1Unit of Reproductive Endocrinology and Unit of Human Reproduction, First Department of Obstetrics and Gynecology, 2Third Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
Pregnancy-induced hypertension (PIH) complicates 6-10% of pregnancies. It is defined as systolic blood pressure (SBP) >140 mmHg and diastolic blood pressure (DBP) >90 mmHg. It is classified as mild (SBP 140-149 and DBP 90-99 mmHg), moderate (SBP 150-159 and DBP 100-109 mmHg) and severe (SBP ≥160 and DBP ≥110 mmHg). PIH refers to one of four conditions: a) pre-existing hypertension, b) gestational hypertension and preeclampsia (PE), c) pre-existing hypertension plus superimposed gestational hypertension with proteinuria and d) unclassifiable hypertension. PIH is a major cause of maternal, fetal and newborn morbidity and mortality. Women with PIH are at a greater risk of abruptio placentae, cerebrovascular events, organ failure and disseminated intravascular coagulation. Fetuses of these mothers are at greater risk of intrauterine growth retardation, prematurity and intrauterine death. Ambulatory blood pressure monitoring over a period of 24 h seems to have a role in predicting deterioration from gestational hypertension to PE. Antiplatelet drugs have moderate benefits when used for prevention of PE. Treatment of PIH depends on blood pressure levels, gestational age, presence of symptoms and associated risk factors. Non-drug management is recommended when SBP ranges between 140-149 mmHg or DBP between 90-99 mmHg. Blood pressure thresholds for drug management in pregnancy vary between different health organizations. According to 2013 ESH/ESC guidelines, antihypertensive treatment is recommended in pregnancy when blood pressure levels are ≥150/95 mmHg. Initiation of antihypertensive treatment at values ≥140/90 mmHg is recommended in women with a) gestational hypertension, with or without proteinuria, b) pre-existing hypertension with the superimposition of gestational hypertension or c) hypertension with asymptomatic organ damage or symptoms at any time during pregnancy. Methyldopa is the drug of choice in pregnancy. Atenolol and metoprolol appear to be safe and effective in late pregnancy, while labetalol has an efficacy comparable to methyldopa. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists are contraindicated in pregnancy due to their association with increased risk of fetopathy.
Antihypertensive treatment, Gestational hypertension, Methyldopa, Pre-eclampsia, Pregnancy-induced hypertension
INTRODUCTION
Definition and classification
Pregnancy-induced hypertension (PIH) complicates about 6-10% of pregnancies.1 It is defined as systolic blood pressure (SBP) >140 mmHg and diastolic blood pressure (DBP) >90 mmHg. It is classified as mild (SBP 140-149 and DBP 90-99 mmHg), moderate (SBP 150-159 and DBP 100-109 mmHg) and severe (SBP ≥160 and DBP ≥110 mmHg).2
According to the Canadian Hypertension Society, PIH refers to one of four conditions: a) pre-existing hypertension, b) gestational hypertension and PE, c) pre-existing hypertension plus superimposed gestational hypertension with proteinuria and d) unclassifiable hypertension, as is shown in Table 1.3
Epidemiology
An epidemiological study in the USA over the period 1995-2004 showed that gestational hypertension and PE were the most commonly diagnosed hypertensive conditions in pregnancy, whereas pre-existing hypertension was much rarer.4 Studies from Europe revealed a prevalence of preeclampsia at 2.3-3%.5,6
Complications
According to the WHO, PIH is one of the main causes of maternal, fetal and neonatal mortality and morbidity.1 It is the most common cause of maternal death in Europe.7 In a retrospective study over the period 2000-2009 in a tertiary center in India, PIH was the third cause of maternal death. In a similar study, over the period 1996-2009 in Henan Province, China, PIH was the second cause of maternal death. One tenth of maternal deaths in Africa and one quarter in Latin America are due to PIH-associated complications.1,8,9 Another study showed that the most common cause of mortality in cases of preeclampsia was haemolysis, elevated liver enzymes and low platelet count (HELLP) or partial HELLP syndrome (83.3%). Haemorrhagic stroke and pulmonary edema have been reported as the most common causes of death in patients with eclampsia, accounting for as many as 60% of all eclampsia-related deaths.10
