European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 199–205
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European Journal of Obstetrics & Gynecology and
Reproductive Biology
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Associations between phenotypes of preeclampsia and thrombophilia
a, a a b
Durk Berks *, Johannes J. Duvekot , Hillal Basalan , Moniek P.M. De MAAT ,
a a
Eric A.P. Steegers , Willy Visser
a
Department of Obstetrics and Gynecology, Division of Obstetrics and Prenatal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands
b
Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
A R T I C L E I N F O A B S T R A C T
Article history: Objectives: Preeclampsia complicates 2–8% of all pregnancies. Studies on the association of preeclampsia
Received 29 July 2015
with thrombophilia are conflicting. Clinical heterogeneity of the disease may be one of the explanations.
Received in revised form 4 September 2015
The present study addresses the question whether different phenotypes of preeclampsia are
Accepted 17 September 2015
associated with thrombophilia factors.
Study design We planned a retrospective cohort study. From 1985 until 2010 women with
Keywords:
preeclampsia were offered postpartum screening for the following thrombophilia factors: anti-
Fetal growth restriction
phospholipid antibodies, APC-resistance, protein C deficiency and protein S deficiency, hyperhomo-
HELLP syndrome
cysteineamia, factor V Leiden and Prothrombin gene mutation. Hospital records were used to obtain
Pre-eclampsia
information on phenotypes of the preeclampsia and placental histology.
Retrospective study
Thrombophilia Results: We identified 844 women with singleton pregnancies who were screened for thrombophilia
factors. HELLP complicated 49% of pregnancies; Fetal growth restriction complicated 61% of pregnancies.
Early delivery (<34th week) occurred in 71% of pregnancies. Any thrombophilia factor was present in
29% of the women. Severe preeclampsia was associated with protein S deficiency (p = 0.01). Fetal growth
restriction was associated with anti-phospholipid antibodies (p < 0.01). Early onset preeclampsia was
associated with anti-phospholipid antibodies (p = 0.01). Extensive placental infarction (>10%)
was associated with anti-phospholipid antibodies (p < 0.01). Low placental weight (<5th percentile)
was associated with hyperhomocysteineamia (p = 0.03). No other associations were observed.
Conclusions: Early onset preeclampsia, especially if complicated by fetal growth restriction, are
associated with anti-phospholipid antibodies. Other phenotypes of preeclampsia, especially HELLP
syndrome, were not associated with thrombophilia. We advise only to test for anti-phospholipid
antibodies after early onset preeclampsia, especially if complicated by fetal growth restriction. We
suggest enough evidence is presented to justify no further studies are needed.
ß 2015 Elsevier Ireland Ltd. All rights reserved.
Introduction seems to be associated with preeclampsia in cohort studies.
However, these results cannot be reproduced in larger prospective
Preeclampsia complicates 2–8% of all pregnancies [1]. The cause studies [1].
of preeclampsia has not yet been elucidated and is most probably An explanation of these conflicting results might be that
heterogenic [1]. One possible cause is a maternal pro-thrombo- preeclampsia is a heterogenic disease with different phenotypes.
genic state, leading to mal-adaptation of the spiral arteries in early Not only can preeclampsia be classified as mild or severe, it may
pregnancy and placental thrombosis and infarction in mid- and also be complicated by hemolysis, elevated liver enzymes or low
late pregnancy [1]. A pro-thrombogenic state can be caused by platelets (HELLP-syndrome) and/or intrauterine growth restriction
inherited or acquired thrombophilia [2–4]. Maternal thrombophilia (IUGR) and/or early onset preeclampsia. Histological examination
of placentas of pregnancies complicated by preeclampsia may
show extensive infarction, but also no abnormal findings at all
[5]. Some authors suggest that early preeclampsia has another
* Corresponding author at: Department of Obstetrics and Gynecology, Division of
pathophysiological basis than late preeclampsia [6]. It might be
Obstetric and Prenatal Medicine, Erasmus MC, Dr. Molewaterplein 50, 3015 GE
that these different phenotypes of preeclampsia are differently
Rotterdam, The Netherlands. Tel.: +31 10 7036686; fax: +31 10 7036815.
