Med Clin (Barc).

2019;152(7):249–254

www.elsevier.es/medicinaclinica

Original article

Inherited thrombophilia and pregnancy loss. Study of an Argentinian

cohort夽
Silvia Perés Wingeyer a,∗ , Federico Aranda a , Sebastián Udry b , José Latino b , Gabriela de Larrañaga a
a
Laboratorio de Hemostasia y Trombosis, Hospital de Infecciosas “Dr. Francisco Javier Muñiz”, Buenos Aires, Argentina
b
Sección de Enfermedades Autoinmunes, Trombofilia y Embarazo, Hospital General de Agudos “Dr. Carlos G. Durand”, Buenos Aires, Argentina

a r t i c l e i n f o a b s t r a c t

Article history: Background and objectives: Thrombophilia might increase the risk of suffering from obstetric complica-
Received 29 September 2017 tions by adversely affecting the normal placental vascular function. Our aim was to study the distributions
Accepted 28 December 2017 of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, −675 4G/5G PAI-
Available online 14 February 2019
1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein
C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to ana-
Keywords: lyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric
Inherited thrombophilia
pathologies.
Recurrent pregnancy loss
Foetal growth retardation
Patients and methods: We performed a case–control study that included 247 patients with idiopathic
Factor V Leiden RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were
Fibrinogen gamma stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses,
Factor XI n = 107) and according to the type of vascular obstetric pathologies.
Results: No differences were found in the distribution of the genetic variants among RPL group vs.
control/reference group (p > .05). Similarly, no differences were observed in their distributions when
analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p > .05),
except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34
vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24–40.93], p = .03).
Conclusions: Factor V Leiden might have a significant impact on certain obstetric pathologies such as foetal
growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated
with thromboembolic disease, would not have an impact on PRE.
© 2018 Elsevier España, S.L.U. All rights reserved.

Trombofilia hereditaria y pérdidas de embarazo. Estudio de una cohorte de

Argentina

r e s u m e n

Palabras clave: Antecedentes y objetivo: La trombofilia aumentaría el riesgo de complicaciones obstétricas al afectar la
Trombofilia hereditaria función vascular normal a nivel placentario. Nuestro objetivo fue estudiar las distribuciones genotípi-
Pérdidas recurrentes de embarazo cas de cinco variantes genéticas asociadas a trombosis: factor V Leiden, protrombina G20210A, −675
Retraso del crecimiento fetal
4G/5G PAI-1, 10034C/T fibrinógeno gamma y 7872C/T factor XI y las frecuencias de los déficits de pro-
Factor V de Leiden
teína C/S/antitrombina en pacientes argentinas con pérdida recurrente de embarazo (PRE) y, así, analizar
Fibrinógeno gamma
Factor XI su asociación con PRE, el tiempo gestacional de las pérdidas y el riesgo a sufrir otras complicaciones
obstétricas de origen vascular.

夽 Please cite this article as: Perés Wingeyer S, Aranda F, Udry S, Latino J, de Larrañaga G. Trombofilia hereditaria y pérdidas de embarazo. Estudio de una cohorte de
Argentina. Med Clin (Barc). 2019;152:249–254.
∗ Corresponding author.
E-mail address: sdaperes@yahoo.com.ar (S. Perés Wingeyer).

2387-0206/© 2018 Elsevier España, S.L.U. All rights reserved.

250 S. Perés Wingeyer, F. Aranda, S. Udry, et al. / Med Clin (Barc). 2019;152(7):249–254

Pacientes y métodos: Se realizó un estudio de casos y controles, incluyendo 247 pacientes con PRE (casos),
107 mujeres fértiles (controles) y 224 individuos de población general (grupo de referencia). Los casos
fueron estratificados de acuerdo con el tiempo gestacional de las pérdidas (PRE temprana, n = 89; pérdidas
tardías, n = 158; pérdidas fetales, n = 107) y según el tipo de complicación obstétrica.
Resultados: No se encontraron diferencias significativas (p > 0,05) en la distribuciones genotípicas de
las variantes analizadas entre el grupo PRE comparados con controles/grupo referencia, respectiva-
mente. Tampoco según tiempo gestacional de la pérdida o las complicaciones obstétricas, excepto para
la portación factor V Leiden en pacientes con retraso del crecimiento fetal vs. controles (el 11,8%, 4/34 vs.
el 1,9%, 2/107 p = 0,04) (OR = 7,11 [1,24-40,93], p = 0,03).
Conclusiones: El factor V Leiden cumpliría un rol importante en ciertas patologías obstétricas como retraso
del crecimiento fetal, donde la impronta trombótica parecería tener un papel importante. Las variantes
genéticas 10034C/T fibrinógeno gamma y 7872C/T factor XI, con impacto reconocido en enfermedad
tromboembólica, no estarían asociadas a PRE.
© 2018 Elsevier España, S.L.U. Todos los derechos reservados.