Other maternal short-term complications include central nervous system dysfunction, hepatocellular injury, thrombocytopenia, acute disseminated intravascular coagulation (DIC), oliguria, pulmonary edema, cerebrovascular events and placental abruption.11-14 In one study of 4,188 women with preeclampsia the incidence of one or more systemic complications was 6%. Haematologic complications were most common and the incidence of placental abruption was 2.8%.15
PIH-associated complications are more frequent in early-onset (< gestational week 32) compared to late-onset PE.16 A comparative study showed that women with PE and superimposed PE have the same rates of perinatal complications. By contrast, women with superimposed PE had a significantly higher risk of intervention-related complications, such as delivery at < gestational week 34, caesarean delivery and neonatal intensive care unit admission.17
Fetal/neonatal short-term complications include intrauterine growth restriction (IUGR), small for gestational age (SGA) neonate, low birth weight neonate, preterm birth, intrauterine and perinatal death.18,19 In one study of 17,933 stillbirths, 9.2% were by pregnancies complicated by hypertensive disorders of pregnancy.20 One study from Greece revealed increased neonatal adverse outcomes in infants of preeclamptic women as compared to those of normotensive women.21 A retrospective study showed that hospital-based continuous prenatal care reduced the risk of pre-term delivery and impaired fetal growth in pregnancies complicated by PE.22
Concerning long-term health risk, several studies demonstrated that women with PIH are at greater risk of other medical conditions, such as hypertension, cardiovascular disease, diabetes mellitus and kidney disease in later life.23,24 One study of 3,593 women with preeclampsia during their first singleton pregnancy pointed to a positive association of hypertensive diseases of pregnancy with diseases related to hypertension in later life.25
The risk of diabetes in later life was 2-fold higher in women with PE or gestational hypertension compared with women without them.26 Long-term health risk seems to be increased among the offspring of pregnancies complicated by PIH. These conditions include higher blood pressure in childhood and adulthood and a tendency towards impaired lipid profile, a 2-fold higher stroke risk, lower cognitive ability and mental disorders in later life.27-31
Risk factors
Hypertension, collagen vascular disease, obesity, black race, insulin resistance, diabetes mellitus, gestational diabetes, increased serum testosterone concentrations and thrombophilia are considered risk factors for PIH.32,33
A recent epidemiological study showed that Black and some Hispanic women had markedly increased risk for all hypertensive disorders in pregnancy compared to non-Hispanic white women, while Asian women were at decreased risk. The same study disclosed a positive correlation between pre-pregnancy weight and risk of PIH, whereas parity and smoking were protective for PE development.4 The data for parity are conflicting, as both nulliparity and multiparity seems to predispose to higher risk for PE.34-36
Maternal age >30 years and increased body mass index (BMI) were found to be positively correlated to risk for PIH in Arab women.37 Increased pre-pregnancy BMI was also a risk factor for PE in twin pregnancies.38 In addition, above-average weight gain during pregnancy was positively correlated to PE risk.36 Personal and family history of PE are considered significant risk factors for PE in pregnancy.39-41
Anti-phospholipid syndrome (APS), an autoimmune condition characterized by recurrent thrombosis, is widely recognized as a risk factor for several obstetric complications, including PIH. Approximately one third of women with APS will develop PE.42,43
Two recent meta-analyses concluded that low maternal vitamin D concentrations are associated with increased risk of PE.44,45
PHYSIOLOGY: CARDIOVASCULAR CHANGES DURING PREGNANCY
Significant cardiovascular and haemodynamic changes occur early in pregnancy in order to provide enough blood for the embryo and maintain normal fetal intrauterine growth. Such changes include increased maternal plasma volume, cardiac output and heart rate, and decreased maternal systemic vascular resistance and arterial blood pressure.46
The expansion of maternal plasma volume is due to stimulation of the renin-angiotensin-aldosterone system. As a compensatory mechanism, vasodilator synthesis is increased in order to maintain normotension.47 Such vasodilators include the kallikrein-kinin system, prostacyclin, nitric oxide and vascular-endothelial growth factor (VEGF).48-50