E-mail address: [email protected] (D. Berks). associated with thrombophilia. If this is true, future research
http://dx.doi.org/10.1016/j.ejogrb.2015.09.021
0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
200 D. Berks et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 199–205
should be focused on the pathophysiology, prediction and Patients with an abnormal test result, except for factor V Leiden,
ultimately prevention of preeclampsia in combination with these Prothrombin gene mutation, and serum homocysteine concentra-
thrombophilia factors. tions were retested at least six weeks after the initial test. Only if
This retrospective cohort study addresses the question which the same abnormality was confirmed a patient was considered
phenotypes of preeclampsia are associated with thrombophilia. positive for this coagulation abnormality. If a patient with an initial
abnormal test result was not retested, the presence or absence of
Material and methods this coagulation abnormality was reported as missing.
The percentage of placental infarction was estimated by
From 1985 until 2010 all patients with a singleton pregnancy combining macroscopy and microscopy of the placenta. Placental
who were admitted for mild or severe preeclampsia to the weight was measured without umbilical cord and membranes. The
department of obstetrics of the Erasmus Medical Centre, University percentile was calculated according to a previous study [7].
Medical Centre Rotterdam, were offered to be postpartum The thrombophilia factors were tested for associations. If more
screened for thrombophilia factors. Preeclampsia was diagnosed than one thrombophilia measurements were missing, the category
according to the definition of the International Society for the ‘one or more thrombophilia’ was also marked as missing. The
Study of Hypertension (ISSHP). Severe preeclampsia was diag- phenotypes of preeclampsia tested for associations were: HELLP
nosed if one or more of the following criteria were present: a syndrome, IUGR, early (<34 weeks) or late onset (34 weeks),
blood pressure of 160 mmHg systolic or higher or 110 mmHg minimal (<10%) versus extensive (10%) placental infarction and
diastolic or higher; proteinuria of 5 gram or more in a 24-h urine normal (>5th centile) versus low (5th centile) placental weight.
specimen or dipstick urinalysis of 3+ or greater in two random Furthermore we did a factor analysis with a fixed 2-axis model.
urine samples collected at least 4 h apart; cerebral or visual For this we defined 4 different subgroups with the 2 most
disturbances; elevated liver enzymes; thrombocytopenia; fetal important phenotypes of preeclampsia: IUGR and HELLP. The 4
growth restriction. HELLP was defined as a combination of subgroups were defined as IUGRÀ/HELLPÀ, IUGR+/HELLPÀ,
9
platelet count <100 Â 10 /L, serum aspartate aminotransferase IUGRÀ/HELLP+, IUGR+/HELLP+. For the above mentioned
(ASAT) 30 U/L and serum alanine aminotransferase (ALAT) 11 thrombophilia factors we used the continuous data for the
30 U/L (2 SD above the mean in our hospital). Intrauterine analysis. If more than one sample was available, we used the result
growth restriction (IUGR) was defined as a birth weight below that was least abnormal.
the 10th centile. Associations of thrombophilia factors with the different
At least six weeks postpartum, patients were tested for: anti- phenotypes of preeclampsia and the factor analysis were done
cardiolipin antibodies, lupus anticoagulans, APC-ratio, levels of with the statistical software package IBM SPSS Statistics Version 20
2
protein C and S, homocysteine and heterozygosity for factor V (IBM Corporation, 2011) using X -tests with continuity correction.
Leiden and Prothrombin gene mutation. None of the patients were Missing values were excluded for the analysis. A two-sided p-value
using vitamin supplements during the period of testing. of less than 0.05 was considered statistical significant.
The reference values for the coagulation assays were ascer-
tained in a population of at least 40 normal male volunteers. Anti- Results
cardiolipin antibodies were determined by enzyme-linked immu-
noassay (ELISA) according to the directives of Harris (normal A total of 844 women were tested for thrombophilia. The
values IgG and IgM <31 units GPL and <12 units MPL, respective- general characteristics of these patients are summarized in Table 1.
ly). The presence of lupus anticoagulant was determined with the Placental histology was available for 545 women.
