Inheritance and perinatal consequences of inherited
thrombophilia in Greece
Marina Karakantzaa,⁎, Georgios Androutsopoulosb, Athina Mougioua,
Georgios Sakellaropoulosc, Georgios Kourounisb, Georgios Decavalasb
aDepartment of Internal Medicine, Division of Hematology, University of Patras Medical School, Patras, Greece
bDepartment of Obstetrics and Gynecology, University of Patras Medical School, Patras, Greece
cDepartment of Medical Physics, University of Patras Medical School, Patras, Greece
Received 28 April 2007; received in revised form 3 August 2007; accepted 7 August 2007
Objective: To investigate the impact of inherited thrombophilic factors on the gestational
outcome of unselected pregnant women. Method: A total of 392 women with spontaneous
pregnancy were investigated for Factor V Leiden, prothrombin G20210A, and MTHFR C677T
mutations. Adverse pregnancy outcomes were recorded. Results: Thrombophilic genotypes were
significantly higher in women with placental abruption. Heterozygocity for Factor V Leiden
increased the risk for placental abruption 9.1 times. The MTHFR T677T genotype increased the
risk for placental abruption 4.8 times despite folate supplements, and normal serum folate and
B12levels. Women with inherited thrombophilia and previous obstetric complications were at
significant risk for complications in a subsequent pregnancy (Pb0.05). Conclusion: Women with
placental abruption should be screened for thrombophilic factors and plasma homocysteine
should be measured. Subgroups of women with inherited thrombophilia and obstetric
complications might benefit from prophylactic anticoagulation in subsequent pregnancies.
© 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
Factor II G20210A;
Factor V Leiden;
A significant percentage of pregnant women experience
serious complications during pregnancy such as spontaneous
abortion, placental abruption, intrauterine growth restric-
tion (IUGR), intrauterine fetal death (IUFD), and pre-
eclampsia . These problems may be associated with
pathological placental vasculature leading to inadequate
fetomaternal circulation . Based on the assumption of the
pathogenetic role of abnormal hemostasis in the develop-
ment of placental vasculopathy, and the knowledge of the
association of inherited and acquired thrombophilia with the
development of thromboembolic complications, a cause and
⁎ Corresponding author. Department of Internal Medicine, Division
of Hematology, University of Patras, Medical School, Rion 26500,
Greece. Tel.: +30 2610999255; fax: +30 2610991991.
E-mail address: firstname.lastname@example.org (M. Karakantza).
0020-7292/$ - see front matter © 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
available at www.sciencedirect.com
International Journal of Gynecology and Obstetrics (2008) 100, 124–129
effect relationship has been assumed between thrombophilia
and pregnancy. The gene mutations most commonly inves-
tigated are Factor V Leiden (FV G506A) mutation, prothrom-
bin G20210A gene mutation, and methylenetetrahydrofolate
reductase (MTHFR) C677T gene mutation.
Data from observational studies suggest an association of
FV Leiden mutation and prothrombin G20210A gene mutation
with placental abruption and severe pre-eclampsia [2,3],
while the association of inherited thrombophilia with IUGR
remains controversial [3–5]. In addition, meta-analyses of
the large number of women from published studies suggest a
moderate association between heterozygosity for the FV
Leiden mutation and prothrombin G20210A gene mutation
with spontaneous abortion and IUFD [6,7].
MTHFR is an enzyme responsible for the metabolism of
homocysteine. Presence of MTHFR T677T genotype predisposes
to the appearance of hyperhomocysteinemia, an independent
risk factor for atherosclerosis, peripheral and cardiovascular
disease, and stroke. Although there are reports suggesting an
association of MTHFR T677T genotype with spontaneous
abortion, IUGR, pre-eclampsia, and placental abruption
[2,8,9], recent meta-analyses have shown a relationship only
with severe pre-eclampsia . The data on MTHFR T677T
genotype should be interpreted with caution. Its phenotype is
modified by many acquired factors including availability of co-
Studies investigating the effect of plasma levels of homocys-
teine, folate and B12on gestational complications suggest an
association between hyperhomocysteinemia and pre-eclamp-
folate deficiency and spontaneous abortion [10–12]. As there
are no studies investigating the metabolic pathway of MTHFR
the development of gestational complications remains
In the present study, the association between sponta-
neous abortion, placental abruption, IUGR, IUFD, and pre-
eclampsia with the 3 major thrombophilic mutations was
investigated prospectively in a cohort of Greek women.
