Mol. Hum. Reprod. Advance Access originally published online on March 2, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Molecular Human Reproduction, Vol. 10, No. 5, pp. 321-324, 2004
© European Society of Human Reproduction and Embryology 2004
Vascular endothelial growth factor gene polymorphisms and pre-eclampsia
1Second Department of Internal Medicine, Medical School, 2Department of Obstetrics and Gynecology, Medical School, 3Department of Radiotherapy–Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece and 4Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden
5 To whom correspondence should be addressed at: Patriarhou Grigoriou 97–99, 68100 Alexandroupolis, Greece. e-mail: dapap{at}otenet.gr
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionMaterials and methodsResultsDiscussionREFERENCES |
|---|
Vascular endothelial growth factor (VEGF) plays a crucial role in physiological vasculogenesis and vascular permeability and has been implicated in the pathogenesis of pre-eclampsia. Our present study was undertaken to identify associations between three functional VEGF gene polymorphisms, linked with altered VEGF gene responsiveness, and pre-eclampsia. The study involved 42 pre-eclamptic and 73 healthy control women who were genotyped for the –2578C/A, –634G/C and 936C/T polymorphisms of the VEGF gene. No significant association between genotypic or allelic frequencies in women with pre-eclampsia relative to controls was found. A statistically significant difference was found for allelic frequencies of the 936C/T polymorphism between women with severe pre-eclampsia and controls (odds ratio: 2.70; 95% confidence interval: 1.09–6.63; P = 0.019). VEGF gene polymorphisms studied are unlikely to be major predisposing factors for pre-eclampsia. The presence of the 936T allele probably has a considerable effect on disease modification.
Key words: Key words: pre-eclampsia/polymorphisms/vascular endothelial growth factor
|
Introduction |
|---|
|
TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
|---|
Pre-eclampsia (PE) is a multisystem disorder that is unique to human pregnancy and remains a major cause of maternal and fetal morbidity and death (Murphy and Stirrat, 2000). Susceptibility gene studies of PE so far have been based upon the currently most widely accepted hypotheses on its aetiology and pathogenesis. These hypotheses comprise placental ischaemia, oxidative stress and maternal–fetal immune maladaptation (Dekker and Sibai, 1998). These are all thought to be associated with the two key features of the clinical syndrome of PE; shallow endovascular trophoblast invasion in the spiral arteries in early pregnancy and generalized endothelial cell dysfunction (Dekker and Sibai, 1998).
Vascular endothelial growth factor (VEGF) is a major angiogenic factor and is a prime regulator of endothelial cell proliferation. It plays a crucial role in physiological vasculogenesis and vascular permeability (Ferrara et al., 1992). The gene encoding VEGF is located on chromosome 6 band p21 and comprises a 14 kb coding region with 8 exons and 7 introns (Vincenti et al., 1996). It binds to Flt-1 (also named VEGFR1) and to flk1 (also named KDR VEGFR2), both tyrosine kinase receptors present on endothelial cell membranes (de Vries et al., 1992; Terman et al., 1992). VEGF (or VEGF-A) belongs to a gene family that includes placental growth factor (PLGF), VEGF-B, VEGF-C and VEGF-D. They share structural features typical of the VEGF family, but display different biological activities, mainly owing to their different specificities for the known VEGF receptors. Homologues of VEGF have also been identified in the genome of the parapoxvirus Orf virus and shown to have VEGF-like activities (Ferrara et al., 2003).
Expression of VEGF mRNA is rapidly and reversibly induced by hypoxia both in vitro and in vivo (Minchenko et al., 1994; Gargett et al., 2001). Its expression is also up-regulated in both physiological and pathological states where increased angiogenesis occurs (Gargett et al., 2001). VEGF and its receptors may play a pivotal role in the altered function of PE (Brockelsby et al., 1999). Several groups have demonstrated that circulating total VEGF concentrations are significantly elevated in women with PE (Baker et al., 1995; Kupferminc et al., 1997; Hunter et al., 2000). Free (unbound) VEGF concentrations have been reported to be significantly lower (Lyall et al., 1997; Maynard et al., 2003). This inconsistency is probably due to highly elevated levels of the soluble fms-like tyrosine kinase 1 (sflk1) receptor which captures free VEGF (Maynard et al., 2003). A positive correlation between VEGF concentrations and systemic or uterine vascular resistance has been described (Simmons et al., 2000) and a negative correlation between VEGF and the stable nitric oxide metabolite nitrate (El-Salahy et al., 2001) has been demonstrated in women with PE. Because patients who are predestined to have PE demonstrate increased concentrations of VEGF before the clinical onset, VEGF has been suggested to be involved in the pathogenesis of PE rather than being an effect of the disease (Hunter et al., 2000; Simmons et al., 2000; El-Salahy et al., 2001). The VEGF system is up-regulated, both at the transcriptional and translational level, in response to chronic placental hypoxia (PE) (Trollmann et al., 2003). Moreover, it has been demonstrated that mice lacking one VEGF allele in renal podocytes develop the typical renal pathology found in pregnant women with PE, which comprises additional evidence for a critical role of VEGF in renal disease during PE (Eremina et al., 2003).
