Krzysztof Drews

The significance of -786T > C polymorphism of endothelial NO synthase (eNOS) gene in severe preeclampsia.

Objective. Preeclampsia (PE) is believed to be induced by endothelial cell dysfunction in placenta. Highly polymorphic endothelial nitric oxide synthase (eNOS) activity belongs to the factors significantly influencing vaso-motor tone in placenta and PE susceptibility. The aim of this study was to evaluate prevalence of −786T/C polymorphism of eNOS gene in the groups of women with mild and severe PE. Study design. The study was performed in the group of 218 preeclamptic (including 136 with severe PE) and of 400 normotensive healthy women delivered normally after a healthy gestation. The eNOS −786T/C polymorphism was determined using PCR/RFLP assay. Additionally, detailed correlation between eNOS genotypes and clinical/laboratory data in the PE group has been analyzed. Results. The higher frequency of mutated homozygous CC genotypes (17.4% vs. 11.5% in controls, OR 1.62, n.s.) and of C alleles (allelic frequency 44.1 vs. 36.6%; OR 1.36, p = 0.012) in the group of PE has been determined. Furthermore, in the group of severe PE the overrepresentation of mutated CC genotypes (23.5% vs. 11.5%, OR 2.37, p = 0.0014) and mutated C alleles (47.8 vs. 36.6%, OR 1.58, p = 0.0016) has been found. Conclusions. The presence of mutated homozygous CC genotype and C allele of −786T/C polymorphism of eNOS gene influences the higher susceptibility to develop severe PE development.

1166C mutation of angiotensin II type 1 receptor gene is correlated with umbilical blood flow velocimetry in women with preeclampsia

OBJECTIVE To ascertain the frequency of polymorphic variants of the gene coding for angiotensin II type 1 receptor (AT1) and its correlation with umbilical artery (UA) blood flow velocity in a group of women with preeclampsia (PE). STUDY DESIGN AT1 polymorphism, pulsatility index (PI) in UA, and perinatal outcome in 47 women with PE and in 113 healthy pregnant women were investigated. Investigation of AT1 receptor genotypes was performed by PCR/RFLP assays. PI value has been measured by Doppler velocimetry technique. RESULTS The overrepresentation of CC homozygotic genotype in PE group (6.4% vs. 2.7%) and the overrepresentation of mutated C allele in the PE group were observed (28.7% vs. 23.0%). Analyzing PI index we observed statistically significant differences between PE and control groups. Comparing PI values in PE group between genotypes: AA vs. AC + CC statistically significant differences (p < 0.05) have been observed. CONCLUSIONS Observed overrepresentation of mutated C allele of the AT1 gene was correlated with increased blood flow in umbilical artery in women with preeclampsia. Doppler velocimetry might be a useful tool for indication in the high-risk group with overrepresentation of C alleles.

Fetal and maternal Doppler velocimetry and cytokines in high-risk pregnancy

Abstract Objective: Fetal hypoxia and preterm delivery are reported to be strongly associated with brain damage and neurodevelopmental delay. Doppler signs of fetal brain sparing have been described during chronic hypoxia, but whether they are related to brain damage is unknown. The aim of this study was to evaluate if markers of tissue injury, i.e., tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are related to signs of increased perinatal vascular impedance and/or fetal brain sparing in high-risk pregnancies. Study design: TNF-α and IL-6 levels were evaluated in maternal blood serum of 67 high-risk pregnancies. Serum samples were taken at the time of umbilical, middle cerebral artery and uterine artery Doppler velocimetry examination. The values for TNF-α and IL-6 were correlated with reference median values obtained with gestational age in the form of a Z-score. Results: TNF-α levels showed values within the normal range in only four cases. IL-6 values were found normal in 14 cases. The Z-score for mean middle cerebral artery pulsatility index (PI) showed a significant correlation to TNF-α and IL-6 levels, P<0.0001 and P<0.003, respectively. This might suggest a strong correlation between signs of fetal brain sparing and increased maternal serum TNF-α and IL-6 levels. Abnormal uterine artery PI and the presence of a “notch” were also highly significantly related to TNF-α and IL-6 levels, which were nearly two-fold higher compared to normal uterine artery blood flow and the absence of a “notch”. Abnormal cerebro/placental ratios showed significant correlations to TNF-α and IL-6 levels. Conclusion: The present results suggest a strong correlation between levels of TNF-α and IL-6 not only for signs of fetal brain sparing, but also for uteroplacental blood flow. This finding supports the role of tissue injury in cases of fetal brain sparing, but whether this is a reflection of brain damage or secondary to placental pathology needs further evaluation.