In addition to the functional adaptation of the maternal cardiovascular system, structural changes also occur during pregnancy. This adaptive remodelling results in cardiac hypertrophy that enables the heart to cope with the increased demands of gestation. This hypertrophy is reversible and is not associated with long-term cardiovascular dysfunction.51
In summary, haemodynamic changes during pregnancy include a reduction of systolic, diastolic and mean arterial blood pressure in the second trimester followed by a slight increase in the third, a reduction of total vascular resistance, especially in the second trimester, and an increase of cardiac output.52
PATHOPHYSIOLOGY
PIH and especially PE is considered to be a multifactorial disease. Many theories have been developed about its pathogenesis. Their common characteristic is the central role of the placenta. The modified theory of the “two-stage model” suggests that abnormal placental implantation, vascularization or function together with the contribution of maternal factors can lead to PE.53 Factors that have been implicated in PE pathophysiology are cardiovascular maladaptation and vasoconstriction, genetic predisposition, immunologic intolerance between feto-placental and maternal tissue, platelet activation and vascular endothelial dysfunction.54 Moreover, coexisting metabolic factors can contribute to endothelial dysfunction, and hyperlipidaemia and insulin resistance have been associated with preeclampsia.55-57
Immune factors, such as auto-antibodies, oxidative stress and natural killer (NK)-cell abnormalities, cause placental dysfunction and impaired placental perfusion. The latter acts as a stimulus of placental release of anti-angiogenic and inflammatory mediators that eventually cause endothelial dysfunction and organ damage.58 Increased numbers of activated monocytes and macrophages have been described in the endometrium of women with PE.59 A misbalance between antioxidant and pre-oxidant factors and increased production of ROS results in vascular endothelium dysfunction in women with PE.60 One study showed that women with early-onset severe preeclampsia have increased NK cell function related to cytokine production.61
Angiogenic factors, such as VEGF family members (VEGF, PIGF), angiopoietins and their receptors, are thought to be significant for the regulation of placental growth and vascular development.62 Angiopoietin 1 binds to Tie receptors, whereas angiopoietin 2 acts as an antagonistic ligand.63 Impaired expression of demonstrated decreased VEGF levels in the umbilical cord from pregnancies complicated by hypertension as compared to normal pregnancies.66 The angiopoietin 1/angiopoietin 2 ratio was found significantly lower in women who developed preeclampsia than in normal pregnant women.67
Anti-angiogenic factors, such as sFlt1 [soluble Flt1 (fms-like tyrosine kinase 1)] and soluble endoglin (sEng), inhibit angiogenesis and promote vascular dysfunction. sFlt-1 binds to VEGF and PlGF, and sEng impairs binding of TGF-β1 to its receptor, blocking their actions.68,69 Both of them are expressed by normal placenta.70,71 Many studies have amplified the theory of the misbalance of circulating angiogenic factors in PE and the sFlt-1/PlGF ratio has been proposed as an additional diagnostic or predictive tool for PE.72-74 A meta-analysis showed increased concentrations of placental and maternal sFlt1 and sEng and decreased concentrations of PIGF in pregnancies which developed PE. VEGF was lower, though not significantly different, between the women who developed PE and those who did not.75
Several studies have shown an increased risk of PIH and PE in pregnancies with positive familial history of PE.76,77 The latter implies a genetic predisposition. Many single nucleotide polymorphisms (SNPs) in candidate genes of clotting factors, vascular growth factors, vasoactive proteins, oxidative stress related factors, immunoactive mediators and components of the renin-angiotension-aldodterone system have been associated with PE development.78,79
FOLLOW-UP
The assessment of women with pregnacies complicated by PIH includes clinical follow-up, serological investigation and fetal ultrasound evaluation.80,81 The type and frequency of follow-up depends on the kind and severity of the hypertensive disorder.