Introduction while the genetic variants factor V Leiden (FVL) and prothrom-
bin G20210A (II20210A) stand out among those of the second.
A third postulated mechanism corresponds to the inhibition of
Among women of reproductive age, 1–3% of them suffer an
the fibrinolytic system, as would be the case of polymorphism
obstetric pathology called recurrent pregnancy loss (RPL). RPL is
−675 4G/5G of the plasminogen activator inhibitor type 1 (−675
defined as the consecutive loss of two or more clinical pregnancies.1
4G/5G PAI-1), although its role as a classic isolated thrombophilia is
Among these losses, approximately only half have known aetiology
controversial.14 On the other hand, there are two other genetic vari-
while the rest are considered idiopathic. The main causes, whose
ants, related to the coagulation system, that have been associated
association with RPL have been clearly established, include uter-
with deep vein thrombosis but whose impact on pregnancy losses
ine malformations, chromosomal defects, infections, autoimmune
has not yet been studied: the variants gamma fibrinogen 10034C/T
diseases, haematological diseases and endocrinopathies such as
(FGG10034T) and 7872 C/T from the factor XI gene (FXI7872C).15,16
thyroid disease and diabetes.2
On the basis of all the above, our objective was to study the
The haemostatic system relevantly intervenes in the reproduc-
frequencies of the deficiencies and/or dysfunctions of PC, AT and
tive process. During normal pregnancy, a state of physiological
PS and the genotypic distributions of genetic variants associated
hypercoagulability occurs, as there is an increase in the levels
with thrombosis (FVL, II20210A, −675 4G/5G PAI-1, FGG10034T
of coagulation factors and a decrease in those of the coagulation
and FXI7872C) in a group of Argentine women, who have experi-
cascade inhibitors, among other changes. A successful pregnancy
enced RPL, without apparent cause, and compare them with those
depends, among other factors, on the balance of all the mechanisms
corresponding to a strictly selected control group of post-fertile
involved in haemostasis in order to ensure adequate placental
women and with those of a second reference group from the gen-
circulation.3 Consequently, it has been postulated that throm-
eral Argentine population, respectively. Similarly, our secondary
bophilia – defined as a hereditary or acquired abnormality of
objective is to analyse the possible association between carrying
haemostasis that results in an increased risk of thrombosis – would
these genetic variants and the gestational time of the losses and
increase the risk of obstetric complications by affecting normal vas-
an increased risk of suffering other obstetric complications such as
cular functioning of the placenta. In addition, thrombophilia could
foetal growth retardation, PA and PE.
also affect the growth and differentiation of the trophoblast.4,5
An alteration of the foetus–maternal circulation would produce
placental insufficiency, which is associated with loss of pregnancy
Patients and methods
(unprovoked spontaneous abortion or foetal death) or obstetric
complications of vascular origin such as preeclampsia (PE), foetal
A descriptive and cross-sectional study of cases and controls was
growth retardation and placental abruption (PA), among others.6
carried out. The protocol was approved by the participating hospi-
Antiphospholipid syndrome, considered an acquired throm-
tals’ Research and Teaching Ethics Committee and carried out in
bophilia, is the most common cause of PRE and obstetric
accordance with the 1975 Declaration of Helsinki ethical standards
complications of vascular origin.7 It has also been suggested
and current national regulations. In all cases, each participant’s
that hereditary thrombophilia is another possible cause of these
informed consent was obtained before they were included in the
pathologies, however there is no concurrence in the literature
study.
regarding its causal role in PRE. Numerous studies have been carried
A total of 578 subjects participated: 247 women with a history of
out to determine whether there is an association between the pres-
pregnancy loss (patient-cases), 107 women from a strictly selected
ence of hereditary thrombophilia, either maternal and paternal,
control group (control group) and 224 subjects from the general
and an increased risk of pregnancy loss and other obstetric com-
population (reference group).
plications, but the results obtained have been contradictory.8–12
All 247 participants were patients of the Dr. Carlos G. Durand
Some of these studies showed that certain risk factors would be
General Hospital high-risk pregnancy clinic and were selected
more strongly associated with pregnancy losses at certain gesta-
from a more extensive cohort of 1185 patients treated at that
tional times, mainly according to losses occurring before or after
clinic during June 2010 and March 2016. The patients excluded
the tenth week of gestation. This could explain, at least in part, the
from the study included: those with known causes for their preg-
discrepancies between the studies mentioned.13
nancy losses, anatomical and endocrinological alterations (diabetes
Hereditary thrombophilia is essentially caused by two differ-
mellitus, hypothyroidism, hyperthyroidism, polycystic ovarian
ent mechanisms: the loss of natural anticoagulant function or the
syndrome, hyperprolactinemia), chromosomal alterations identi-
gain of procoagulant factor function. Deficiencies or dysfunctions
fied in parenteral karyotypes; those with other clinical pathologies
of antithrombin (AT), protein C (PC) or protein S (PS) are the most
such as liver, renal, cardiovascular and neurological diseases; those
common alterations among those following the first mechanism,
whose data were incomplete and those who refused to give their
 S. Perés Wingeyer, F. Aranda, S. Udry, et al. / Med Clin (Barc). 2019;152(7):249–254 251