The Optimal Treatment of Thyroid Gland Function Disturbances During Pregnancy

Thyroid disorders are quite a common health problem in pregnant women, thus adequate treatment in this period is very important in order to decrease maternal and fetal morbidity. The prevalence of hyperthyroidism is estimated to be present in approximately 0.2-0.4% of all pregnancies and the most common is Graves disease. Untreated hyperthyroidism is connected with disturbed fertilisation, recurrent miscarriages, preeclampsia development, hypotrophy of the fetus, and haemorrhage in the postpartum period. Hypothyroidism is found in pregnant women in 0.3-0.7% of all cases. Uncontrolled hypothyroidism in pregnancy can lead to preterm birth, low birth weight and mental retardation. The goal of the treatment of both hypo- and hyperthyroidism is to reach a stable euthyroid state by applying thyroid hormones or antithyroid drugs, respectively. It seems that well-controlled management of thyroid diseases does not pose any problem for pregnancy. However, the most important is to avoid any neurological abnormalities in the fetus in hyperthyroid women resulting from antithyroid drugs exposure. Moreover, it is also crucial to abstain from subclinical hypothyroidism and hypothyroxinaemia in the mother and its effect on the fetuss development which merits exact screening and intense monitoring. In this paper we described the complex pharmacology of the drugs that are used in pregnant women suffering from thyroid disorders, considering the clinical application, practical recommendation, and side effects in pregnancy and lactation. This systematic analysis could contribute some pharmacological knowledge which will be helpful in the clinical management of thyroid disorders during pregnancy.

The importance of MTHFR, MTR, MTRR and CSE expression levels in Caucasian women with preeclampsia.

OBJECTIVE Preeclampsia (PE) is a major cause of maternal and perinatal mortality and morbidity. The studies suggest that both polymorphisms and changes of expression in genes encoding enzymes involved in the methionine and homocysteine metabolism (MHM), such as methylenetetrahydrofolate, reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR) and cystathionine gamma-lyase (CSE), could play a role in the development of hypertension during pregnancy. The aim of the study was to determine the expression level of MTHFR, MTR, MTRR and CSE genes in the development of PE in Caucasian women. STUDY DESIGN The control group consisted of 74 healthy pregnant women and 90 patients with diagnosed pre-eclampsia. Total RNA was isolated from placenta and the mRNA level of examined genes was to determine using real-time PCR. RESULTS The expression level of MTHFR gene showed no statistically significant difference in the study group as compared to the control group. An increase of mRNA levels for MTR and CTH was observed by 124.7% (p<0.0001) and 26.6% (p>0.05), respectively. However, a decrease of placental expression was noted for MTRR by 50% in preeclamptic women as compared to control group (p<0.0001). CONCLUSIONS Our findings suggest that the elevated RNA expression of MTR in placenta of preeclamptic patients is probably results of a potential compensation mechanism of the MHM while elevated CSE expression indicates that homocysteine may be eliminated through the alternate transsulfuration pathway.

The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women

OBJECTIVE The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. METHODS A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. RESULTS After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). CONCLUSIONS Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women.

Coexistence of ACE (I/D) and PAI-1 (4G/5G) gene variants in recurrent miscarriage in Polish population

OBJECTIVES Recurrent miscarriage (RM) is one of the most common obstetric complications. Numerous studies have suggested that genetic variants leading to an impaired balance between coagulation and fibrinolysis may contribute to elevated risk of pregnancy loss. The aim of the study was to investigate a possible association between angiotensin-converting enzyme (ACE, rs1799752) I/D and plasminogen activator inhibitor type 1 (PAI-1, rs1799768) 4G/5G polymorphisms with RM among Polish women. MATERIAL AND METHODS DNA was extracted from peripheral blood samples of 152 women with a history of ≥ 2 consecutive pregnancy losses before 22 weeks of gestation, and 180 healthy controls with at least 1 live birth at term and no history of pregnancy loss. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to identify the polymorphisms. RESULTS No statistically significant differences were found in genotype and allele frequencies of the studied polymorphisms. The most relevant difference between the study group and controls was found for the ID genotype distribution of the ACE gene (52.6 vs. 46.7%, OR = 1.27, p = 0.28). The analysis of genotype coexistence revealed a higher incidence of the combination of the ACE II and the PAI-1 4G/4G genotypes in the control group (10.0 vs.5.9% in control group; p = 0.17). CONCLUSIONS The obtained results suggest no apparent association between the ACE I/D, PAI-1 4G/5G polymorphisms and increased RM susceptibility in the analyzed Polish population.

