Thrombosis Research 128 (2011) 77–85

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Thrombosis Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s

Regular Article

The association between antiphospholipid antibodies and placenta mediated

complications: A systematic review and meta-analysis
Karim Abou-Nassar a, Marc Carrier a,b, Tim Ramsay b, Marc A. Rodger a,b,⁎
a
Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
b
Clinical Epidemiology Program, The Ottawa Health Research Institute, Ottawa, Ontario, Canada

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

Article history: Background: The association between antiphospholipid antibodies (APLA) and placenta mediated pregnancy
Received 6 October 2010 complications (pre-eclampsia, intrauterine growth restriction (IUGR), late fetal loss and placental abruption)
Received in revised form 21 January 2011 remains controversial.
Accepted 10 February 2011 Methods: We performed a systematic review of published case-control, cohort and cross sectional studies
Available online 21 March 2011
(MEDLINE (1975 to 2009), EMBASE 16 (1980 to 2009) and all EBM Reviews (2009)) to evaluate the
association between APLA and placenta mediated complications in untreated women without autoimmune
diseases.
Results: Our search strategy identified 1207 potentially relevant studies. Twenty eight were included in the
final analysis. LA was associated with pre-eclampsia (OR 2.34; 95%CI 1.18-4.64), IUGR (OR 4.65 95% CI 1.29-
16.71) and late fetal loss (OR 4.73; 95%CI 1.08-20.81) amongst case-control studies and only with late fetal
loss (OR 10.59 95% CI 1.87-59.88) amongst cohort studies. ACA were associated with pre-eclampsia (OR 1.52;
95%CI 1.05-2.20) and late fetal loss (OR 4.29; 95% CI 1.34-13.68) amongst case-control studies and only late
fetal loss (OR 8.85 95% CI 1.84-42.50) amongst cohort studies. Finally, anti-B2 GP1 antibodies showed
associations with pre-eclampsia (OR 19.14, 95% CI 6.34-57.77), IUGR (OR 20.03; 95%CI 4.59-87.43) and late
fetal loss (OR 23.46, 95% CI 1.21-455.01) in two cohort studies.
Conclusion: APLAs appear to be associated with late fetal losses. However, the association between APLAs and
other placenta mediated complications is inconsistent. LA is most strongly and consistently associated with
placenta mediated complications. There are currently insufficient data to support a significant link between
anti-B2 GP1 antibodies and pregnancy morbidity.
© 2011 Elsevier Ltd. All rights reserved.

Introduction and placenta mediated pregnancy complications such as late fetal

Antiphospholipid antibodies (APLA) are a group of auto-antibodies
that have the ability to bind to cardiolipin alone, to cardiolipin
complexed to a cofactor or to a cofactor alone. APLA are found in up to
5% of healthy subjects [1] in the general population and in 35% of
patients with SLE [2,3]. The prevalence of APLA in the low risk
obstetrical population ranges from 1-9% [4–8]. The concept of
antiphospholipid syndrome (APS) was first introduced when the
association between APLA and hypercoagulability became evident
[9,10]. In addition to an increased risk of vascular thrombosis in
women with APLA, some studies have suggested an association with
pregnancy complications including recurrent pregnancy losses (RPL)
⁎ Corresponding author at: Division of Hematology, Clinical Epidemiology Program,
Ottawa Hospital Research Institute, University of Ottawa, Ottawa Hospital, General
Campus, 501 Smyth Road, Room W6116, Eye Institute, Ottawa, ON, Canada K1H 8L6.
Tel.: +1 613 737 8899x74641; fax: +1 613 739 6102.
E-mail address: mrodger@ohri.ca (M.A. Rodger).
losses, pre-eclampsia, placental abruption and intrauterine growth
restriction (IUGR) [11].
The international preliminary classification criteria for APS
(Sapporo criteria) were first introduced in 1998 [12] and were
revised in 2005 [13]. The current definition requires at least one
clinical and one laboratory criterion to make a diagnosis of APS.
Clinical criteria include the presence of vascular thrombosis and/or
pregnancy complications. As described by the revised Sapporo
criteria, pregnancy morbidity includes ≥1 unexplained deaths of
morphologically normal fetus at ≥10 weeks gestation; ≥1 premature
birth of morphologically normal neonate before 34 weeks gestation
because of preeclampsia, eclampsia or features of placental insuffi-
ciency (non-reassuring fetal surveillance test, abnormal Doppler flow
velocimetry suggestive of fetal hypoxiemia, oligohydramnios, intra-
uterine growth restriction (IUGR)); ≥3 unexplained spontaneous
abortions at b10 weeks gestation not due to anatomic or hormonal
abnormalities in the mother or chromosomal abnormalities on
maternal or paternal side. Laboratory criteria require one of the
following detected in patient's serum or plasma on two separate