diluted Prothrombin time (Recombiplastin, Instrumentation Lab- Table 2 shows the preeclampsia phenotypes and the preva-
oratories, Italy, normal ratio < 1.20) and the activated partial lence of the thrombophilia. Overall 29% of the women had one or
thromboplastin time assay (Platelin, Organon Teknika, USA, more abnormal thrombophilia results. Severe preeclampsia was
normal value < 40 s). Effect of factor deficiency was eliminated significantly associated with a higher presence of one or more
by mixing 1:1 patient and normal pool plasma. Protein S (normal thrombophilia result (p = 0.01) and with more prevalent protein-S
range 0.70–1.40 U/ml) was determined as protein S activity by a deficiency (p = 0.01) compared to mild preeclampsia. IUGR was
clotting assay (Diagnostica Stago, France) and as free protein S by significantly associated with a higher presence of one or more
an ELISA (Biopool, USA). Protein S deficiency is defined as an thrombophilia factors (p < 0.01) and more prevalent anti-
outcome of <0.70 (IU/ml) for two assays at least 6 weeks apart phospholipid antibodies (p < 0.01) compared to normal grown
without use of oral contraceptives. Protein C (normal range 0.70–
1.40 U/ml) deficiency was determined by measuring protein C
Table 1
activity (IL Testkit ProclotTM Proclot, Instrumentation Laboratory,
General characteristics (N = 844); values are presented as % of the study population
Italy) and protein C antigen by a house-made ELISA with the use of
(n) or as median (range).
rabbit antihuman anti-protein C (Dako Cytomation, Denmark).
Maternal age at conception (years) 29 (17–43)
Protein C deficiency is defined as an outcome of <0.70 (IU/ml) for
Nulliparous 74% (627)
two assays at least 6 weeks apart. Gestational age at delivery (weeks) 31 (27–40)
Serum homocysteine concentrations were measured both after Gestational age at onset of 29 (15–40)
preeclampsia (weeks)
(an overnight) fasting and 6 h after an oral loading dose of
Severe preeclampsia 91% (768)
L-methionine (0.1 g/kg body weight). During the test the patients
HELLP syndrome 49% (413)
were given a standardized methionine-poor breakfast and lunch. Intra uterine growth restriction 61% (512)
EDTA-blood samples were kept on ice and plasma was separated Eclampsia 3% (28)
Placental abruption 4% (30)
within 1 h for determination of homocysteine. Plasma total
Birth weight (grams) 1090 (275–3720)
homocysteine was determined using HPLC with fluorescence
Birth weight percentile 3.1 (0–100)
detection. The patients were considered to have hyperhomocys-
Fetal death 14% (116)
teineamia if the fasting homocysteine concentration exceeded Information on placental histology 65% (545)
15 mmol/L and/or the post-load value exceeded 45 mmol/L. Placental weight (grams) 235 (45–700)
Placental weight percentile 6.5 (0–100)
Factor V Leiden and Prothrombin gene mutation were deter-
Placental infarction (%) 5 (0–90)
mined by polymerase chain reaction.
D. Berks et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 199–205 201
fetuses. Early onset preeclampsia (gestational age <34 weeks at
delivery) was significantly associated with a higher presence of
one or more thrombophilia factors (p < 0.01) and more prevalent
p5 anti-phospholipid antibodies (p = 0.01) compared to late pre-
eclampsia (gestational age 34weeks at delivery). Increased
placental infarction (10% of total volume) was significantly
associated with more prevalent anti-phospholipid antibodies
(p < 0.01) compared to normal placental infarction (<10% of total p5 /237 (3.8%) 8/193 (4.1%)
>
volume). A low placental weight (5th percentile) was signifi-
%) 12/237 (5.1%) 13/194 (6.7%) 2%) 16/221 (7.2%) 10/185 (5.4%) cantly associated with more prevalent hyperhomocysteineamia
8%) 14/185 (7.6%) 9/159 (5.7%)
(p = 0.03) compared to normal placental weight (>5th percentile).
HELLP was not associated with any thrombophilia. The following
10%
1/118 (0.8%) 1/230 (0.4%) 1/188 (0.5%) thrombophilia factors were not associated with any phenotype of
preeclampsia: Protein-C deficiency, APC-resistance, factor V
Leiden mutation and Prothrombin gene mutation.