The RANKL/RANK/OPG signal trail: significance of genetic polymorphisms in the etiology of postmenopausal osteoporosis

OBJECTIVES Recent studies have demonstrated that disorders of bone metabolism, which is regulated by RANK/RANKL/OPG signaling pathway, are the cause of osteoporosis. The aim of the study was to investigate the distribution of genotypes of the RANK 575C>T and RANKL -643C>T polymorphisms and to analyze their relationship with bone parameters in postmenopausal women. MATERIAL AND METHODS A total of 310 postmenopausal Caucasian women (139 with osteoporosis, 107 with osteopenia, and 64 healthy postmenopausal controls) were included. Bone mineral density (BMD) at the lumbar region of the spine (L2-L4) was measured by dual energy X-ray absorptiometry (DXA). Genetic analysis was performed using the PCR-RFLP method. RESULTS Analysis of the frequency of genotypes and alleles of the RANK 575C>T and RANKL -643C>T polymorphisms did not show any statistically significant differences between the study groups (osteoporosis and osteopenia) and postmenopausal women with normal t-score value (ns). Notably, a significant association between the RANKL -643C>T polymorphism and body mass, such as BMI values in osteoporotic women (p<0.05), was observed. CONCLUSIONS Our results suggest lack of association between the 575C>T RANK polymorphism and the development of osteoporosis. The -643C>T RANKL polymorphism, through its significant influence on body weight and BMI value, may contribute to the development of osteoporosis in postmenopausal women.

Correlation between factor VII and PAI-1 genetic variants and recurrent miscarriage

BACKGROUND Polymorphisms which are presented below may be the cause of inherited thrombophilia and may result in pregnancy loss. The hypothesis is based on a number of cardiology studies which have confirmed the involvement of these polymorphisms in thrombotic incidents. OBJECTIVES To evaluate the role of polymorphisms of factor VII gene (Arg353Gln, -122T > C) and PAI-1 gene (-675 4G/5G) in the etiology of recurrent miscarriage. MATERIAL AND METHODS The study group included 152 women with a positive history of ≥ 2 consecutive pregnancy losses (114 and 38 women with 2 and ≥ 3 miscarriages, respectively), while 180 healthy women were recruited as controls. Genetic analysis was performed with the use of PCR/RFLP. RESULTS Lower frequency of Arg353/Gln353 was observed in women with 2 and ≥ 3 miscarriages as compared to controls (21.1% vs. 23.9% and 13.2% vs. 23.9%, respectively). The frequency of Gln353 was lower in women with ≥ 3 miscarriages as compared to controls (6.6% vs. 11.9%, p = ns). The frequency of -122TT was higher in women with ≥ 3 miscarriages as compared to controls (86.84% vs. 76.67%, p = ns), whereas -122TC was more frequent in controls (13.16% vs. 22.78% in controls, p = ns). The frequency of -122T was higher in patients with ≥ 3 abortions as compared to controls (93.42% vs. 88.06%, p = ns), and -122C was observed more frequently in controls (6.58% vs. 11.94% in controls, p = ns). There were no significant differences as far as the -675 4G/5G polymorphism was concerned. CONCLUSIONS The obtained results suggest a possible protective role of Gln353 and -122C alleles in recurrent miscarriage.

Disordered eating attitudes during pregnancy in mothers of newborns requiring Neonatal Intensive Care Unit admission: a case control study

Abstract Objective: The aim of the study was to assess disordered eating attitudes and other related factors in mothers of newborns requiring Neonatal Intensive Care Unit (NICU) admission compared to those of mothers who delivered healthy infants. Methods: An anonymous self-report study conducted among 199 mothers of newborns hospitalized in NICU, and a control group of 127 mothers of healthy newborns. Eating Attitudes Test-26 (EAT-26) and a survey regarding other perinatal health issues were used. Results: Women in the study group (SG) gained significantly less weight during pregnancy when compared to control group (CG; p = 0.001). There were fewer women with appropriate pre-gestational BMI in the SG (p = 0.052). Women who feared weight-gain during pregnancy were younger (p < 0.001) and had higher EAT-26 scores (p < 0.001). Women with EAT-26 scores >20 smoked significantly more often during their last pregnancy in the SG (p = 0.010). Cesarean section was more frequent in the SG (p = 0.017). Conclusions: Disordered eating attitudes in gestation may significantly influence the pregnancy outcomes and newborns’ health. Hence, it is vital for perinatal counseling and obstetrical care to focus on these issues to facilitate early diagnosis and intervention.