2. Materials and methods
The study included 392 consecutive women with spontaneous
pregnancies attending the Outpatient Clinic of the Obstetrics and
Gynecology Department of the University of Patras, Greece, from
women from southwestern Greece. Thestudy was approved by the
Ethical Committee of the Hospital and informed consent was ob-
tainedfrom each woman. Demographic data were collected at the
first appointment (6–8 weeks of gestation) and included informa-
tion on thrombophilic and obstetric history, current medication,
and family history. At the first appointment, all women were
started on supplements of folate (5 mg per day) and iron.
Exclusion criteria in the study were known risk factors for
gestational complications. These included known inherited
thrombophilic factors (FV Leiden, prothrombin G20210A, and
S, and antithrombin III deficiencies. In addition, women with
hypertension, renal disease, diabetes mellitus, thalassemia
intermediate and thalassemia major were also excluded.
The women were investigated for the 3 most common
thrombophilic mutations (FV Leiden, prothrombin G20210A, and
standard protocol. Adverse outcomes included all fetal losses
(spontaneous abortion and IUFD), as well as placental abruption,
IUGR and pre-eclampsia, and all gestational complications with
increased perinatal mortality and morbidity rates, in which
fetomaternal circulatory disturbances were implicated.
Placental abruption was defined as the separation of the
placenta from its site of implantation before the delivery of the
fetus  and was documented by ultrasound in all cases.
Ultrasound was performed routinely on all women, once in the
second and once in the third trimester. Additional ultrasounds
were performed on women with vaginal bleeding and/or
abdominal pain. IUGR was defined as a birth weight below the
5th percentile for gestational age . Pre-eclampsia was
defined as blood pressure above 140/90 mm Hg after 20 weeks
of gestation, proteinuria of 300 mg/24 h or a persistent level of
30 mg/dL (1+ dipstick) in random urine samples. The term
“severe pre-eclampsia” is defined as blood pressure above 160/
110 mm Hg recorded at least 6 h apart, and proteinuria greater
than 5 g in a 24-hour urine collection . IUFD was defined as
without gestational complications (n=392)
Demographics of the study participants with and
Variables Women with
Number of pregnancies
Complications in previous pregnanciesb
Yes 33 (34.4)
Personal thrombotic history
No 95 (99)
Family thrombotic history
No 93 (96.9)
No 61 (63.5)
Yes 35 (36.5)
No 90 (93.7)
32 (33.3)124 (41.9) NS
Values are given as number (percentage).
bGestational complications included spontaneous abortion, in-
trauterine fetal death, placental abruption, intrauterine growth
restriction, and pre-eclampsia.
125 Inheritance and perinatal consequences of inherited thrombophilia in Greece
fetal loss after 24 weeks of gestation. No fetal malformations
were detected during pregnancy or immediately after birth.
Blood samples were collected in EDTA from all women on
their first visit to the Outpatient Clinic. Molecular diagnosis of
the FV Leiden mutation, prothrombin gene mutation, and MTHFR
gene mutation was performed after DNA isolation, polymerase
chain reaction (PCR) amplification, and hybridization of ampli-
ficationproducts using allele specific oligonucleotide probes, for
the detection of FV G506A, prothrombin G20210A, and MTHFR
C677T normal and mutated alleles (thrombophilia gene mutation
assay kit; Vienna Lab, Vienna, Austria).
Measurements of serum folic acid and B12concentrates were
performed routinely in all women at their first appointment.
Plasma homocysteine levels are not routinely measured in
pregnant women in Greece and, therefore, could not be con-
sidered in this study.
Comparisons between groups were performed using Pearson's
χ2test. Odds ratio (OR) and 95% confidence intervals (CI) were
calculated. Statistical analysis was performed with SPSS version
12 (SPSS Inc, Chicago, IL, USA). The significance level was set at
Among the 392 women included in the study, 96 (24.5%)
recorded a gestational complication at follow-up of the
current pregnancy. The demographics of women with and
without gestational complications are shown in Table 1.