informed consent. Pregnancies were confirmed by ultrasound and Table 1

Clinical characteristics of patients with pregnancy loss.
a positive foetal heartbeat. Considering that the tenth week of
gestation would mark the end of the embryonic period and the Clinical characteristics (n = 247)
beginning of the foetal period, the patients were stratified accord- Age (years) 32 (26–37)
Body mass index (kg/m2 ) 23.9 (21.8–27.2)
ing to the gestational time of the losses: (a) early RPL, defined as the
Number of losses 3 (2–4)
consecutive and inexplicable loss of at least two confirmed preg- Early losses (n) 89
nancies within the first 10 weeks and (b) late losses, defined as the Late losses (n) 158
loss of at least one pregnancy occurring at 10 or more weeks.17 Dead foetus 107
A subgroup of patients who suffered foetal losses was also ana- Vascular complications (n)
lysed, defining foetus deaths as those that were miscarried at 20 Foetal growth retardation 34
or more weeks, when the gestational age was known, and when Placental abruption 16
Preeclampsia 17
it was not, foetuses that weighed greater than 350 g, which corre-
sponds to the 50th percentile of weight at 20 weeks’ gestation.1 Results are expressed in medians and interquartile ranges or percentages as appro-
priate.
Patients were also classified according to the following obstetric
complications of vascular origin: PE, PA and/or foetal growth retar-
dation. PE was defined as the presence of hypertension (systolic Roche Diagnostics, GmbH, Mannheim, Germany). Genotyping
blood pressure > 140 mmHg or diastolic pressure ≥90 mmHg) and of the FVL and II20210A variants was performed through the
proteinuria 24 h ≥ 0.3 g.18 PA was defined as bleeding associated real-time PCR technique using the factor V Leiden Kit and
with partial or total separation of the placenta from its normal factor II (Prothrombin) G20210A Kit (LightCycler 2.0 – Roche
insertion site, the uterine fundus, from the 20th week of gesta- Diagnostics) diagnostic kits, while the genotyping of the vari-
tion until before the birth of the foetus.1 Delayed foetal growth ants FGG10034T, FXI7872T and −675 4G/5G PAI-1 were carried
was defined as the presence of a foetus with more than 20 weeks out by PCR-RFLP techniques designed and tuned up in our
of gestation with growth measurements below the 3rd percentile, laboratory.
or below the 10th percentile and Doppler alterations (ultrasound
diagnosis).19
Data analysis
Obstetric antiphospholipid syndrome was diagnosed according
to the international classification criteria established by the Sydney
The statistical analysis was performed using the statistical pro-
Consensus 2006.20 ®
gram SPSS version 21.0 for Windows (IBM SPSS Statistics 21, USA).
We also studied a strictly selected control group of 107 women
The genotypic distributions of each variant in the case, control and
with a history of at least two normal pregnancies, currently in
general population groups were described as percentages. In order
menopause or in post-menopause, whose children were born
to evaluate the association of the genetic variants and the different
healthy and within normal weight, and without any history of
clinical variables studied, a contingency table was constructed to
obstetric complications; and a general population reference group
test the hypothesis of association through a  test.2 The odds ratios
of 224 subjects, not selected, in order to estimate the genotypic
and their corresponding 95% confidence intervals were estimated
frequencies of the genetic variants.
by binary logistic regression. A value of p < 0.05 was considered
All the subjects who participated in the study, whether as
statistically significant.
patients or in the control and reference groups, were Argentines of
Argentine descent, of similar ethnic, geographical and social origins
and were representative of the urban population of Buenos Aires, Results
Argentina. This population is the result of genetic mixing processes
that involved mainly Europeans, mostly Spaniards and Italians, and Table 1 shows the clinical characteristics of the group of patients
Native Americans.21 with pregnancy loss studied. We can see that 51 patients (20.1%)
After fasting for eight hours, a blood sample was taken from had antiphospholipid syndrome.
all patients by venous puncture in plastic tubes with: (a) 3.2% When studying hereditary thrombophilias, in the group of
sodium citrate (ratio 9:1) and (b) EDTA. From the sodium citrate women with RPL, PC deficit was found in 0.4% (1/247), AT deficit in
samples, we obtained plasma by centrifugation at 3500 g for 0.8% (2/247) and free PS deficit in 0.4% (1/247).
15 min, from which aliquots were obtained and stored at −40 ◦ C Table 2 shows the genotypic distributions of all the genetic vari-
until analysis; the aliquots we used were thawed only once in a ants studied in the group of patients with RPL, compared with
water bath at 37 ◦ C before use. The blood collected in tubes with the frequencies obtained in the control group and in the reference
EDTA was stored at −40 ◦ C for later use in the molecular biology group of the general population, respectively. No significant differ-
techniques. ences (p > 0.05) were found in the genotypic distributions of any
They were quantified by chromogenic method using a Destiny of the variants analysed between these groups. The heterozygous
Max coagulometer (Tcoag, Ireland): PC (Stachrom PC, Stago, France) A/G genotype of II20210A was more frequent in patients with RPL
and AT (AT Xa – Chromogenix, Mölndal, Sweden); and, by immuno- than in the control group (5.3 vs. 0.9%), however this difference was
turbidimetric method, the functionally active form of PS: Free PS not significant (p = 0.10). Likewise, no significant differences were
(Liatest PSL, Stago, France). Those cases where patients had PC lev- observed in the distributions of the variants when considering the
els of less than 70%, AT of less than 80% and/or free PS of less than different models of allelic dominance. The genotypic frequencies
60%, were defined as a deficit of the corresponding natural antico- observed in the reference group for all the genetic variants studied
agulant. Given that the levels of free PS vary in pregnancy, in the were in Hardy–Weinberg equilibrium (p > 0.05).
patients who were pregnant, we considered the cut-off point to We subsequently analysed the possible association between
be the values suggested by Szecsi et al.22 adjusted to the week of having any of these genetic variants with the gestational time
gestation. PC and AT levels do not change during pregnancy. PC, the loss occurred. When comparing the groups of patients with
AT and free PS deficits were confirmed with a second independent early RPL (n = 89), late losses (n = 158) or dead foetus (n = 107)
sample. individually compared to the control group, no significant differ-
The extraction of human DNA was carried out by a semi- ences (p > 0.05) were found in the genotypic distributions of those
automated method (High Pure PCR Template Preparation Kit, genetic variants, even considering the different models of allelic
252 S. Perés Wingeyer, F. Aranda, S. Udry, et al. / Med Clin (Barc). 2019;152(7):249–254