Table 3 shows adjusted odds-ratios for thrombophilia factors if
51 (34.2%) 48/116 (41.4%) 82/217 (37.8%) 61/180 (33.9%)
only HELLP or only IUGR is present. After adjusting for gestational 10%
<
age at onset of preeclampsia, correlations with IUGR disappear for
protein-S deficiency.
.3%) 55/336 (16.4%) 19/113 (16.8%) 42/209 (20.1%) 24/176 (13.6%)
The factor analysis with fixed 2-axis model performed poorly,
only explaining 34% of the variance in the results of thrombophilia
34 weeks factors. < 101/323 (31.3%) 66/200 (33.0%) 20/78 (25.6%) 28/111 (25.2%) 46/117 (39.3%)
Discussion
Thrombophilia was more present if the preeclampsia was 34 weeks
severe, combined with IUGR, a delivery before the 34th week of
gestation, placental infarction was more than 10% or placental
weight was lower than the 5th centile. To our knowledge this
is the largest cohort-study so far, testing for the association
between different phenotypes of preeclampsia and thrombo- 0.05).
< philia.
p
Previous studies show wide ranges in the prevalence of
thrombophilia factors as shown in Table 4. This is probably caused
by differences in known confounders [8] like laboratory methods,
chosen cut-off points to define abnormal results, definition of the
presence of thrombophilia factors (one or two positive tests),
timing of the testing and heterogeneity of the cases race,
gestational age at delivery and preeclampsia severity.
If preeclampsia was severe, we found a higher prevalence of
protein-S deficiency. Associations disappeared when testing for
the other phenotypes of preeclampsia. Two previous studies also
found a significant association between severe preeclampsia
compared to normal controls [9,10].
If preeclampsia was accompanied with IUGR, we found a higher
prevalence of anti-phospholipid antibodies. Yasuda et al. [11]
found similar results in 22 women with IUGR without preeclamp-
sia, while another study did not find this association in 25 women
[12]. Other studies did not perform a comparative analysis [13] or
were unable to do so because of a 94% incidence of IUGR in their
cohort [14].
In early preeclampsia we found a higher prevalence of anti-
phospholipid antibodies. Another study did not show a difference
Mild Severe Absent Present Absent Present in anti-phospholipid antibodies in women with preeclampsia that
delivered before and after the 28th gestational week [15].
In case of increased placental infarction >10% we found a higher
prevalence of anti-phospholipid antibodies. No previous study
tested this association.
239/740 (32.3%) 12/68 (17.6%) 227/672 (33.8%) 108/369 (29.3%) 131/371 (35.3%) 74/295 (25.1%) 163/443 (36.8%) 49/208 (23.6%) 190/532 (35.7%) 120/3 38/807 (4.7%)25/806 1/75 (3.1%) (1.3%) 2/75 37/732 (2.7%) (5.1%) 23/731 20/410 (3.1%) (4.9%) 9/409 18/397 (2.2%) (4.5%) 16/397 11/322 (3.4%) (4.0%) 27/482 9/321 (5.6%) (2.8%) 6/237 16/482 (2.5%) (3.3%) 32/570 4/237 (5.6%) (1.7%) 21/380 21/569 (5.5%) (3.7%) 10/122 13/380 (8.2 (3.4%) 6/121 (5.0%) 9 45/640 (7.0%) 6/56 (10.7%) 39/584 (6.7%) 20/321 (6.2%) 25/319 (7.8%) 15/246 (6.1%) 28/392 (7.1%) 12/182 (6.6%) 33/458 (7.2%) 22/301 (7.3%) 6/103 (5.