0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2011.02.006
78 K. Abou-Nassar et al. / Thrombosis Research 128 (2011) 77–85
occasions ≥ 12 weeks apart: 1) lupus anticoagulant (LA), 2) antic-
ardiolipin antibodies (ACA) of IgG and/or IgM isotype present in
medium/high levels (N40 GPL or MPL or N99th percentile) by
standardized ELISA or 3) anti-B2 glycoprotein 1 (anti-B2 GP1) IgG
and/or IgM antibodies in levels N 99th percentile by standardized
ELISA.
Most of the data supporting the association between APLA and
pregnancy complications are derived from small case-control studies
that have inherent limitations including retrospective outcome
determination and ascertainment of exposure (i.e. APLA) often well
after the outcome. The association between APLA and recurrent fetal
losses in women without autoimmune diseases was thoroughly
examined in a recent systematic review and meta-analysis of 25
studies. This association was strongest with LA and varied signifi-
cantly according to the type and levels of the APLA studied. [14].
We performed a systematic review and meta-analysis to study the
association between APLAs currently included in the Sapporo criteria
for the diagnosis of the APS and late placenta mediated pregnancy
complications (late fetal loss, pre-eclampsia, IUGR, placental abrup-
tion) in women without autoimmune diseases.
Methods
Data sources and searches
A systematic literature search strategy was initially conducted to
identify potentially eligible studies from MEDLINE (1950 to October
week 2 2007), EMBASE (1980 to 2007 week 42) and all EBM Reviews
(3rd quarter of 2007) using the OVID interface. The search was
subsequently updated to May 2009 using the same databases. The
systematic search strategy is outlined in Appendix Table 1 (on-line).
The search was restricted to English and French language articles.
References of included studies and reviews were also searched for
potential studies.
Study selection
Studies included in this systematic review consisted of observa-
tional studies that met all the following inclusion criteria: 1) One
documented positive test for either lupus anticoagulant, anti-beta2
glycoprotein 1 antibodies of IgG and/or IgM isotype, anticardiolipin
antibodies of IgG and/or IgM isotype; 2) One or more of late placenta
mediated pregnancy complications primary outcome measures
reported (late fetal loss, pre-eclampsia, IUGR, placental abruption);
3) Case-control study, prospective and retrospective cohort study and
cross sectional study design; 4) No thromboprophylaxis in pregnancy.
We excluded studies who met the following criteria: 1) Patients with
autoimmune diseases (SLE); 2) Patients undergoing assisted repro-
ductive treatments; 3) Patients receiving any form of anticoagulants
(ASA and/or unfractionated heparin (UFH) or low molecular weight
heparin (LMWH)); 4) randomized controlled trials, case reports and
case series.
Exposure
The exposure of interest consisted of the presence of APLA (LA,
ACA IgG/IgM, anti-B2 GP1 IgG/IgM). Presence of LA could be
confirmed by both activated partial thromboplastin time (APTT)-
based assays or dilute Russell's viper venom time (dRVVT) [13]. The
presence ACA and anti-B2 GP1 antibodies of IgG and /or IgM isotype
required testing by means of standard ELISA. Moderate to high levels
of ACA IgG/IgM antibodies were defined as N99th percentile or N40
GPL or MPL units [13,15]. After reviewing the literature, we were
unable to analyze the data for ACA and anti-B2 GP1 antibodies
according the cutoff levels recommended in the revised Sapporo
criteria (levels N 40 GPL/MPL units or N99th percentile) as determined
a priori. We therefore considered levels N 5 GPL/MPL units as positive
for the purpose of this analysis and performed sensitivity analysis for
levels N 20 GPL/MPL units. Although confirmatory repeat testing of
ACA and anti-B2 GP1 antibodies is required in the Sapporo criteria for
APS, most studies did not comply with this requirement but were
nonetheless included in this review.
Outcome measures
The primary outcome measure was the occurrence of one of the
following late placenta mediated pregnancy complications: 1) pre-
eclampsia; 2) placental abruption; 3) late pregnancy loss or 4) IUGR.
Pre-eclampsia was defined as proteinuric hypertension, specifically:
blood pressure ≥140/90 with proteinuria. Proteinuria was defined as
2+ on a dipstick or greater than 300 mg in a 24 hour urine collection.
Placental abruption was defined as antepartum bleeding with
objective evidence of placental thrombus. Objective evidence includ-
ed either antenatal ultrasound, inspection of the placenta at birth or
placental pathology report. Late pregnancy loss was defined as an
intrauterine death of a morphologically normal fetus at ≥ 10 weeks
gestation. Intrauterine growth restriction (IUGR) was defined as a
birth weight less than the 10th percentile of the population, matched
for sex and gestational age (GA) [16].
Data extraction and quality assessment
Two independent reviewers (KA and MC) applied the inclusion
criteria to the identified articles from the initial search strategy.
Articles for potential full review were discussed between the two
reviewers. Discrepancies were noted and the decision to include/
exclude the article(s) was adjudicated by a third party (MR).
Data abstraction and quality assessment was performed by 2
independent reviewers (KA and MC) for all eligible studies using a
standardized data abstraction form. Any discrepancies were docu-
mented and adjudicated by a third reviewer (MR). The methodolog-
ical quality of observational studies was evaluated by the validated
Newcastle-Ottawa scale [17].
Data synthesis and analysis
For eligible studies, the rates of primary outcome measures (pre-
eclampsia, placental abruption, late pregnancy loss and IUGR) were
compared between patients with and without specific APLA (LA, ACA
and anti-B2 GP1 antibodies). When possible, data extracted for ACA
and anti-B2 GP1 antibodies was further stratified by isotype (IgG and
IgM) and levels. Certain studies did not discriminate between ACA or
anti-B2 GP1 antibody isotyopes or levels. In these cases, ACA and anti-
B2 GP1 antibody positivity was defined as the presence of either IgG
and/or IgM in positive levels as defined by the authors. Individual and
pooled odds ratio (OR) with 95% confidence intervals (CI) were
calculated using a random-effects model. Individual trial estimates
and pooled estimates were performed with the Review Manager
software (Cochrane Collaboration's Information Management Sys-
tem). An OR of N1 suggests that more primary outcomes occur in the
presence of a particular APLA. Post-hoc power was calculated under
the assumption of a fixed-effects model. For the case-control studies, a
two-to-one control/case ratio was assumed. The latter assumption
gives a higher estimated post-hoc power than a one-to-one ratio. A
two-to-one ratio was higher than the average ratio observed among
the different case-control studies. Heterogeneity was assessed using
the Higgins I2 test. The I2 statistic can be interpreted as the proportion
of total variation across studies that is due to heterogeneity (0%–
100%) [18]. An I2 of b25% was considered as low-level heterogeneity,
25% to 50% was moderate level and higher than 50% was considered as
high level [18].
 K. Abou-Nassar et al. / Thrombosis Research 128 (2011) 77–85 79