Table 2
Genotypic distribution of genetic variants in recurrent pregnancy loss in relation to the control group and the general population reference group respectively.

Variables studied (%, n) Patients (n = 247) Control group (n = 107) p Patients (n = 247) Reference group (n = 224) p

FVL
96.8 (239) 98.1 (105) 0.72 96.8 (239) 96.9 (217) 0.94
3.2 (8) 1.9 (2) 3.2 (8) 3.1 (7)

II20210A
G/G 94.7 (234) 99.1 (106) 0.10 94.7 (234) 97.8 (219) 0.14
A/G 5.3 (13) 0.9 (1) 5.3 (13) 2.2 (5)

−675 4G/5G PAI-1

5G/5G 41.4 (99) 31.8 (34) 0.25 41.4 (99) 30.8 (69) 0.36
4G/5G 45.6 (109) 52.3 (57) 45.6 (109) 46.3 (104)
4G/4G 15.6 (39) 14.9 (16) 15.6 (39) 22.9 (51)

10034C/T FGG
C/C 66.2 (163) 65.4 (70) 0.99 66.2 (163) 68.2 (153) 0.83
C/T 31.4 (78) 32.7 (35) 31.4 (78) 30.0 (67)
T/T 2.4 (6) 1.9 (2) 2.4 (6) 1.8 (4)