Personal and family history of thromboembolic disease did
not differ between women with complications and those
without. As expected, significantly more women with
gestational complications were over 35 years of age. All
women included in the study had normal serum folate and B12
levels (data not shown).
studied (21.2%). Among them, 13 women (3.3%) were
heterozygous for Factor V G506A mutation (FV Leiden
genotype), 12 (3%) were heterozygous for the prothrombin
G20210A gene mutation (FII G20210A genotype), and 52
(MTHFRT677Tgenotype).Six women had combineddefects: 4
(1%) were heterozygous for FV Leiden and homozygous for
MTHFR C677T gene mutation (FV Leiden (+/−) / MTHFR
T677T), and 2 women (0.5%) were heterozygous for FII
G20210A and homozygous for MTHFR C677T gene mutation
(FII G20210A (+/−) / MTHFR T677T). Homozygosity for the FV
Leiden and prothrombin G20210A mutation was not detected.
When women with and without gestational complications
during the current pregnancy were analyzed separately, the
prevalence of each thrombophilic genotype did not differ
significantly between the 2 groups (Table 2).
A total of 96 women developed complications, but none
fulfilled the criteria for severe pre-eclampsia. The incidence
Table 2 Prevalence of thrombophilic genotypes in women with and without gestational complications
Thrombophilic genotypeWomen with
(95% confidence interval)
FV Leiden (+/−)
FII G20210A (+/−)
FV Leiden (+/−)/MTHFR T677T
FII G20210A(+/−)/MTHFR T677T
Abbreviations: (+/−) = heterozygocity; NS, not significant.
Table 3 Prevalence of thrombophilic genotypes in women with specific gestational complications (n=96)a
12 weeks (n=44)
12 weeks (n=7)
n (%)OR (95% CI) n (%)OR (95% CI) n (%) OR (95% CI)n (%)n (%)OR (95% CI) n (%) OR (95% CI)
0– 3 (20)9.1
2 (4.5) 1.6
6 (40) 4.8
Abbreviations: OR, odds ratio; CI, confidence interval; IUFD, intrauterine fetal death; IUGR, intrauterine growth restriction.
aThe odds ratios and confidence intervals represent the prevalence of abnormal genes in women with a specific complication
compared with women without complications.
bTwo women had a combined FV Leiden (+/−)/MTHFR T677T genotype.
126M. Karakantza et al.
ofall abnormal genotypes in women with placental abruption
was 46.7%, a statistically significant difference compared
with women without complications (Pb0.05). The presence
of an abnormal genotype increased the risk for placental
abruption 6.45 times (95% CI 2.2–18.65) compared with a
normal genotype. The presence of the FV Leiden genotype
increased the risk for placental abruption 9.1 times (95% CI
2.2–37), while the presence of MTHFR T677T genotype
increased the risk 4.8 times (95% CI 1.6–14) compared with a
normal genotype (Table 3). Although the number of women
with combined defects was small (6 in total) they were also
analyzed separately. The presence of FV Leiden (+/−) /
MTHFR T677T genotype significantly increased the risk for
placental abruption compared with a normal genotype (OR
20.6; 95% CI, 2.69–158).
Six women had more than one complication recorded at
follow-up of the current pregnancy. Four women with
placental abruption developed a secondary complication: 1
had a spontaneous abortion a few weeks later, 1 experienced
IUGR, 1 had IUFD, and 1 developed pre-eclampsia. Two
women had IUGR and pre-eclampsia. Five of these women
had normal thrombophilic genotypes.
Fifty-two women developed gestational diabetes during
pregnancy, and 6 of those developed gestational complica-
tions: 1 IUGR, 2 pre-eclampsia, and 3 spontaneous abortion.
Two of these 6 women, and 8 of the 46 women without
gestational complications, had thrombophilic genotypes;
this difference was not statistically significant.