Clinical follow-up includes blood pressure measurements using mercury sphygmomanometry (Korotkoff phase V), in the sitting position, and evaluation of any signs or symptoms indicative of clinical deteroriation.82 Biochemical and urine tests include urine dipstick, urinalysis for proteinuria, if urine dipstick has >1+, full blood count (haematocrit, haemoglobin, platelets), liver enzymes, serum urea, creatinine, eloctrolytes and serum uric acid. Similarly, frequency of fetal monitoring depends on the type of hypertensive disorder. In pregnancies complicated by chronic hypertension, fetal ultrasound, amniotic fluid volume assessment and umbilical artery Doppler velocimetry are recommended at gestational weeks 28-30 and 32-34. Cardiotocography is suggested if fetal activity is abnormal. Fetal follow-up is also recommended for cases of mild or moderate gestational hypertension. For cases with severe gestational hypertension or PE, fetal ultrasound, amniotic fluid volume assessment and umbilical Doppler velocimetry is recommended to be performed not more frequently than every two weeks. Cardiotocography is recommended if abnormal fetal activity, vaginal bleeding or deterioration of the pre-existing condition is observed.83
Non-invasive ambulatory blood pressure monitoring (ABPM) seems to be a useful tool for the diagnosis, differential diagnosis and follow-up of PIH. It contributes to identification of cases with white-coat hypertension (WCH), prediction of PE, prognosis in late pregnancy and treatment modification.84-88
WCH refers to elevated blood pressure measurements when “in clinic”, while “out of clinic” measurements are normal. WCH in pregnancy is a frequent and benign condition with good prognosis and no apparent need for antihypertensive treatment. Despite that, a small proportion of patients with WCH in early pregnancy will develop PE later in pregnancy.89,90 Consequently, it is essential to differentiate WCH from PIH, thus avoiding exposing these women to the possible adverse effects of antihypertensive treatment as well as unnecessary caesarean sections. In addition, detection of that group of women with WCH who are going to develop PE is important for pregnancy outcome. ABPM contributes to the achievement of both the above goals, in parallel with the evaluation of treatment efficacy.84,89,91,92
TREATMENT
Treatment of PIH depends on blood pressure levels, gestational age, presence of symptoms and associated risk factors.
Mild to moderate hypertension
Data for the treatment of mild to moderate PIH are controversial, making it difficult to formulate clear recommendations.80,81,93,94
Randomized controlled trials (RCTs) that compared pharmaceutical treatments with placebo or no treatment in mild cases of PIH had conflicting results. Prospective controlled studies of metoprolol-hydralazine, nifedipine and labetalol-methyldopa treatment administered to pregnant women with mild PIH, unclassifiable hypertension or mild PE showed no significant improvement of pregnancy outcome as compared to the non-treated group.95-98 Labetalol had no effect on development of proteinuria in a trial of 114 women with PIH and nifedipine had no effect on PE-related hypocalciuria as compared to the control group.99,100 Other RCTs resulted in better pregnancy outcome in the treated groups. In contrast to the above findings, atenolol and labetalol prevented proteinuria in the treatment group as compared to the control group.101-103 RCTs with methyldopa pointed to better pregnancy outcome in cases of mild PIH and mild PE with regard to mid-pregnancy abortions and progression to severe PE, respectively.104,105 Another trial of methyldopa in mild PIH demonstrated a significant prolongation of pregnancy, by about 10.3 days, with no adverse effect on birth weight.106 An RCT of 100 pregnant women with mild PIH who were treated either with methyldopa or labetalol and 50 controls confirmed the positive effect of antihypertensive treatment on pregnancy outcome. Maternal outcomes that were significantly improved by the antihypertensive treatment were progression to severe PIH, proteinuria, hospitalization before term and delivery by caesarean section, whereas fetal/neonatal outcomes were SGA, preterm birth and admission to neonatal unit.107
Early treatment with clonidine plus hydralazine compared to the non-treatment group prevented premature delivery in primigravid diagnosed with mild PIH (<170/110 mmHg).108 Treatment with nifedipine in cases of mild PE had a positive effect on renal function with significant reduction of urea, creatinine and 24 h urine protein in the treatment group.109 Isradipine treatment was found to have no adverse affect on maternal kidney or liver function or blood flow in the umbilical artery.110