Many polymorphisms of the VEGF gene have been identified so far. A few of them have been correlated with variation in VEGF protein production (Brogan et al., 1999; Renner et al., 2000; Watson et al., 2000; Awata et al., 2002). In the present study we investigated whether there is any association between PE and three common functional VEGF single nucleotide polymorphisms, –2578C/A in the promoter region (Brogan et al., 1999), –634G/C in the 5'- untranslated region (Awata et al., 2002) and 936C/T in the 3'-untranslated region (Renner et al., 2000).
|
Materials and methods |
|---|
|
TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
|---|
The study included a total number of 115 women (42 with PE and 73 controls). Patients with PE were recruited at the Department of Obstetrics and Gynecology, Democritus University of Thrace, General Hospital of Alexandroupolis. PE was defined as systolic blood pressure of
140 mmHg and/or diastolic blood pressure of 90 mmHg on two occasions 6 h apart after 20 weeks of gestation, but before the onset of labour, plus proteinuria of 2+ (dipstick method) or 0.3 g/24 h (American College of Obstestricians and Gynecologists, 1996). Severe pre-eclampsia was defined as a higher blood pressure 160 mmHg systolic or 110 mmHg diastolic on two occasions 6 h apart, and a proteinuria level 5 g/24 h or 3+ by dipstick testing on at least two separate occasions (American College of Obstestricians and Gynecologists, 1996). According to the above criteria, 22 patients had mild, while 20 patients had severe, pre-eclampsia. The control group consisted of 73 post-menopausal women with a history of at least two uncomplicated pregnancies. Demographic data of participants and clinical characteristics of patients are shown in Table I. All participants were of Greek ethnicity. Women with chronic hypertension were excluded from the study. Written informed consent was obtained from all participating women.
|
DNA was isolated from 200 µl of anticoagulated peripheral blood using a commercially available kit according to the manufacturer’s instructions (QIAamp DNA Blood Mini Kit; Qiagen Inc., USA). Amplification of the three regions of the VEGF gene, containing the polymorphisms –2578C/A, –634G/C and 936C/T, were carried out in a Mastercycler gradient (Eppendorf–Netheler–Hinz GmbH, Germany) thermal cycler in 20 µl reaction volumes containing 20 mmol/l Tris–HCl (pH 8.4), MgCl2, 50 mmol/l KCl, 0.2 mmol/l of each nucleotide, 20 pmol of each of the forward and reverse primers, 1 U Platinum Taq polymerase (Gibco–BRL, USA) and 500 ng of DNA. MgCl2 concentrations were optimized for each amplification (2.75 mmol/l for –2578C/A, 4 mmol/l for –634G/C and 4.5 mmol/l for 936C/T). Following an initial denaturation step (5 min at 94°C), samples were subjected to 35 rounds of PCR consisting of 94°C for 40 s, 62°C (–2578C/A), 58°C (–634C/G) or 64°C (936C/T) for 1 min; and 72°C for 40 s with a final extension time of 5 min at 72°C. For the –2578C/A polymorphism the following specific/common primers were used, generating a PCR product of 77 bp: 5'-TAGGCCAGACCCTGGCAC-3' (C polymorphism) or 5'-TAGGCCAGACCCTGGCAA-3' (A polymorphism) with 5'-TGCCCCAGGGAACAAAGT-3'. For the –634G/C the following primers amplified a fragment of 304 bp: forward 5'-ATTTATTTTTGTCTGTCTGTCTGTCCGTCA-3' and for the 936C/T the following primers amplified a fragment of 208 bp: forward 5'-AAGGAAGAGGAGACTCTGCGCAGAGC-3', reverse 5'-TAAATGTATGTATGTGGGTGGGTGTGTCTACAGG-3'. The VEGF –634G/C polymorphism was analysed by digestion of the PCR product with restriction endonuclease BsmFI (New England Biolabs, USA). The –634G allele was cut into two fragments of 193 and 111 bp while the –634C allele remained uncut (304 bp). The VEGF 936C/T polymorphism was analysed by digestion of the PCR product with restriction endonuclease NlaIII (New England Biolabs). The 936C allele remained uncut (208 bp), while the 936T was cut into two fragments of 122 and 86 bp. PCR products and restriction fragments were analysed by electrophoresis through 2.0% agarose gels, stained with ethidium bromide, and photographed.