59/759 (7.8%) 3/72 (4.2%) 56/687 (8.2%) 27/391 (6.9%) 32/368 (8.7%) 15/294 (5.1%) 44/463 (9.5%) 8/220 (3.6%) 51/539 (9.5%) 22/353 (6.2%)In 16/121case (13. of a low placental weight 5th percentile we found a
higher prevalence of hyperhomocysteineamia. Only one previous
study found an association between elevated homocysteine levels
and placental vasculopathy [16]. One study showed an increased
placental weight when folic acid supplementation was started
preconceptionally [17]. Since folic acid lowers homocysteine
factor (heterozygous) gene mutation (heterozygous) (FVL excluded) antibodies
1 thrombophilia levels, these and our results suggest that elevated homocysteine
Factor Overall Preeclampsia severity HELLP syndrome IUGR Gestational age Placental infarction Placental weight percentile Hyperhomocysteineamia 125/424Factor V Leiden (29.5.8%) 6/30Prothrombin (20.0%) 119/394 (30.2%) 51/193 (26.4%) 74/231 (32.0%) 37/141 (26.2%) 88/283 (31.1%) 24/101 (23.8%) APC Resistance Anti-phospholipid Protein-C deficiencyProtein-S deficiency 6/778 99/720 (0.8%) (13.8%) 0/72 2/66 (0.0%) (3.0%) 6/706 97/654 (14.8%) (0.8%) 43/354 2/395 (12.1%) 56/366 (0.5%) (15.3%) 4/383 32/292 (11.0%) (1.0%) 67/425 3/311 (15.8%) (1.0%) 20/204 (9.8%) 3/464 79/516 (0.6%) (15 2/229 (0.9%) 4/549 (0.7%) 3/368 (0.8%)
Table 2 Prevalence of thrombophilia factors (figures presented as % (total tested in subgroup), greyed numbers represent levels could impair placental growth capability.
202 D. Berks et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 199–205
Table 3
Odds-ratios for phenotypes of preeclampsia, grey cells flag p < 0.05.
Factor Model 1 Model 2 Model 3
IUGR without HELLP (cases = 241, controls = 190)
One or more thrombophilia factor 2.02 (1.26–3.22) 1.87 (1.16–3.01) 1.79 (1.05–3.05)
Anti-phospholipid antibodies 1.6 (0.7–3.67) 1.43 (0.61–3.32) 0.99 (0.39–2.53)
Protein-C deficiency 0.85 (0.05–13.61) 0.98 (0.06–16.26) 2.93 (0.15–58)
Protein-S deficiency 2.21 (1.11–4.39) 2.01 (1–4.04) 1.87 (0.86–4.03)
APC Resistance (FVL excluded) 1.9 (0.71–5.07) 2.02 (0.74–5.53) 2.37 (0.8–7.01)
Hyperhomocysteineamia 1.38 (0.71–2.68) 1.46 (0.74–2.86) 1.62 (0.75–3.49)
Factor V Leiden (heterozygous) 1.58 (0.62–4.03) 1.45 (0.56–3.77) 1.16 (0.41–3.31)
Prothrombin gene mutation (heterozygous) 0.65 (0.17–2.47) 0.53 (0.13–2.13) 0.42 (0.09–1.92)
HELLP without IUGR (cases = 138, controls = 190)
One or more thrombophilia factor 1.54 (0.91–2.61) 1.41 (0.82–2.41) 1.39 (0.8–2.41)
Anti-phospholipid antibodies 0.92 (0.32–2.66) 0.98 (0.33–2.88) 0.82 (0.27–2.44)
Protein-C deficiency 2.81 (0.25–31.35) 2.43 (0.22–27.35) 2.22 (0.18–27.15)
Protein-S deficiency 2.06 (0.97–4.34) 1.81 (0.85–3.87) 1.97 (0.89–4.33)
APC Resistance (FVL excluded) 2.11 (0.73–6.12) 1.89 (0.64–5.55) 1.81 (0.61–5.41)
Hyperhomocysteineamia 1.5 (0.7–3.18) 1.58 (0.73–3.4) 1.68 (0.77–3.67)
Factor V Leiden (heterozygous) 0.77 (0.22–2.7) 0.68 (0.19–2.41) 0.51 (0.14–1.85)
Prothrombin gene mutation (heterozygous) 1.09 (0.29–4.14) 1.01 (0.26–3.89) 0.98 (0.25–3.87)
HELLP and IUGR (cases = 271, controls = 190)
One or more thrombophilia factor 2.21 (1.41–3.47) 2.05 (1.29–3.26) 2 (1.15–3.45)
Anti-phospholipid antibodies 2.16 (0.98–4.73) 2.1 (0.95–4.67) 1.15 (0.46–2.88)
Protein-C deficiency 1.45 (0.13–16.13) 1.4 (0.12–15.99) 3.11 (0.11–91.97)
Protein-S deficiency 2.17 (1.12–4.23) 1.67 (0.84–3.34) 1.92 (0.85–4.35)
APC Resistance (FVL excluded) 1.59 (0.6–4.24) 1.76 (0.64–4.83) 2.81 (0.89–8.89)
Hyperhomocysteineamia 1.63 (0.88–3.03) 1.79 (0.95–3.36) 1.9 (0.91–3.97)
Factor V Leiden (heterozygous) 1.47 (0.58–3.71) 1.41 (0.55–3.65) 0.84 (0.28–2.5)
Prothrombin gene mutation (heterozygous) 1.76 (0.61–5.07) 1.63 (0.55–4.79) 1.51 (0.43–5.25)
Controls: no IUGR and no HELLP.