7872C/T FXI
C/C 29.7 (73) 32.7 (35) 0.66 29.7 (73) 31.7 (71) 0.77
C/T 47.7 (118) 43.0 (46) 47.7 (118) 48.2 (108)
T/T 22.6 (56) 24.3 (26) 22.6 (56) 20.1 (45)

dominance. Finally, when considering clinical subgroups according However, we must also note that other studies have presented
to the obstetric complications suffered: foetal growth retardation results that contradict these associations.6,27 Furthermore, part of
(n = 34), PA (n = 16) or PE (n = 17) and comparing them with the these discrepancies could be due mainly to confounding factors
control group, no significant differences of these genetic distribu- such as differences in the ethnic origin of the populations studied
tions were observed except for patients carrying the heterozygous and the use of different definitions for foetal growth retardation,
genotype for FVL with a history of foetal growth retardation. 11.8% among other factors.
(4/34) of the patients with this complication were found to be het- In our opinion, the finding obtained in our study is relevant for
erozygous carriers of the FVL variant, while only 1.9% (2/107) of the two reasons: firstly, because the delay of foetal growth is an impor-
women in the control group were found to be carriers (p = 0.04). Of tant cause of perinatal morbidity and mortality that increases the
the four patients with foetal growth retardation who were carriers risk of cardiovascular disease, hypertension, type 2 diabetes and
of VLF, only one had another thrombophilia (AL) while among the other comorbidities in the adult life of the affected child28 and, sec-
other 30 patients with non-VLF foetal growth retardation, there was ondly, because it reinforces the hypothesis that certain hereditary
one heterozygous II20210A carrier and seven carriers of acquired thrombophilias should be studied in vascular obstetric complica-
thrombophilia. We performed a binary logistic regression analy- tions. This is a controversial issue that generates debates around
sis that included as independent variables the presence of FVL and the world: “who should we study and when?”. Updated recommen-
II20210A (heterozygous genotype) and it was found that having the dations from different scientific societies around the world agree
FVL allele turned out to be predictive of foetal growth retardation that hereditary thrombophilias should not be studied in pregnan-
(OR: 7.11 [1.24–40.93], p = 0.03). cies losses occurring before ten weeks, but there is no unanimity
regarding losses after the tenth week of gestation. While the Royal
Discussion College of Obstetricians and Gynecologists recommends conducting
FVL, II20210A and PS studies, both the American College of Chest
The results obtained in this study indicate that there is no asso- Physicians and the European Society of Human Reproduction and
ciation between being a carrier of any of the genetic variants FVL, Embryology recommend not carrying them out.29–31 In Argentina,
II20210A, −675 4G/5G PAI-1, FGG10034T and FXI7872C and an the latest consensus of the Argentine Federation of Gynecology and
increase in the risk of suffering RPL, either generally or in a stratified Obstetrics Societies recommends assessing each case on an indi-
manner according to the gestational time of the losses. As men- vidual basis and, if studies are to be carried out, analyses of PC,
tioned, the role of hereditary thrombophilia in pregnancy losses free PS, activated protein C/FVL resistance and II20210A should be
continues to be controversial worldwide and its causality is not requested.
clear. Earlier studies, mainly case–control studies and mostly retro- The variants FGG10034T and FXI7872C are two genetic poly-
spective, found a strong association between being a carrier of FVL, morphisms that were recently described as being associated with
II20210A and PS deficiency and late pregnancy losses9.12 although an increased risk of suffering deep vein thrombosis,15,16,32 prob-
in subsequent prospective cohort studies these associations were ably due to an increase in the capacity of thrombin generation,
not confirmed.6,23 The results obtained in our study concurs with so, theoretically, they could also be involved in obstetric compli-
the latter. Likewise, we have not found a clear, if any, association cations with a physiopathological basis of thrombotic origin. The
between a predisposition to suffering RPL and the deficit of PC or AT first national data of its distribution are presented in this study.
or PS, although our cohort’s sample size and the very low population As mentioned above, our results indicate that being a carrier of
prevalence is a limitation to the interpretation of the results.24 any of these two variants is not associated with the predisposition
Like other studies that have found that being a carrier of of suffering RPL, with gestational time of the losses or with other
FVL is associated with an increased risk of PE and foetal growth obstetric complications of vascular origin.
retardation,25,26 our results indicate that when the progenitor is Regarding highly prevalent genetic variants such as −675
heterozygous for FVL, it increases the chances of the foetus pre- 4G/5G PAI-1 and the thermolabile variant C667T of the enzyme
senting such a complication by almost seven. In any case, we must methylenetetrahydrofolate reductase - whose implication in RPL
recognise that the sample size of our patients with foetal growth has generated much debate around the world – we can today
retardation is a limiting factor when interpreting this result. confirm, based on many studies,33 that there is no evidence to
 S. Perés Wingeyer, F. Aranda, S. Udry, et al. / Med Clin (Barc). 2019;152(7):249–254 253

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