Differences in the VEGF genotype and allele frequencies between the study and control groups were analysed by 
2-test or Fisher’s exact test. P < 0.05 was considered statistically significant. Statistical analysis was performed by using standard software (V10, SPSS for MS Windows).
|
Results |
|---|
|
TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
|---|
We examined genotype and allele frequencies of three common single nucleotide polymorphisms of the vascular endothelial growth factor gene in 42 women with PE and 73 controls. Genotypes were found to be in Hardy–Weinberg equilibrium in both the study and control groups. Genotypic and allelic frequencies of cases and controls are shown in Tables II and III respectively. There was no significant association between genotypic or allelic frequencies in women with pre-eclampsia relative to controls. Additional subgroup analyses (mild and severe pre-eclampsia) revealed a statistically significant difference (P = 0.019) for allelic frequencies of the 936C/T polymorphism between women with severe pre-eclampsia and controls (Table IV) but not for the other polymorphisms studied (data not shown).
|
|
|
|
Discussion |
|---|
|
TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
|---|
Family studies have shown that genetic factors play a role in pre-eclampsia but the exact inheritance pattern is still unknown (Chesley et al., 1986; Arngrimsson et al., 1995). Studies investigating the effects of plasma/serum from women with pre-eclampsia suggest that there are several characteristics that any candidate factor(s) must possess. These include the ability to pass freely into the maternal circulation, increase cellular permeability and cell turnover and alter prostacyclin and NO production (Hayman et al., 1999). VEGF is one such candidate as it possesses the characteristics of all of the above.
In this study we attempted to establish an association between three common functional polymorphisms of the VEGF gene and PE. We did not find any significant association between these polymorphisms and the occurrence of PE, but a limitation of our study is in its relatively small sample size which theoretically increases the likelihood of a type II error. Another concern relates to the selection of a proper control group. Studies investigating women with pre-eclampsia usually use age-matched controls to compare genotype frequencies. This strategy does not rule out a possible future pre-eclamptic pregnancy. To avoid this possible bias, all control women were post-menopausal at the time of blood sampling. A statistically significant correlation was found between the 936C/T polymorphism and the severity of PE.
The role of VEGF in pre-eclampsia has received substantial attention. Several authors have reported increased systemic VEGF levels in women with PE (Baker et al., 1995; Kupferminc et al., 1997; Hunter et al., 2000) whereas other authors have reported decreased levels (Lyall et al., 1997; Maynard et al., 2003), a discrepancy which probably has to do with the methodology (Maynard et al., 2003). In pregnancy, as compared to the non-pregnant state, most VEGF is bound to circulating sFlt1 due to very high levels of the latter. There is circumstantial evidence that antagonism of VEGF may have a role in hypertension and proteinuria (Koga et al., 2003; Maynard et al., 2003). Free VEGF levels, which more accurately reflect effective circulating VEGF, are substantially lower than total VEGF levels. It seems therefore that PE is characterized by normal to high total VEGF levels (perhaps induced by placental hypoxia) but low free VEGF levels, owing to a vast excess of sFlt1 which antagonizes the VEGF effects on the formation of placental vasculature and maternal endothelial cell function (Maynard et al., 2003). It should also be mentioned that sFlt1 acts through its antagonism of both VEGF and placental growth factor (PlGF), since the VEGF antagonist sFlk1 does not produce the pre-eclampsia phenotype in pregnant rats (Maynard et al., 2003). The origin of the elevated VEGF levels has not been confirmed conclusively. Conflicting results have been reported regarding the regulation of the VEGF system in PE at the transcriptional and translational level in the placenta (Cooper et al., 1995; Ranheim et al., 2001; Geva et al., 2002; Trollmann et al., 2003). Most candidate genes and all genome-wide scans so far have focused mainly on maternal genetic factors, but evidence is growing that the fetal gene load influences a mother’s susceptibility to pre-eclampsia (Lachmeijer et al., 2002). Seen in this light, measuring VEGF levels in the umbilical vein and artery and investigating maternal and fetal VEGF polymorphisms would be more informative about possible associations between VEGF and PE.