Sensitivity analyses were performed to evaluate the effects of various
ACA levels on their associations with placenta mediated complications
using a cut off of 20 GPL/MPL units. Sensitivity analyses were also
performed for the timing of RFL losses. As such, studies were stratified
based on RFL occurring at N20 weeks vs. 10 weeks GA.
Results
Our search strategy identified 1794 citations (Fig. 1). Twenty-eight
studies were included in the final analysis (Table 1) [6,8,19–44].
Formal quality assessment using the NewCastle-Ottawa scale [17] was
performed on the included studies; results are reported in
Appendix Table 2 (on-line). Twenty studies were case-control studies
and 8 were cohort studies. Their results were analyzed separately.
There was significant variation in the reporting of ACA and anti-B2
GP1 IgG and IgM antibody levels. Most studies of ACA used GPL and
MPL units, however one used percentiles from the mean [34], one
used ACA index [25], one used ELISA units (EU) [27], one used
international units (IU) [23] and three used optical density (OD)
standard deviations (SD) from the mean [40,42,43]. Similarly, 2
studies reported values of anti-B2 GP1 antibodies as percentiles from
the mean [33,34] and one as OD SD [40] while the rest used GPL and
MPL units. With respect to the latter units, different cutoff values were
used to define ACA antibody positivity of the IgG or IgM isotypes
ranging from N6 GPL and N5 MPL to N20 GPL/MPL for ACA IgG and IgM
respectively. Similar variability was observed for anti-B2 GP1 IgG and
IgM antibodies (Table 1). Many of the included studies did not
differentiate between IgG and IgM isotypes of ACA or anti-B2 GP1
antibodies. Only two studies on ACA [20,44], two studies on LA [20,44]
and one study on anti-B2 GP1 antibodies [44] repeated the assays on
two separate occasions at least six weeks apart. The definition of late
fetal loss was heterogeneous ranging from N10 weeks to N24 weeks
gestation amongst different studies (Table 1).
Lupus anticoagulant
For ten case-control studies identified, associations were found
between LA and IUGR (OR 4.65, 95% CI 1.29-16.71), late fetal loss
(N10 weeks GA) (OR 4.73, 95% CI 1.08-20.81) as well as pre-eclampsia
(OR 2.34, 95% CI 1.18-4.64). When the analysis was restricted to three
cohort studies (n = 4657), the association with pre-eclampsia was not
detected (OR 5.17, 95% CI 0.60, 44.56) and exhibited a higher degree of
heterogeneity (I2 76.1%). However, the association between LA and
late fetal losses (N10 weeks gestation) remained (OR 10.59, 95% CI
1.87-59.88). Lastly, sensitivity analysis focused on late fetal losses
occurring after 20 weeks of gestation failed to reveal a stronger
association with LA for two case-control studies whereas results from
one cohort study revealed a stronger association (Table 2).

Total articles found 1794
MEDLINE 807
EMBASE 940
ALL EBM REVIEWS 44
Duplicates removed (n = 587)
Records Screened (n = 1207)
Irrelevant (n = 729)
Non eligible design (n = 197)
Inadequate control group (n = 75)
On treatment (n = 71)
Early fetal losses only (n = 34)
Autoimmune conditions (n = 28)
Other (n = 14)
Assisted reproduction (n = 7)
Article records screened for
eligibility (n = 52)
Insufficient outcome data (n = 13)
Insufficient comparator data (n = 6)
Other (n = 4)
Inadequate control group (n = 2)
Studies included in meta-
analysis up to 2007 (n = 27)
Anticardiolipin antibodies
Results derived from nineteen case-control studies showed a
statistically significant association for ACA IgG and/or IgM (N5 GPL/
MPL) and pre-eclampsia (OR 1.52, 95% CI 1.05-2.20) and late fetal loss
(N10 weeks GA) (OR 4.29, 95% CI 1.34, 13.68). A sensitivity analysis
restricted to studies using a cutoff value of N20 GPL/MPL units did not
strengthen these associations although this could not be performed
for all clinical outcomes due to insufficient data (Table 3). Similarly,
ACA did not reveal a stronger association with late fetal loss when the
analysis was restricted to losses occurring after 20 weeks GA.
Amongst seven cohort studies, an association was identified between
ACA IgG and/or IgM (N5GPL/MPL) and late fetal loss (N10 weeks GA)
(OR 8.85, 95% CI 1.84, 42.50). Furthermore biologic gradient with late
fetal loss (N 10 weeks GA) was observed in a sensitivity analysis using
ACA IgG in levels N 20 GPL based on 2 studies (n = 1997) (OR 14.57,
95% CI 2.26, 94.01). However, ACA did not exhibit a stronger
association when the analysis was restricted to fetal losses occurring
after 20 weeks GA. Furthermore, moderate to high heterogeneity was
observed in many of these analyses (Table 4).
Anti-B2 glycoprotein 1 antibodies
Results derived from two cohort studies (n = 1618) revealed
associations with pre-eclampsia (OR 19.14, 95% CI 6.34-57.77) and
late fetal loss (N10 weeks GA) (OR 23.46, 95% CI 1.21-455.01). One
cohort study (n = 1108) demonstrated an association with IUGR (OR
20.03, 95%CI 4.59-87.43). However, four smaller case-control studies
(n = 1150) failed to show similar associations (Table 5). There was
insufficient data to perform sensitivity analysis for antibody levels and
timing of fetal losses.