Model 1: crude estimates.
Model 2: adjusted for maternal age at conception and nulliparous.
Model 3: model 2 + adjusted for gestational age at onset of preeclampsia.
We found no association between HELLP and any kind of This study has several limitations. Firstly, bias in patient
thrombophilia, unlike other studies [5,10,18]. The factor analysis inclusion before 2006 could not be excluded. Until 2006 mainly
did not show any association in the continuous results also. severe cases of preeclampsia were being screened for thrombo-
Our study found no association between any of the philia. Since 2006 screening for thrombophilia is offered to all
preeclampsia phenotypes and factor V Leiden. Previous cohort women with preeclampsia. Secondly, placental infarction was not
and case-control studies showed conflicting results on the scored using a standardized protocol, lowering the power of the
association between the occurrence of preeclampsia and factor findings with regard to placental infarction. Thirdly, the tests of
V Leiden [10,12,18–28]. However, reported prevalence range association we performed were numerous, causing multiple-
widely from 2% to 28%. Ethnicity may explain some of this testing. Forth, abnormality of some factors of thrombophilia had a
variance, next to small study groups and bias due to study design. low prevalence in this population (protein-C), leading to a probable
In larger studies [15,29] as well as in prospective cohort studies power-problem. On the other hand, the low prevalence indicates a
(systematically review by Rodger et al. [30]) prevalence ranged low clinical value, sustaining our conclusion.
from 3 to 7%, showing no association with preeclampsia and are The most important strength of this study is the high number
in line with our findings. This leaves factor V Leiden only a of cases, which enabled comparisons between preeclampsia
possible associated factor in Ashkenazi-Jews, but not in phenotypes.
Caucasians. Overall, preeclampsia is associated with anti-phospholipid
We found no associations with Prothrombin gene mutations. antibodies in case of early onset preeclampsia and in association
Previous cohort and case-control studies showed conflicting with placental insufficiency (placental infarction and IUGR), but
results [10,18–21,24,25,27,31]. However, a systematic reviews of not with HELLP syndrome. We hypothesize that this is due to the
only prospective cohort studies [30], showed no associations. fact that this thrombophilic factor does not act through systemic
We found no associations with protein-C deficiency and (non- coagulation pathways, but at the placental side. Ernst et al. report
factor V Leiden) APC-resistance. Although the incidence in our on the pathophysiologic mechanisms of anti-phospholipid syn-
population was very low, it confirms the findings in other studies drome [36]. The primary hypothesis is that anti phospholipid
[12,18,20,26,32,33]. antibodies cause placental thrombosis, leading to placental
Whether IUGR should be a defining condition of preeclampsia is infarction. The associations we found between anti phospholipid
still under debate. In its revised classification of hypertensive antibodies and placental infarctions, impaired fetal growth and
disorders in pregnancy, the ACOG removed IUGR as defining deliveries before the 34th gestational week confirm this hypothe-
condition of preeclampsia [34], whilst meanwhile the ISSHP added sis, since the one phenotype is very likely to result from the other.