We found a statistically significant correlation between the 936C/T polymorphism and the severity of PE. Subjects carrying the T allele have significantly lower VEGF plasma levels than subjects carrying the VEGF 936CC genotype (Renner et al., 2000). Interestingly, there is an independent association between plasma VEGF concentration and plasma PlGF concentration and pre-eclampsia (Livingston et al., 2000) and the clinical severity of pre-eclampsia seems to correlate with the magnitude of various cytokine abnormalities including VEGF (Madazli et al., 2003). It has also been demonstrated that second-trimester analysis of circulating VEGF appears to be a useful tool for the early identification of pregnant women at increased risk for developing severe, early-onset PE (Polliotti et al., 2003).
In summary, it seems plausible that angiogenic molecules such as VEGF, PlGF and Flt1 may be important regulators of early placental development and pseudovasculogenesis. Although the power of this study was limited, we conclude that the VEGF gene polymorphisms studied are unlikely to be major predisposing factors for pre-eclampsia. Nevertheless, taking into account that VEGF has an important role during pregnancy, the present data strongly suggest that a reduced ability of mother’s tissue to up-regulate VEGF (as predicted by the 936C/T VEGF polymorphism) has a considerable effect on disease modification. Further studies should investigate whether other genetic alterations could predict this catastrophic disease early in pregnancy or even before conception.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionMaterials and methodsResultsDiscussionREFERENCES |
|---|
1 American College of Obstestricians and Gynecologists (1996) Hypertension in pregnancy. Technical Bulletin, No. 219, January 1996 (replaces no. 91, February 1988). Int J Gynaecol Obstet 53,175–183.[CrossRef][Medline]
Arngrimsson R, Bjornsson H and Geirsson RT (1995) Analysis of different inheritance patterns in preeclampsia/eclapmsia syndrome. Hypertens Pregn 14,27–38.[CrossRef][Web of Science]
Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I and Katayama S (2002) A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51,1635–1639.
Baker PN, Krasnow J, Roberts JM and Yeo KT (1995) Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol 86,815–821.[CrossRef][Web of Science][Medline]
Brockelsby J, Hayman R, Ahmed A, Warren A, Johnson I and Baker P (1999) VEGF via VEGF receptor-1 (Flt-1) mimics preeclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: implications in the pathogenesis of preeclampsia. Lab Invest 79,1101–1111.[Web of Science][Medline]
Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V and Hutchinson IV (1999) Novel polymorphisms in the promoter and 5' UTR regions of the human vascular endothelial growth factor gene. Hum Immunol 60,1245–1249.[CrossRef][Web of Science][Medline]
Chesley LC and Cooper DW (1986) Genetics of hypertension in pregnancy: possible single gene control of pre-eclampsia and eclampsia in the descendants of eclamptic women. Br J Obstet Gynecol 93,898–908.[Web of Science][Medline]
Cooper JC, Sharkey AM, McLaren J, Charnock-Jones DS and Smith SK (1995) Localization of vascular endothelial growth factor and its receptor, flt, in human placenta and decidua by immunohistochemistry. J Reprod Fertil 105,205–213.
Dekker GA and Sibai BM (1998) Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 179,1359–1375.[CrossRef][Web of Science][Medline]
deVries C, Escobedo JA, Ueno H, Houck K, Ferrara N and Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255,989–991.
El-Salahy EM, Ahmed MI, El-Gharieb A and Tawfik H (2001) New scope in angiogenesis: role of vascular endothelial growth factor (VEGF), NO, lipid peroxidation, and vitamin E in the pathophysiology of pre-eclampsia among Egyptian females. Clin Biochem 34,323–329.[CrossRef][Web of Science][Medline]
Eremina V Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH and Quaggin SE (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111,707–716.[CrossRef][Web of Science][Medline]
Ferrara N, Houck K, Jakeman L and Leung DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13,18–32.
Ferrara N, Gerber HP and LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9,669–676.[CrossRef][Web of Science][Medline]
Gargett CE and Rogers PA (2001) Human endometrial angiogenesis. Reproduction 121,181–186.[Abstract]
Geva E, Ginzinger DG, Zaloudek CJ, Moore DH, Byrne A and Jaffe RB (2002) Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J Clin Endocrinol Metab 87,4213–4224.