Additional studies identified Discussion

up to May 2009 (n=4) On treatment (n = 1)
To our knowledge, this is the most comprehensive systematic
Duplicate publication (n = 1) review and meta-analysis analysis examining the association between
Studies included in meta- APLA and placenta mediated complications. Our results indicate that
analysis (n=28) Insufficient data (n = 1)
most studies conducted to date have been considerably underpow-
ered to detect significant associations between APLA and placenta
Fig. 1. Study Flow Diagram. mediated pregnancy complications. Despite pooling data from
80 K. Abou-Nassar et al. / Thrombosis Research 128 (2011) 77–85

Table 1
Characteristics of included studies.

Study Study Design # / Definition of cases* # / Definition of controls* APLA (isotype and levels)* Outcomes measured*

Lupus Anticoagulant (LA)

Alfirevic, 2001 [19] Case-control 102 ♀ admitted with ≥ 1 of: 44 ♀ with uncomplicated LA Pre-eclampsia, Placental
pre-eclampsia, placental pregnancies abruption, IUGR, Stillbirth
abruption, IUGR, stillbirth (N 23 weeks GA)
(N 23 weeks GA)
Bocciolone, 1994 [20] Case-control 99 ♀ with late fetal loss 85 ♀ with uncomplicated LA × 2 6 weeks apart Late fetal loss
(≥20 weeks GA) pregnancies (≥ 20 weeks GA)
Deryfus, 2001 [21] Case-control 180 ♀ with pre-eclampsia 360 ♀ with uncomplicated LA Pre-eclampsia
pregnancies
Kaleli, 1998 [22] Case-control 36 ♀ with eclampsia 30 ♀ with uncomplicated LA Eclampsia
pregnancies
Mello, 1999 [23] Case-control 34 ♀ with late fetal loss 80 ♀ with uncomplicated LA Late fetal loss
(N 12 weeks GA) pregnancies (N 12 weeks GA),
46 ♀ with preeclampsia Pre-eclampsia
Milliez, 1991 [24] Case-control 50 ♀ with IUGR 100 ♀ with uncomplicated LA IUGR
pregnancies
Moodley, 1995 [25] Case-control 34 ♀ with preeclampsia 15 ♀ with uncomplicated LA Pre-eclampsia
pregnancies (antenatal)
Schjetlein, 1998 [28] Case-control 200 ♀ with pre-eclampsia 97 ♀ with uncomplicated LA Pre-eclampsia
pregnancies
Vahid, 2006 [29] Case-control 50 ♀ with pre-eclampsia 50 ♀ with uncomplicated LA Pre-eclampsia
pregnancies
Vora, 2008 [44] Case-control 268 ♀ with late fetal loss 100 ♀ with uncomplicated LA × 2 3 months apart Late fetal loss
pregnancies (≥ 12 weeks GA)
Pattison, 1993 [26] Prospective cohort 933 pregnant ♀ n/a LA Pre-eclampsia, Late fetal
loss (N 10 weeks GA)
Rix, 1992 [27] Prospective Cohort 2856 pregnant ♀ n/a LA Late fetal losses
(N 12 weeks GA),
IUGR, Pre-eclampsia
Wharfe, 1999 [30] Prospective cohort 868 pregnant ♀ n/a LA Pre-eclampsia, Stillbirth

Anticardiolipin Antibodies (ACA)