IUGR as defining condition of preeclampsia [35]. Adjusting the One acting mechanism might be through Beta-2GP1 molecule,
analysis in Table 2, column ‘preeclampsia severity’ for the presence present on the surface of trophoblastic cell membranes. It appears
or absence of IUGR, which is more in line with the new definition of to inhibit thrombosis by reducing the conversion of Prothrombin
the ACOG, significance was lost for ‘1 thrombophilia factor’, to thrombin on platelets and inhibiting the activation of the
whilst the other outcomes remained the same (results not shown). intrinsic coagulation cascade [36]. Beta-2GP1 antibodies block the Table 4 Overview of studies on preeclampsia and thrombophilia (C: cohort study, C-C: Case-control study, PC: prospective cohort study, SR: systematic review, SPE: severe preeclampsia, MPE: mild preeclampsia, PlacPath: placental pathology, ACA: anti-cardiolipin antibodies, LAC: lupus anti-coagulans, PCD: protein-C deficiency, PSD: protein-S deficiency, rAPC: APC-resistance, HHC: hyperhomocysteineamia, MLT: methionine loading test, FVL: factor V Leiden, PGM: Prothrombine gene mutation).
Study Study-type Comparisons n (PE) All AFS PCD PSD rAPC HHC FVL PGM Country (Ethnicity) Special remarks
ACA LAC Æ,++ Æ,++ Current C ÆSPE, ÆIUGR, ÆHELLP, 890 32.9% 9.0% 1.9% 0.7% 13.5% 7.1% 28.9% 5.0% 2.9% Netherlands 91% severe PE, ÆPlacPath, Æ34w 2 Â positive = positive 1995, Dekker et al. [9] C ÆSPE Netherlands 100% severe, FVL not
yet known D.
2001, Many et al. [38] C ÆSPE, ÆIUGR, 101 28.4% 0.0% 1.2% 24.7% 16% 17.7% Israel Placental parameters Berks ÆPlacPath
2002, Sikkema et al. [5] C-C ÆPlacPath 25 48.0% Netherlands SPE and/or IUGR et
<34w, al.
/
1 Â positive = positive European 2005, Mello et al. [10] C-C ÆSPE, ÆMPE 47 68% 4% 7% 13% 9% 57% 21% Italy, 100% Caucasian 100% mild PE 2006, Van Rijn et al. [39] CPEÆ HELLP, 402 16.7% 3.2% 3.2% 4.0% Netherlands 100% early onset PE, 1 Â positive = positive
PE Æ IUGR, Æ28w Only total Journal thrombophilia
factors compared of
2008, Muetze et al. [27] C ÆHELLP 120 24% 0.8% 2.5% 1.7% 3% 17% 11% Germany 100% HELLP Obstetrics 2009, Facchinetti et al. [40] C ÆSPE 68 16.9% 4.2% Italy, 100% Caucasian 60% severe PE, 2 Â positive = positive Only total
thrombophilia &
factors compared Gynecology 2009, Kahn et al. [19] C-C ÆPE 60 46.7% 35% 20% 11.7% 28.3% 20% Montreal, Canada ?% severe PE 2010, Sep et al. [18] CPEÆ HELLP 113 5.4% 14.3% 2.7% Netherlands 100% HELLP 2010, Sep et al. [18] CPEÆ HELLP 75 8% 3% 0% 4% 2.0% 3% Netherlands 100% PE without HELLP
and Robertson 2006 [41] SR ÆPE, ÆIUGR 481 8.9% 9.1% 2.9% 5.0% 32.1% 11.3% 7.2%% 3.5% 481 –
1995, Yasuda et al. [11] PC PEÆ S, ÆIUGR 22 31.2% Japan 36% severe PE Reproductive 1998, Nagy et al. [28] C-C ÆSPE 69 18.8% Hungary, 100% Cauc 100% severe PE 1999, Kupferminc et al. [25] C-C ÆSPE, ÆIUGR 34 26.5% 5.9% Israel, 44% Ashkenazi 100% severe PE 1999, Mello et al. [26] C-C ÆPE 46 2.2% 2.2% 2.2% 4.3% 26.1% 26.1%% Italy, 100% Caucasian 1999, O’Shaughnessy et al. [29] C ÆPE 283 5.3% UK
1999, Van Pampus et al. [15] C-C ÆSPE, Æ28w 345 11.3% 12.1% 6.0% Netherlands 100% severe, Biology 1 Â positive = positive
2000a, Kupferminc et al. [31] C-C ÆSPE, ÆMPE, ÆIUGR 80 8.8% Israel, 96% Ashkenazi Severe PE (n = 55); 194 PGM 9.1%