None of the women included in the study developed
thromboembolic complication during pregnancy. Of the
women included in the study, 236 had at least one previous
pregnancy and 110 of them had a previous history of
gestational complications (46.6%). This incidence is high for
unselected women observed in an outpatient clinic. How-
ever, women with previous adverse gestational outcomes
may have self-selected to attend the Outpatient Clinic of the
University Hospital of Patras, therefore creating a potential
selection bias in the study population.
A total of 77 women with a history of gestational
complications in previous pregnancies did not have compli-
cations during the study pregnancy, while 33 women with a
history of previous complications developed a gestational
complication during the study pregnancy. The prevalence of
all thrombophilic genotypes in the 33 women with previous
and current pregnancy complications was 36.4%, an inci-
dence significantly higher than those with no complications
in the current pregnancy and a negative history of previous
obstetric complications (Table 4). In women with previous
and current pregnancy complications, the incidence of
MTHFR T677T genotype was close to statistical significance
(P=0.058) compared with women with no complications in
previous pregnancies and the current pregnancy.
All women with FV Leiden, prothrombin G20210A, and
homozygous MTHFR C677T mutations and previous pregnancy
complications were started on prophylactic anticoagulation
with low molecular weight heparin (LMWH) at a dose of 4000
anti-Xa units once a day, throughout pregnancy.
This study reports the association of the 3 most common
genetic thrombophilic factors (FV Leiden, prothrombin
G20210A gene mutation, and homozygosity for MTHFR C677T
gene mutation) with pregnancy complications in 392 women.
The incidence of heterozygosity for FV Leiden (4.3%) was
similar to that reported for southern Europe, but lower than
for central and northern European countries [16,17].
Previous studies have reported that FV Leiden heterozyg-
osity in Europeans is 8.8%, whereas outside Europe the
mutation is very rare . Heterozygosity for prothrombin
G20210A (3.5%) was similar to that reported for Southern
Europe [16,18]. The carrier frequency in southern and
northern Europe is approximately 3.0% and 1.5% respec-
tively, but the prothrombin mutation is very rare in people
of Asian or African descent . The MTHFR C677T allele
frequency, according to the Hardy–Weinberg equilibrium,
has been estimated as 39.5%, while its frequency varies
from 2.0% to 54.5% in different ethnic groups . The
incidence of the MTHFR T677T genotype (14.8%) is higher
than previously reported for Greece .
In the present study, FV Leiden as well as MTHFR T677T
genotypes significantly increased the risk for placental
abruption. Placental abruption is a devastating obstetric
complication resulting in high fetal mortality and maternal
morbidity. Although few studies have investigated placental
abruption as a separate complication, the results suggest an
association with inherited thrombophilia, indicating that
placental vasculopathy represents a significant pathogenetic
mechanism for its development. In the present study,
heterozygocity for FV Leiden mutation increased the risk
for placental abruption 9.1 times, an increase similar to that
reported by others and confirmed in 2 recent meta-analyses
of published studies [3,4,6].
The MTHFR T677T genotype increased the risk for
placental abruption 4.8 times. This increase was noted
despite the fact that all women were given routine folic acid
supplements and had normal serum folate and B12levels.
Although measurements of homocysteine were not included
in the study, the 5 mg dose of folate administered daily to all
women in the study is the recommended treatment for
hyperhomocysteinemia . The biological effect of the
gestational complications in previous pregnancies and
current adverse outcomes compared to other groupsa
Impact of thrombophilia in women with history of
MTHFR T677T 12 (15.6)
4 (5.2) 2 (2.1)2 (6.4)4 (12.1)
5 (6.5) 5 (5.2) 0 (0)1 (3)
Abbreviations: history +, history of previous gestational compli-
cations; history−, no previous gestational complications; cur-
rent +, current pregnancy complications; current−, no current
aValues are given as number (percentage).
bPb0.05 by χ2test.