Allen, 1996 [31] Case-control 100 ♀ with pre-eclampsia 100 ♀ with normal pregnancies ACA IgG/IgM b 10 GPL/MPL Pre-eclampsia
in their 3 rd trimester negative;10–19 borderline;
20–80 positive; N 80 high
Alfirevic, 2001 [19] Case-control 102 ♀ admitted with ≥ 1 of: 44 ♀ with uncomplicated ACA IgG/IgM– levels cutoff Pre-eclampsia, Placental
pre-eclampsia, placental pregnancies not defined abruption, IUGR, Stillbirth
abruption, IUGR, stillbirth (N 23 weeks GA)
(N 23 weeks GA)
Bocciolone, 1994 [20] Case-control 99 ♀ with late fetal loss 85 ♀ with uncomplicated ACA IgG N 6 GPL positive Late fetal loss
(≥ 20 weeks GA) pregnancies ACA IgM N 5 MPL positive (≥ 20 weeks GA)
X2 6 weeks apart
Bowen, 2002 [32] Case-control 21 ♀ with pre-eclampsia and 29 healthy pregnant ♀ in ACA IgG b 19 GPL Pre-eclampsia and
6 ♀ with eclampsia in 3 rd 3 rd trimester neg; N20 positive; N 30 high eclampsia
trimester ACA IgM b 10 MPL
neg; 12–19 positive; ≥ 20 high
Deryfus, 2001 [21] Case-control 180 ♀ with pre-eclampsia 360 ♀ with uncomplicated ACA IgG/IgM– levels cutoff Pre-eclampsia
pregnancies not defined
Kaleli, 1998 [22] Case-control 36 ♀ with eclampsia 30 ♀ with uncomplicated ACA IgG/IgM b 10 GPL/MPL Eclampsia
pregnancies neg; N 100 high
Lee, 2003 [35] Case-control 300 ♀ with pre-eclampsia 100 ♀ with uncomplicated ACA IgG/IgM N 20 GPL/MPL Pre-eclampsia
pregnancies positive
Lee, 1999 [36] Case-control 58 ♀ with late fetal loss 152 healthy fertile ♀ with ≥ 2 ACA IgG/IgM N 20 GPL/MPL Late fetal loss
(N 10 weeks GA) successful pregnancies and ≤ 1 positive (N 10 weeks GA)
fetal loss
Matthiesen, 1999 [8] Case-control 1200 low risk pregnant ♀ 207 ♀ with normal pregnancy ACA IgG N 11 GPL Pre-eclampsia, IUGR,
outcomes taken from initial cohort positive; N 20 high IUFD, Placental abruption
age and parity matched
Mello, 1999 [23] Case-control 34 ♀ with late fetal loss 80 ♀ with uncomplicated ACA IgG / IgM N 20 UI positive Late fetal loss
(N 12 weeks GA), pregnancies (N 12 weeks GA),
46 ♀ with preeclampsia Pre-eclampsia
Moodley, 1995 [25] Case-control 34 ♀ with preeclampsia 15 ♀ with uncomplicated ACA index N 1.3 Pre-eclampsia
pregnancies (antenatal)
Schjetlein, 1998 [28] Case-control 200 ♀ with pre-eclampsia 97 ♀ with uncomplicated ACA IgG N 10 GPL Pre-eclampsia
pregnancies positive; N 80 GPL high
ACA IgM N 10 MPL
positive; N80 MPL high
Uncu, 1996 [39] Case-control 65 ♀ with preeclampsia 23 ♀ with uncomplicated ACA IgG N 8 GPL positive Pre-eclampsia
pregnancies ACA IgM N 6 MPL positive
Vahid, 2006 [29] Case-control 50 ♀ with pre-eclampsia 50 ♀ with uncomplicated ACA IgG / IgM - levels cutoffs Pre-eclampsia
pregnancies not defined
Valdes-Macho, Case-control 100 ♀ with pre-eclampsia 127 ♀ with uncomplicated ACA IgG / IgM OD N 90th Pre-eclampsia
2002 [40] pregnancies percentile positive
Van Pampus, Case-control 345 ♀ with severe 67 ♀ with uncomplicated ACA IgG / IgM ≥ 10 GPL / MPL Severe pre-eclampsia
1999 [41] pre-eclampsia pregnancies positive; ≥20 GPL / MPL high
 K. Abou-Nassar et al. / Thrombosis Research 128 (2011) 77–85 81

Table 1 (continued)
Study Study Design # / Definition of cases* # / Definition of controls* APLA (isotype and levels)* Outcomes measured*

Anticardiolipin Antibodies (ACA)

Vora, 2008 [44] Case-control 268 ♀ with late fetal loss 100 ♀ with uncomplicated ACA IgG/IgM no levels specified x Late fetal loss (≥12 weeks
pregnancies 2 at least 3 months apart GA)
Yamamoto, 1996 [42] Case-control 70 ♀ with pre-eclampsia 45 uncomplicated ACA IgG / IgM positive if OD N 3 SD Pre-eclampsia
pregnant ♀ (20–40 weeks
GA)
De Carolis, 1994 [43] Case-control 259 ♀ with either RSA 106 ♀ with uncomplicated ACA IgG / IgM OD N 5 SD positive Late fetal loss (N 20 weeks
(b 20 weeks GA), neonatal pregnancies GA)
death associated with IUGR,
pre-eclampsia, placental
abruption, late fetal loss
(N 20 weeks GA)
Faden, 1997 [33] Prospective cohort 510 healthy pregnant ♀ n/a ACA IgG N 10 GPL positive; N 80 Pre-eclampsia, IUGR,
between 15–18 weeks GA high Placental abruption, IUFD
ACA IgM N 10 MPL positive; N 60
high
Katano, 1996 [34] Prospective cohort 1125 Japanese pregnant ♀ n/a ACA IgG N 99th percentile IUFD (N12 weeks GA),
recruited at 10 weeks GA Pre-eclampsia, IUGR
Lynch, 1995 [37] Prospective cohort 354 previously healthy n/a ACA IgG N 20 GPL positive Pre-eclampsia, Placental
nulliparous pregnant ♀ ACA IgM N 11 MPL positive Abruption
Pattison, 1993 [26] Prospective cohort 933 pregnant ♀ n/a ACA IgG/IgM – levels cutoff not Pre-eclampsia; Late fetal
defined loss (N 10 weeks GA)
Rix, 1992 [27] Cohort 2856 pregnant ♀ n/a ACA IgG b 35 EU neg Late fetal losses
ACA IgM b 30 EU neg (N 12 weeks GA), IUGR,
Pre-eclampsia
Stuart, 1993 [38] Prospective cohort 121 unselected pregnant ♀ n/a ACA IgG / IgM ≥ 10 GPL/MPL Pre-eclampsia
positive
Yasuda, 1995 [6] Prospective cohort 860 pregnant ♀ n/a ACA IgG N 20 GPL positive Pre-eclampsia, IUGR, Late
fetal loss (N 24 weeks GA)

Anti-B2 Glycoprotein 1 Antibodies (anti-B2 GP1)