Mild PE (n = 25): (2015) PGM = 8.0% ÆSPE 63 66.7% 3.2% 0.0% 7.9% 23.8% 7.9% Israel, 25% Ashkenazi 100% Severe PE 2000b, Kupferminc et al. [20] C-C 2001, Alfirevic et al. [12] C-C ÆSPE, ÆIUGR 63 14.3% 9.5% 15.9% 28.6% 1.6% UK, 88% Caucasian 100% Severe PE 199–205 2001, Dreyfus et al. [32] C-C ÆPE 180 3.9% 0.6% France 35% Severe PE 2002, Agorastos et al. [21] C-C ÆPE, ÆIUGR 16 18.8% 0.0% Greece 2002, Benedetto et al. [22] C-C ÆPE, PE Æ HELLP, 111 7.2% 7.2% Italy PE + HELLP (n = 32): PE Æ IUGR FVL 15.6%, PGM 6.4% PE + IUGR (n = 31): FVL 9.6%, PGM 3.2% 2002, Currie et al. [23] C-C ÆSPE 48 8.3% Australia 100% Severe PE 2002, D’Elia et al. [24] C-C ÆPE 58 5.2% 1.7% Italy
Rodger 2010 [30] SR ÆPE, ÆIUGR 1060 5.1% 4.0% 2000, Murphy et al. [42] PC ÆPE, ÆIUGR 12 0.0% Ireland 2004, Salomon et al. [43] PC ÆPE, ÆIUGR 29 34.5% Israel (only LAC, FVL, PGM) 203
204 D. Berks et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 199–205
Beta-2GP1 molecule, so it can no longer inhibit thrombosis.
Another acting mechanism might be the disruption of annexin V,
that normally binds to the phospholipid molecules on the surface
of the trophoblastic membrane, preventing thrombosis by forming
a protective protein coat.
In 2012 the FRUIT-study [37], a randomized controlled trial
studying the effect of low-molecular weight heparin on recurrence
risk of preeclampsia in women with thrombophilia, suggests that if
inheritable thrombophilia like protein-S deficiency are present,
administration of aspirin and low molecular weight heparin during
a next pregnancy may decrease the recurrence risk. Studies
measuring the effect of low-molecular weight heparin on the
recurrence risk of preeclampsia in thrombophilic women with
acquired thrombophilia like anti-phospholipid syndrome are
10% African Amer, 19% Hisp 34% African Amer, 33% Hisp
currently being conducted.
In conclusion, phenotyping of preeclampsia can help to 4.7% US, 31% Cauc,
,++
determine if screening for thrombophilia is warranted. We advise
Æ
to screen for anti-phospholipid antibodies after early onset
preeclampsia, especially if complicated by IUGR. We do not
0.0% 0.0% Greece 3.7% US,7.0% 69% Cauc, 2.1% Australia 4.7% Scotland
recommend routine screening for thrombophilia and screening ,++
Æ
after other phenotypes of preeclampsia. We suggest that enough
evidence is presented to conclude that associations between
preeclampsia and thrombophilia are not clinically important and
further studies should not be conducted.
Authors’ contribution
D. Berks designed the study, collected, analyzed and inter-
preted the data and wrote the manuscript. J.J. Duvekot
interpreted the data and critically reviewed the manuscript. H.
Basalan designed the study, partially collected the data and
partially wrote the manuscript. M.P.M. de Maat designed the
study an critically reviewed the manuscript. E.A.P. Steegers
critically reviewed the manuscript. W. Visser designed the study,
collected and interpreted the data and critically reviewed the
manuscript. All authors reviewed and approved the final version
of the manuscript.
ACA LAC
Conflict of interest
The authors report no conflict of interest. 8 3466 5.9% Sweden (PE) All AFS PCD PSD rAPC HHC FVL PGM Country (Ethnicity) Special remarks 134 243 129
n Acknowledgements
We are very thankful to M. Ahmadi and S. Petronia in carefully
33w
checking and re-checking the data. Æ
IUGR IUGR, IUGR IUGR IUGR IUGR References Æ Æ Æ Æ Æ Æ
PE, PE, PE, PE, PE, PE,
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