127 Inheritance and perinatal consequences of inherited thrombophilia in Greece
MTHFR T677T genotype depends on the availability of
vitamins folate, B12and B6. Previous studies have not found
a significant association between MTHFRT677T genotype and
the appearance of placental abruption . In the studies
included in the meta-analysis however, data on plasma
homocysteine levels, serum folate and B12levels had not
been analyzed. Although some studies have shown that
elevated homocysteine level is a risk factor for placental
abruption, a recent meta-analysis failed to find a correlation
[3,10,20]. Similarly, a meta-analysis of studies on folate and
B12deficient pregnant women failed to demonstrate a clear
association with placental abruption .The findings of this
study are important as they show that despite normal serum
folate and supplements sufficient to treat hyperhomocystei-
nemia, the genetic defect retained its potential for adverse
clinical outcome, suggesting that other policies should be
considered to deal with this metabolic abnormality. A more
thorough work-up of affected pregnant women, including
repeat measurements of plasma homocysteine levels, may
be needed to optimally adjust the dose of supplements.
However, even in the presence of normal serum folate and
B12concentrations, there is a possibility that the stores of
those vitamins in the placenta are inadequate, resulting in
local hypercysteinemia and placental microvascular disease
In the present study, the prothrombin G20210A gene
mutation was not associated with placental abruption.
Recent meta-analyses of studies in populations with similar
incidence of prothrombin G20210A gene mutation demon-
strated a strong association between the mutation and the
development of placental abruption. This discrepancy
could be due to the small number of women with placental
abruption included in each study analyzed, resulting in
incidental over-or under-representation of certain muta-
tions in the study populations. Data from a larger sample of
women with placental abruption are needed for conclusive
In the present study, other complications of placental
vasculopathy were not found to be increased in women with
inherited thrombophilic factors, specifically spontaneous
abortion after 12 weeks of gestation, pre-eclampsia, IUGR,
and IUFD. It is likely that the size of the study population
was inadequate to identify differences in factors with mild
or minor impact on these complications. Larger studies are
needed to demonstrate an effect for complications in which
vasculopathy does not contribute significantly to pathogen-
esis, or for factors with little impact on the development of
placental vasculopathy. This is particularly obvious in the
literature regarding the effect of FV Leiden and prothrom-
bin G20210A mutation on spontaneous abortion, mild forms
of pre-eclampsia, and IUFD. Although the results of
individual studies are conflicting [4,23–25], meta-analysis
of thousands of women clearly demonstrates a mild effect
of both mutations on the development of these complica-
The association of inherited thrombophilia with IUGR
remains controversial due to heterogeneity of published
studies with respect to ethnic differences and varied
inclusion criteria in the study populations [4,5,23].
The present study did not aim to investigate the
correlation of previous obstetric complications with current
pregnancy outcomes. Pregnant women with adverse out-
comes in previous pregnancies and documented presence of
inherited thrombophilic factors were started on prophylactic
anticoagulation with LMWH during the current pregnancy.
However, despite anticoagulation, these women had a
significantly increased risk for developing gestational com-
plications. When inherited thrombophilic factors were
analyzed separately in women with a history of gestational
complications, only the MTHFR T677T genotype was found to
increase the risk for developing a complication in the current
pregnancy. These findings are difficult to interpret because
the number of women with previous obstetric complications
and presence of inherited thrombophilic factors was small
(33) and because the administration of LMWH confounded
the results. Prophylactic anticoagulation might have
improved the outcome of women with FV Leiden and
prothrombin G20210A mutations, while not affecting the
outcome of those with MTHFR T677T genotype. Folate
administration at a dose of 5 mg daily was not adequate to
prevent reported complications. We conclude that the
currently recommended folate supplements may not always
be adequate in preventing hyperhomocysteinemia and direct
plasma measurements of homocysteine may be needed to
optimally adjust supplement dosage.
In conclusion, the results from the present study strongly
support the role of inherited thrombophilic factors in the
development of placental abruption. Homozygocity for
MTHFR C667T mutation was strongly associated with pla-
cental abruption, despite normal levels of serum folate and
administration of folate supplements adequate for treat-
ment of hyperhomocysteinemia. Women with history of
placental abruption should have a work-up including screen-
ing for inherited and acquired thrombophilic factors and
measurement of plasma homocysteine. Women with inher-
ited thrombophilia and a history of gestational complications
are at increased risk for developing complications in
subsequent pregnancies. Randomized clinical studies are
needed in order to identify the subgroup of women with
inherited thrombophilia likely to benefit from prophylactic
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