Lee, 2003 [35] Case-control 300 ♀ with pre-eclampsia 100 ♀ with uncomplicated Anti-B2 GP1 IgG/IgM N 20 GPL/ Pre-eclampsia
pregnancies MPL positive
Lee, 1999 [36] Case-control 58 ♀ with late fetal loss 152 healthy fertile ♀ with ≥ 2 Anti-B2 GP1 IgG/IgM N 20 GPL/ Late fetal loss (N 10 weeks
(N 10 weeks) successful pregnancies and ≤ 1 MPL positive GA)
fetal
loss
Valdes-Macho, Case-control 100 ♀ with pre-eclampsia 127 ♀ with uncomplicated Anti-B2 GP1 IgG / IgM OD N 90th Pre-eclampsia
2002 [40] pregnancies percentile positive
Vora, 2008 [44] Case-control 268 ♀ with late fetal loss 100 ♀ with uncomplicated Anti-B2 GP1 IgG/IgM no levels Late fetal loss (≥12 weeks
pregnancies specified x 2 at least 3 months GA)
apart
Faden, 1997 [33] Prospective cohort 510 healthy pregnant ♀ n/a Anti-B2 GP1 N 99th percentile Pre-eclampsia, IUGR,
recruited between 15–18 positive Placetnal abruption, IUFD
weeks GA
Katano, 1996 [34] Prospective cohort 1125 Japanese pregnant ♀ n/a Anti-B2 GP1 IgG N 99th percentile IUFD (N12 weeks GA),
recruited at 10 weeks GA Pre-eclampsia, IUGR

*Only information used for data extraction is presented.

twenty-eight studies, lack of adequate power has remained a serious
limiting factor in our ability to draw firm conclusions on the
association between APLA and placenta mediated pregnancy compli-
cations. Certain factors should be considered in interpreting the
results of this meta-analysis. First, there was a lack of consistency
amongst observed associations across various study designs. Second,
high heterogeneity was observed in many associations studied. Lastly,
concerns with respect to patient selection, timing of APLA sampling,
methods used for APLA analysis and cut off used for detection of APLA
all need to be considered.
The literature on the association between APLA and placenta
mediated complications consists mostly of small case-control studies
which are particularly prone to selection and recall bias. For this reason,
cohort studies were analyzed separately. The associations derived from
both types of studies differed significantly and pooled analyses were
therefore not performed. Weaknesses in study design particularly with
respect to comparability may account for these differences (NewCastle-
Ottawa quality assessment scale; Appendix Table 2).
We observed high degrees of heterogeneity in many of the
associations studied. This was consistent across both case-control and
cohort studies. There are numerous explanations for this observation.
First, the criteria used to define various placenta mediated adverse
pregnancy outcomes differed between studies. The definition of a late
pregnancy loss ranged from greater than 8 to 24 weeks of gestation.
The current Sapporo criteria define a late fetal loss as any loss
occurring after 10 weeks gestation. This was the apriori planned cutoff
used in our study. Restricting our analysis to fetal losses occurring
after 20 weeks of gestation did not result in the identification of new
or stronger associations for the most part. However, these analyses
included a considerably lower number of studies and were under-
powered for the most part. Second, there was significant variability in
the quantification of ACA and anti-B2 GP1 antibodies. Although all
studies included in this systematic review used an ELISA method,
standardized ELISAs are currently not widely used. Furthermore, there
was considerable variation in the isotype and levels of ACA and anti-
B2 GP1 antibodies considered positive. Many studies did not
differentiate between IgG and IgM isotypes. This prevented us from
extracting individual isotype data for all included studies and resulted
in lower power to detect statistically significant associations for
individual isotypes. Furthermore, most studies used significantly
lower thresholds to define ACA and anti-B2 GP1 antibodies positivity
than the current Sapporo recommendations of 40 GPM/MPL units or
N99th percentile. There was insufficient data to restrict our analysis of
ACA or anti-B2 GP1 antibodies to the levels suggested in the Sapporo
82 K. Abou-Nassar et al. / Thrombosis Research 128 (2011) 77–85

Table 2
Association between LA and late placenta mediated adverse pregnancy outcomes.

Pre-eclampsia IUGR Placental abruption Late fetal loss N 10 weeks gestation Late fetal loss N 20 weeks gestation

OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)

# studies / participants # studies / participants # studies / participants # studies / participants # studies / participants

Higgins I2 Higgins I2 Higgins I2 Higgins I2 Higgins I2

Power* Power* Power* Power* Power*

Case-control studies
LA 2.34 (1.18, 4.64) 4.65 (1.29, 16.71) 0.26 (0.01, 4.56) 4.73 (1.08, 20.81) 1.64 (0.07, 36.46)
7 / 1324 2/296 1/146 4 / 812 2/330
0% 0% n/a 31.4% 56.0%
12%* 11%*

Cohort studies
LA 5.17 (0.60, 44.56) 13.90 (0.66, 294.11) n/a 10.59 (1.87, 59.88) 54.18 (2.45, 1198.19)
3/ 4657 1 / 2856 3 / 4657 1 / 2856
76.1% n/a 39.3% n/a
99%* 74%*

Bold characters indicate statistically significant associations.