Regarding neonatal glucose concentrations, there was no significant difference between mothers who received either isradipine, atenolol or low sodium diet (control group).111 As far as fetal growth is concerned, atenolol and labetalol treatment in mild PIH and mild PE, respectively, were associated with fetal growth restriction, whereas early antihypertensive treatment with oxprenolol had no such effect.112-115 A meta-analysis of the effect of oral antihypertensive treatment in cases of mild to moderate PIH concluded that greater decrease of blood pressure was associated with fetal growth restriction. The drugs that were used in the RCTs of this meta-regression analysis were a-methyldopa, beta-blockers, thiazides, ketanserin, hydralazine, calcium-channel blockers and clonidine. Birth weights of newborns of the mothers who took antihypertensive therapy during pregnancy were lower than those of the non-treated/placebo group. Decrease in mean arterial pressure of 10 mmHg was associated with a 145 g decrease in mean birth weight, as found in a post-hoc analysis.116
RCTs of methyldopa treatment during pregnancy had smaller head circumference in the treatment group at birth, 2 months, 6 months and 4 years of age as compared to control groups.117-121 In contrast, an RCT with nifedipine treatment in cases of mild to moderate PIH exhibited no difference between the treatment and control groups as far as development and health status at 18 months of age were concerned.122
The ratio of maternal-fetal benefit to risk for fetal adverse effects, such as low birth weight, need to be further evaluated.116,123,124 A Cochrane systematic review on the control of blood pressure in mild to moderate PIH did not reach conclusive results due to insufficient data.125
In general, non-pharmacological treatment is suggested for pregnant women with mild to moderate PIH that do not fulfil the criteria for pharmacologic treatment. According to the WHO, lifestyle modification, such as strict bed rest and salt restriction, are not recommended in PIH or PE.1 Compliance with the recommendations for the pre-pregnancy BMI-dependent indicated weight gain is essential due to the fact that both obesity and gestational weight gain are risk factors for PIH, PE or eclampsia.34,36,126 Strict follow-up and early diagnosis of progression to a more severe condition is necessary.
Women at high risk of PE are recommended to receive 75 mg aspirin and calcium supplements daily, especially when dietary calcium intake is low. Vitamins C, E, D are not recommended for PE prevention due to insufficient data.1,127 Magnesium sulphate (MgSO4) is recommended for eclampsia prevention in women with severe PE or as a supplementary treatment modality in eclampsia.1
Severe hypertension
Blood pressure thresholds for drug treatment initiation in PIH vary between different health organizations. According to the 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines, antihypertensive treatment in pregnancy is recommended when blood pressure levels are ≥150/95 mmHg (Table 2). Initiation of antihypertensive treatment at lower levels (≥140/90 mmHg) is suggested for women with a) gestational hypertension with or without proteinuria, b) pre-existing hypertension with the superimposition of gestational hypertension or c) hypertension with asymptomatic organ damage or symptoms at any time during pregnancy.127
The aim of antihypertensive treatment is to prevent complications, such as maternal cerebral haemorrhage and eclampsia, and allow prolongation of pregnancy. According to the National Institute of Clinical Excellence (NICE) guideline for “management of hypertensive disorders during pregnancy 2010”, the therapeutic goal in severe PIH is a gradual decrease of blood pressure to <150/100 mmHg.128
Methyldopa is considered the drug of choice in pregnancy due to its effectiveness and long safety record. Labetalol can be given intravenously in emergency cases. Calcium channel blockers (CCB), such as nifedipine per os or isradipine IV, are effective and have no major teratogenic risk. A potential synergism with MgSO4 that may induce hypotension must be taken into consideration. Atenolol and metoprolol appear to be safe and effective in late pregnancy. Hydralazine is no longer the parenteral drug of choice in emergency cases due to perinatal adverse effects and slower therapeutic response.129-132 A Cochrane review about the use of diuretics for prevention of PE and its complications disclosed no significant difference in pregnancy outcomes between the treated group and the placebo or no-drug groups.133 Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are contraindicated in pregnancy due to their association with an increased risk of fetopathy.134-136 Women who are treated with an ACE or ARB before conception should be advised to avoid exposure to these drugs during pregnancy by replacing them with a different antihypertensive drug as soon as pregnancy is confirmed.128 Studies of pregnant women who received the above classes of drugs and animal experimental studies showed increased risk of fetal hypotension, decreased glomerular perfusion pressure, impaired renal tubular development, reduced fetal urine output or complete anuria and oligohydramnios, limb contractures, pulmonary hypoplasia, cranio-facial deformation and impaired ossification, intrauterine growth restriction and decreased placental and umbilical perfusion. Epidemiological studies demonstrated an increased risk of congenital malformations among neonates of mothers who received ACEIs and ARBs during pregnancy compared to controls.137
