive and Gram-negative infections. This observation is novel and needs additional consideration, because susceptibility to infection may be partially explained by polymorphisms of the genes encoding proteins involved in mediating and controlling the innate immune response, inflammatory processes, coagulation cascade, and fibrinolysis.30,31 We could identify no previous study that had demonstrated a potential link of factor XIII gene variants and infection or sepsis. Factor XIII catalyzes the formation of bonds between fibrin monomers causing increased mechanical strength of the thrombus. The factor XIII-Val34Leu polymorphism is known to alter the fibrin meshwork to thinner fibers, smaller pores, and variable permeation characteristics.5 So far, no experimental proof has been made to determine whether the thinner fibrin meshwork leads to changes in the stability of the thrombus. As sepsis is suggested to have a multifactorial pathophysiology, and hemostatic changes may potentially result in alterations of blood viscosity, enhanced susceptibility to microbial pathogens, and increased chemoattraction of inflammatory cells. However, our current data require a conservative interpretation, because: (1) functional data describing the effect of the factor XIII-Val34Leu polymorphism on local/systemic infection markers are not yet available; (2) confirmation by an independent genetic association study is essential; and (3) factor XIII-Val34Leu polymorphism has a much lower impact on catheter infection than known clinical risk factors, such as gestational age or need for intravenous line catheters. With regard to a previous study reporting a significant survival advantage of heterozygous factor V Leiden carriers in human severe sepsis and animal models with endotoxinemia,32 we did not observe a similar effect of factor V Leiden mutation in our cohort of VLBW infants (data not shown).
The factor VII-323del/ins polymorphism was found to be a potential protective factor against BPD. The factor VII-323del/ins polymorphism is associated with decreased factor VII levels, and factor VII deficiency is regarded as phenotypically pleomorphic, ranging from asymptomatic patients to those with severe bleedings. However, the biochemical effect of the factor VII-121del/ins polymorphism for protection of lung damage is yet unclear. Therefore, future studies are needed to confirm the association and to evaluate a potential underlying mechanism, for example, improved perfusion/ventilation ratio of preterm lungs.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We could not confirm associations found previously between hemostasis gene variants and IVH in a large cohort of VLBW infants. Other than a population size much larger than studies performed previously, the strengths of this investigation are its prospective fashion and its relatively homogenous cohort of VLBW infants. The latter point is of great importance, because racial disparities and considerably varying frequencies of polymorphisms between ethnic groups may account for different association data described previously. Although we are convinced that susceptibility to IVH and other diseases of VLBW infants is influenced by genetic factors, our current results indicate that valid and reproducible gene-disease associations require the prospective development of large-scale cohorts of preterm infants with well-defined phenotypes and functional data to characterize the gene-dose effect in VLBW infants.
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ACKNOWLEDGMENTS |
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This work was supported by the Deutsche Forschungsgemeinschaft, grant Go 955/1-1-3, and by the University of Lübeck, Forschungsschwerpunkt Reproduktionsmedizin, grant 8/2004.
We thank Anja Sewe and Sabine Ziesenitz for excellent laboratory assistance; Birgit Roenspiess and Anne Hoegemann for skillful data collection; all of the doctors and nurses of the participating hospitals; and especially all of the infants and their parents for their support.
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FOOTNOTES |
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Accepted Mar 2, 2006.
Address correspondence to Wolfgang Göpel, MD, Department of Pediatrics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. E-mail: goepel{at}paedia.ukl.mu-luebeck.de
The authors have indicated they have no financial relationships relevant to this article to disclose.
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