*Post-hoc power to detect OR ≥ 1.5 where statistical significance was not reached.

criteria. It is possible that the inclusion of patients with low titers of
APLA may have biased our analysis and prevented us from finding
significant associations. However, restricted analysis using cutoff
levels of N20 GPL/MPL units for ACA did not result in the identification
of stronger associations although these analyses were underpowered
for the most part. Nevertheless, this raises serious questions about the
validity of using these cut-offs as laboratory criteria in combination
with placenta mediated pregnancy complication clinical criteria for
the diagnosis of APS.
The timing of APLA testing in relation to the outcome studied
varied significantly between studies. Furthermore, only a minority of
the included studies confirmed APLA positivity by repeat testing on
two separate occasions 12 weeks apart according to the current
recommendations [13]. Transient APLA positivity occurs frequently
and is of uncertain clinical significance [45]. This may account for
some of the observed heterogeneity and bias our results by limiting
the magnitude of the observed associations.
The question of whether APLA antibodies are associated with
placenta mediated adverse pregnancy outcomes remains unan-
swered. The importance of answering this question cannot be over-
emphasized. Practice guidelines based on the Sapporo criteria are
emerging. The 8th edition of the American College of Chest
Physicians Antithrombotic and Thrombolytic Therapy guidelines
currently recommend screening women with severe preeclampsia,
IUGR and late fetal losses in addition to RFL for the presence of APLA
[46]. Furthermore, the administration of antepartum prophylactic

Table 3
Association between ACA and late placenta mediated adverse pregnancy outcomes derived from case-control studies.

Pre-eclampsia IUGR Placental abruption Late fetal loss N 10 weeks gestation Late fetal loss N 20 weeks gestation

OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)

# studies / participants # studies / participants # studies / participants # studies / participants # studies / participants

Higgins I2 Higgins I2 Higgins I2 Higgins I2 Higgins I2

Power* Power* Power* Power* Power*

aCL IgG/IgM 1.52 (1.05, 2.20) 1.97 (0.19, 19.96) 1.30 (0.35, 4.78) 4.29 (1.34, 13.68) 1.86 (0.39, 8.88)
14/2947 2/410 2/410 7/1601 3/679
34% 65.2% 4.6% 71.6% 57.5%
48%* 48%* 68%*
aCL IgG/IgM N 20 GPL/MPL 1.95 (0.76, 4.98) n/a n/a 1.94 (1.13, 3.33) n/a
6/1236 3/655
37.1% 0%
80%*
aCL IgG 1.46 (0.77, 2.77) 4.34 (0.68, 27.85) 2.63 (0.43, 16.05) 15.17 (4.29, 53.59) n/a
13/2527 2/410 2/410 4/946
44.4% 0% 0% 0%
95%* 34%* 34%*
aCL IgG N20 GPL 1.63 (0.82, 3.26) n/a n/a n/a n/a
4/722
45.8%
48%*
aCL IgM 1.49 (1.00, 2.20) 0.79 (0.17, 3.77) 0.88 (0.18, 4.23) 3.13 (0.76, 12.83) n/a
11/2187 1/146 1/146 3/892
0% n/a n/a 50.5%
94%* 18%* 18%* 63%*
aCL IgM N20 MPL 1.18 (0.34, 4.14) n/a n/a 2.77 (0.77, 9.96) n/a
4/722 1/210
0% n/a
27% 9%

Bold characters indicate statistically significant associations.

*Post-hoc power to detect OR ≥ 1.5 where statistical significance was not reached.
 K. Abou-Nassar et al. / Thrombosis Research 128 (2011) 77–85 83

Table 4
Association between ACA and late placenta mediated adverse pregnancy outcomes derived from cohort studies.

Pre-eclampsia IUGR Placental abruption Late fetal loss N 10 weeks gestation Late fetal loss N 20 weeks gestation

OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)

# studies / participants # studies / participants # studies / participants # studies / participants # studies / participants

Higgins I2 Higgins I2 Higgins I2 Higgins I2 Higgins I2

Power* Power* Power* Power* Power*

aCL IgG/IgM 1.78 (0.39, 8.16) 2.84 (0.76, 10.59) 1.56 (0.07, 32.26) 8.85 (1.84, 42.50) 9.26 (0.86, 99.81)
7/6751 4/5343 2/864 5/6276 2/3716
82.3% 34.1% 52.8% 51.7% 38.9%
100%* 99%* 19%* 28%*
aCL IgG/IgM N 20 GPL/MPL 1.77 (0.38, 8.25) 2.35 (0.38, 14.57) 2.00 (0.10, 39.81) 4.79 (0.41, 55.29) n/a
4/5187 3/4833 1/354 3/4833
66% 55.1% n/a 59.1%
100%* 99%* 11%* 88%*
aCL IgG 1.82 (0.27, 12.13) 3.92 (0.63, 24.52) 2.00 (0.10, 39.81) 14.57 (2.26, 94.01) n/a
4/2333 2/1977 1/354 2/1977
76.4% 46.1% n/a 0%
94%* 74%* 11%*
aCL IgG N20 GPL 2.20 (1.08, 4.49) 3.92 (0.63, 24.52) 2.00 (0.10, 39.81) 14.57 (2.26, 94.01) n/a
3/2331 2/1977 1/354 2/1977
76.4% 46.1% n/a 0%
74%* 11%*
aCL IgM 0.69 (0.22, 2.15) 0.63 (0.04, 10.31) 1.31 (0.07, 25.99) 0.57 (0.03, 9.35) n/a
2/3210 1/2856 1/354 1 / 2856
0% n/a n/a n/a
98%* 88%* 11%* 67%*
aCL IgM N20 MPL 0.50 (0.03, 8.21) 0.63 (0.04, 10.31) n/a 0.57 (0.03, 9.35) n/a
1/2856 1/2856 1/2856
n/a n/a n/a
97%* 88%* 67%*

Bold characters indicate statistically significant associations.