Hayman R, Brockelsby J, Kenny L and Baker P (1999) Preeclampsia: the endothelium, circulating factor(s) and vascular endothelial growth factor. J Soc Gynecol Invest 6,3–10.[Medline]
Hunter A, Aitkenhead M, Caldwell C, McCracken G, Wilson D and McClure N (2000) Serum levels of vascular endothelial growth factor in preeclamptic and normotensive pregnancy. Hypertension 36,965–969.
Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, Takeda S, Yano T, Tsutsumi O and Taketani Y (2003) Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab 88,2348–2351.[Abstract]
Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ, Gull I and Lessing JB (1997) Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol 38,302–306.[Web of Science][Medline]
Lachmeijer AM, Dekker GA, Pals G, Aarnoudse JG, ten Kate LP and Arngrimsson R (2002) Searching for preeclampsia genes: the current position. Eur J Obstet Gynecol Reprod Biol 105,94–113.[CrossRef][Web of Science][Medline]
Livingston JC, Chin R, Haddad B, McKinney ET, Ahokas R and Sibai BM (2000) Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol 183,1554–1557.[CrossRef][Web of Science][Medline]
Lyall F, Greer IA, Boswell F and Fleming R (1997) Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br J Obstet Gynecol 104,223–228.[Web of Science][Medline]
Madazli R, Aydin S, Uludag S, Vildan O and Tolun N (2003) Maternal plasma levels of cytokines in normal and preeclamptic pregnancies and their relationship with diastolic blood pressure and fibronectin levels. Acta Obstet Gynecol Scand 82,797–802.[CrossRef][Web of Science][Medline]
Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE et al (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111,649–658.[CrossRef][Web of Science][Medline]
Minchenko A, Bauer T, Salceda S and Caro J (1994) Hypoxic stimulation of vascular endothelial growth factor expression in vivo and in vitro. Lab Invest 71,374–379.[Web of Science][Medline]
Murphy DJ and Stirrat GM (2000) Mortality and morbidity associated with early-onset preeclampsia. Hypertens Pregn 9,221–231.
Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C and Miller RK (2003) Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol 101,1266–1274.[CrossRef][Web of Science][Medline]
Ranheim T, Staff AC and Henriksen T (2001) VEGF mRNA is unaltered in decidual and placental tissues in preeclampsia at delivery. Acta Obstet Gynecol Scand 80,93–98.[CrossRef][Web of Science][Medline]
Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B and Pilger E (2000) A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res 37,443–448.[CrossRef][Web of Science][Medline]
Simmons LA, Hennessy A, Gillin AG and Jeremy RW (2000) Uteroplacental blood flow and placental vascular endothelial growth factor in normotensive and pre-eclamptic pregnancy. Br J Obstet Gynaecol 107,678–685.[Web of Science]
Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D and Bohlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187,1579–1586.[CrossRef][Web of Science][Medline]
Trollmann R, Amann K, Schoof E, Beinder E, Wenzel D, Rascher W and Dotsch J (2003) Hypoxia activates the human placental vascular endothelial growth factor system in vitro and in vivo: up-regulation of vascular endothelial growth factor in clinically relevant hypoxic ischemia in birth asphyxia. Am J Obstet Gynecol 188,517–523.[CrossRef][Web of Science][Medline]
Vincenti V, Cassano C, Rocchi M and Persico G (1996) Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93,1493–1495.
Watson CJ, Webb NJ, Bottomley MJ and Brenchley PE (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12,1232–1235.[CrossRef][Web of Science][Medline]
Submitted on August 16, 2003; resubmitted on January 26, 2004; accepted on January 31, 2004.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. C. Sandrim, A. C. T. Palei, R. C. Cavalli, F. M. Araujo, E. S. Ramos, G. Duarte, and J. E. Tanus-Santos Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension Mol. Hum. Reprod., February 1, 2009; 15(2): 115 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. Brosens, P. De Sutter, T. Hamerlynck, L. Imeraj, Z. Yao, B. Cloke, J. J. Brosens, and M. Dhont Endometriosis is associated with a decreased risk of pre-eclampsia Hum. Reprod., June 1, 2007; 22(6): 1725 - 1729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Banyasz, S. Szabo, G. Bokodi, A. Vannay, B. Vasarhelyi, A. Szabo, T. Tulassay, and J. Rigo Jr Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia Mol. Hum. Reprod., April 1, 2006; 12(4): 233 - 236. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||