Several RCTs compared different antihypertensive drugs in pregnancy. A Cochrane systematic review included 24 RCTs that compared at least two antihypertensive drugs.138 The review did not come to a clear conclusion due to insufficient data. Hydralazine as compared to nifedipine and isradipine was seen to be less effective as regards persistent high blood pressure. No difference was detected between hydralazine and prostacyclin. Ketanserin is a selective S2-serotoninergic antagonist exerting alpha-1 receptor antagonistic action, especially with higher doses of the drug. It inhibits the vasoconstriction and platelet aggregation induced by serotonin.139
Hydralazine was associated with lower risk for persistent high blood pressure as compared to ketanserin but with increased rate of adverse effects. Urapidil is an alpha-1 receptor antagonist with agonistic action at serotonin 5-HT1A receptors. It also has a central sympatholytic effect mediated via stimulation of serotonin 5HT1A receptors in the central nervous system. It reduces blood pressure by decreasing peripheral vascular resistance.140 Studies comparing hydralazine to urapidil provided insufficient data. One prospective study of 100 women with severe PIH showed that urapidil was effective in 80% of cases.141
Data were also insufficient as regards the comparison of labetalol to hydralazine, methyldopa and nicardipine. Labetalol was associated with marginally less hypotension and caesarian section rate compared to diazoxide. MgSO4 had a higher risk of persistent high blood pressure, of maternal respiratory distress and of postpartum haemorrhage but a lower risk of eclampsia compared to nimodipine. Isosorbide was associated with lower frequency of caesarian section than MgSO4.
An RCT of 200 pregnant women who were treated with hydralazine IV or labetalol for severe PIH resulted in a significantly higher rate of palpitations and maternal tachycardia in the hydralazine-treated group and higher rate of hypotension and bradycardia in the labetalol-treated group.142 Another smaller (n=16) trial of hydralazine or labetalol in acute severe PIH revealed the high effectiveness of both drugs, with no effect of either of them on fetal Doppler.143 In contrast, the group that received hydralazine had a significant increase in uterine arteries resistance. Hydralazine IV as compared to mini bolus diazoxide resulted in a significantly higher rate of persistent hypertension.144 The latter was also observed in a trial of hydralazine IV or nifedipine per os in hypertensive crisis. Another smaller study of dihydralazine and urapidil found no difference as regards effectiveness between the two drugs.145 Treatment with nitroglycerine IV plus plasma volume expansion and MgSO4 as compared to sublingual nifedipine plus plasma volume expansion and MgSO4 showed no difference in effectiveness or maternal and fetal-neonatal adverse effects.146 Finally, a double-blind RCT of nifedipine per os versus labetalol IV resulted in no significant difference in the time needed to achieve the therapeutic goal or the overall efficacy between the two drugs.147
Acute severe hypertension in pregnancy is considered a medical emergency and requires hospitalization. Labetalol, hydralazine and nifedipine are used as first line treatment.148 A double-blind randomized trial compared the effectiveness of oral nifedipine and intravenous labetalol in pregnant women with gestational hypertension and BP ≥160/110 mmHg. No significant difference in BP decrease was found between the two groups.149 Intravenous nitroglycerin, oral methyldopa or oral clonidine can be used as second line treatment.148 Magnesium sulfate can be used in combination with an antihypertensive agent for the prophylaxis of seizures in cases of severe preeclampsia or eclampsia.150
Therapeutic options for severe hypertension are shown in Table 3.148
CONCLUSIONS
In conclusion, PIH is a common health problem with adverse effects for both mother and fetus/neonate. It is believed to be a multifactorial health condition the pathogenetic mechanism of which is not as yet fully understood. More studies clarifying the latter will also contribute to more effective medical treatment and optimization of pregnancy outcome. The use of antihypertensive treatment, especially in cases of mild hypertension, is meanwhile of great concern. More randomized controlled studies are necessary for further evaluation of the ratio of maternal-fetal benefit to risk for fetal adverse effects.
CONFLICT OF INTERESTS
All authors declare no potential conflicts of interest.
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Address for correspondence:
Assistant Prof. Vasilios Kotsis,
Third Department of Internal Medicine, “Papageorgiou” General Hospital, Ring
Road, 54601 Nea Efkarpia, Thessaloniki, Greece, Tel.: +2310 693131, Fax: +2310
991510, E-mail: vkotsis@auth.gr
Received: 22-05-2014, Accepted: 10-02-2015