*Post-hoc power to detect OR ≥ 1.5 where statistical significance was not reached.

anticoagulation combined with ASA in women with APLA and RFL controversial. Nevertheless, these patients can easily be labeled with
and/or late fetal losses is also recommended [46]. However, the APS based on the Sapporo criteria without solid evidence linking
recommendations on the management of pregnant women with APLA antibodies and late placenta mediated pregnancy complica-
APLAs in the setting other placenta mediated complications remains tions. This may lead to women receiving ASA, heparin or low

Table 5
Association between anti-B2 glycoprotein 1 antibodies and late placenta mediated adverse pregnancy outcomes.

Pre-eclampsia IUGR Placental abruption Late fetal loss N 10 weeks gestation

OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)

# studies / participants # studies / participants # studies / participants # studies / participants

Higgins I2 Higgins I2 Higgins I2 Higgins I2

Power* Power* Power* Power*

Case-control studies
Anti-B2 GP1 IgG/IgM 0.57 (0.32, 1.04) n/a n/a 2.83 (0.28, 28.84)
2/607 2/543
0% 78%
67%* 63%*
Anti-B2 GP1 IgG 0.87 (0.38, 2.01) n/a n/a 3.43 (0.12, 97.02)
2/607 2/545
0% 70.6%
44%* 41%*
Anti-B2 GP1 IgM 0.37 (0.16, 0.85) n/a n/a 2.98 (0.48, 18.63)
1/400 2/543
n/a 47.6%
39%* 49%*

Cohort studies
Anti-B2 GP1 IgG/IgM 19.14 (6.34, 57.77) 20.03 (4.59, 87.43) 2.64 (0.14, 50.63) 23.46 (1.21, 455.01)
2/1618 1/1108 1/510 2 / 1618
0% n/a n/a 64.8%
13%*
Anti-B2 GP1 IgG 24.00 (5.81, 99.13) 20.03 (4.59, 87.43) n/a 73.00 (11.76, 453.07)
1/1108 1/1108 1/1108
n/a n/a n/a
Anti-B2 GP1 IgM n/a n/a n/a n/a

Bold characters indicate statistically significant associations.

*Post-hoc power to detect OR ≥ 1.5 where statistical significance was not reached.
84 K. Abou-Nassar et al. / Thrombosis Research 128 (2011) 77–85

molecular weight heparin in pregnancy without being at risk let Appendix Table 2
alone the limited evidence that these interventions are effective to NewCastle- Ottawa Quality Assessment Scale Results of Included Studies.

prevent complications in women with APLA antibodies and prior late Study Selection Comparability Exposure Outcome
pregnancy complications. Heparin and LMWH are associated with
Case-control
bleeding risk, risk of osteoporotic fracture, withholding of epidural Alfirevic 2001 [19] 4 2 3 n/a
analgesia at term, inconvenience and cost of daily subcutaneous Allen 1996 [31] 2 0 3 n/a
injections (N$4000 per pregnancy). On the other hand, the morbidity Bocciolone 1994 [20] 1 0 2 n/a
Bowen 2002 [32] 3 0 3 n/a
and mortality [47,48] associated with pre-eclampsia, placental
De Carolis 1994 [43] 1 0 3 n/a
abruption, IUGR, and fetal death represents a significant disease burden Dreyfus 2001 [21] 3 2 3 n/a
for thrombophilic women and their children. Pre-eclampsia frequently Kaleli 1998 [22] 1 0 3 n/a
leads to maternal morbidity, causes one-third of maternal deaths and is a Lee 1999 [36] 0 0 3 n/a
frequent cause of fetal and neonatal morbidity and mortality [49]. IUGR Lee 2003 [35] 3 0 3 n/a
Matthiessen 1999 [8] 3 2 3 n/a
often results in long-term effects to the affected child (developmental
Mello 1999 [23] 3 2 3 n/a
delay, poor school performance) that last into adulthood (less likely to Milliez 1991 [24] 2 0 3 n/a
attain higher academic and professional achievement) [50–53]. Fetal Moodley 1995 [25] 1 2 2 n/a
death is a devastating event for pregnant women and their families. Thus, Schjetlein 1998 [28] 3 0 3 n/a
Uncu 1996 [39] 2 0 3 n/a
the clinical, emotional and economic importance of these complications of
Vahid 2006 [29] 1 0 3 n/a
pregnancy in this potentially high risk prevalent subgroup dictate that Valdes-Macho 2002 [40] 3 0 3 n/a
definitive causal evidence for a link between APLA and placenta-mediated Van Pampus 1999 [41] 2 0 2 n/a
pregnancy complications is required, particularly in the case of anti-B2 Vora 2008 [44] 2 1 3 n/a
GP1 antibodies. Yamamoto 1996 [42] 1 0 3 n/a

In conclusion, the association between various APLA and placenta

Cohort
mediated pregnancy complications are inconsistent and the literature Faden 1997 [33] 4 0 n/a 2
examining this association is often underpowered. There is currently Katano 1996 [34] 2 0 n/a 2
insufficient data to establish a significant link between anti-B2 glycopro- Pattison 1993 [26] 4 0 n/a 3
Rix 1992 [27] 3 0 n/a 2
tein 1 antibodies and pregnancy morbidity. Caution should be used when
Stuart 1993 [38] 3 0 n/a 1
establishing a diagnosis of APS based on the presence of any APLA, Wharfe 1999 [30] 4 0 n/a 3
particularly anti-B2 GP1 antibodies, in the setting of late pregnancy Yasuda 1995 [6] 4 2 n/a 2
complications. Lynch 1995 [37] 4 0 n/a 3

Conflict of interest statement

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