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Safety and Efficacy of Enoxaparin in Pregnancy: A Systematic Review and Meta-Analysis
Safety and Efficacy of Enoxaparin in Pregnancy: A Systematic Review and Meta-Analysis
https://doi.org/10.1007/s12325-019-01124-z
REVIEW
Twenty publications [22–41], pertaining to and similar between groups. All studies reported
19 clinical trials [22–33, 35–41] were included in on their prespecified primary outcome, as
the Cochrane risk of bias assessment. A sum- mentioned in the publication. Finally, no other
mary of the assessment for the randomized tri- sources of bias other than the ones previously
als is presented (Table S3 in the Electronic described were detected across the studies.
Supplementary Material). The risk of bias across Four studies were included in the NOS
the included studies was generally low and quality assessment, all of which were cohort
limited to the blinding of participants and per- studies [42–45]. A summary of the assessment is
sonnel (performance bias) and the blinding of presented in the Electronic Supplementary
outcome assessment (detection bias): 14 studies Material (Table S4). One study had a score of 8
were judged to be at low risk for the random and three studies scored the maximum score of
sequence generation item in the selection bias 9. All studies scored the maximum score of 4
domain [23–33, 38–40], three studies were stars in the selection category, indicating that
judged as unclear, as the random sequence the data used was representative of the targeted
generation methods were not clearly described community. For the comparability category,
[22, 35, 40], and four studies were considered one study scored only one star because the
high risk as they were non-randomized authors did not describe any additional baseline
[36, 37, 42, 43]. Regarding allocation conceal- characteristics that were well matched between
ment, 14 studies were considered to be at low cohorts [42] and the other three studies scored
risk of bias [22–25, 27, 28, 30–32, 35, 36, 38, 40, the maximum score of 2 stars [43–45]. Finally,
41], four studies were considered unclear as in the outcome category, all studies scored the
methods for allocation concealment were not maximum of 3 stars.
provided or not clearly described, one study was
considered as high risk as randomization was Thromboembolic Events: Efficacy
not carried out and the groups were made aware and Safety
of the treatment they received upon enrollment
[37]. Few studies presented adequate blinding Only two studies looked at enoxaparin in the
methods to reduce performance bias: only three context of thromboprophylaxis; a pooled meta-
studies were considered as low risk for suffi- analysis was therefore not possible.
ciently packaging their treatments to disguise In terms of safety of enoxaparin, a pooled
their identities to patients receiving them at all meta-analysis for thromboembolic events was
points in the study [28, 38, 41], eight studies not feasible because of the low number of
were considered unclear as blinding methods reported cases across treatment comparisons.
were not provided, ten studies were open-label Data reported in the studies are summarized in
for participants and personnel and were thus Table S6 (Electronic Supplementary Material).
considered to be at high risk for performance Two cases of DVT were reported in patients with
bias [22, 24, 25, 27, 30–33, 37, 40]. Similarly, for recurrent pregnancy loss who received enoxa-
detection bias, only five studies were considered parin monotherapy compared to four cases in
low risk [28, 30, 38, 39, 41], six studies were of patients who received no intervention (RR 0.5;
unclear risk as the study was not described as 95% CI 0.09–2.69) [22]. No thromboembolic
either open-label or blinded events were reported in patients receiving
[23, 29, 35, 36, 42, 43], and nine studies were combined therapy with enoxaparin plus aspirin.
considered high risk because of an open-label In one study that compared enoxaparin plus
study design [22, 24–27, 31, 33, 37, 40]. All aspirin versus aspirin in women with a history
studies were considered as low risk in the of preeclampsia, one case of superficial venous
domains of incomplete outcome data (attrition thrombosis was reported in patients who
bias) and selective reporting (reporting bias). received aspirin [34].
Most studies used an intent-to-treat analysis in
their primary outcome analysis, and where
dropouts were present, the numbers were few
Adv Ther
Comparison: 4
63 records accepted (based on
title and abstract) Animal study: 3
Publication date cutoff: 3
Not English: 1
Comparison: 13
24 records accepted (based on Outcomes: 13
full text) Study design: 4
Intervention: 3
Duplicate publication: 3
Population: 3
Included
Bleeding
Study withdrawal was reported in eight studies.
Enoxaparin vs 5 1.35 (0.88–2.07); However, five reported zero discontinuations in
placebo/controls I2 = 16.05 the remaining three studies, and each of them
reported a unique treatment comparison
Enoxaparin vs aspirin 3 0.93 (0.62–1.39);
involving enoxaparin.
I2 = 0
Enoxaparin ? aspirin vs 4 0.95 (0.71–1.28);
aspirin I2 = 11.28 DISCUSSION
Pregnancy loss The findings of this systematic review and meta-
Enoxaparin vs 6 0.58 (0.34–0.96); analysis were that antenatal enoxaparin use was
placebo/controls I2 = 65.80 generally safe, but that enoxaparin efficacy
specifically for antenatal VTE could not be
Enoxaparin vs aspirin 4 0.39 (0.15–1.01); examined as a result of only two studies meet-
I2 = 78.24 ing the inclusion criteria. Given that the use of
Enoxaparin ? aspirin vs 8 0.42 (0.32–0.56); enoxaparin in pregnancy remains off-label,
careful individual benefit–risk assessment and
aspirin I2 = 14.10
informed consent are still required before its
Enoxaparin ? aspirin vs 2 0.66 (0.33–1.34); use. In terms of efficacy. These findings are
UFH ? aspirin I2 = 0 aligned with those of the review conducted by
Greer et al. [14] in LMWH in general.
Adv Ther
Adv Ther
b Fig.2 Relative risk of bleeding events with enoxaparin when prescribing enoxaparin in pregnancy;
compared to a placebo/no treatment or b aspirin. c Relative caution is required when using enoxaparin in
risk of bleeding events with enoxaparin ? aspirin com- pregnancy and is a trade-off between maternal
pared to aspirin bleeding and prevention of VTE.
In terms of safety, enoxaparin was associated
with a reduction in pregnancy loss in this
analysis, which is an unexpected result, as a
In terms of safety, the incidence of throm- significant benefit of LMWH for prevention of
boembolic events was rare, with only two recurrent pregnancy loss has not been observed
antenatal cases of DVT with enoxaparin repor- in other systematic reviews and meta-analyses
ted in a single study. More bleeding events [47, 48]. Observational data and RCTs were
occurred with enoxaparin than placebo/un- included in our review, and this finding must be
treated controls, but the risk of bleeding was interpreted cautiously as a safety signal rather
lower compared to aspirin. Risk of pregnancy than an efficacy signal. Adequately powered
loss was lower with enoxaparin compared to robust clinical studies are required to demon-
placebo/untreated controls, aspirin, and UFH strate the efficacy of enoxaparin to prevent
plus aspirin. Statistically significant reduction recurrent pregnancy loss in patients with
in risk of pregnancy loss was shown for enoxa- acquired or inherited thrombophilia. One such
parin plus aspirin compared to aspirin alone. ongoing study is ALIFE-2, a robust RCT, which
Few studies reported thrombocytopenia and is investigating the efficacy of enoxaparin in
congenital malformations occurring with preventing pregnancy loss in women with
enoxaparin, the majority reporting only one or inherited thrombophilia and recurrent miscar-
two events. riage [49]. There is evidence that enoxaparin
In terms of safety, anticoagulant treatment does not benefit patients with pregnancy loss
with enoxaparin is expected to have higher unrelated to thrombophilia and the practice of
bleeding rates when compared to placebo. A treating women with enoxaparin for pregnancy
recent systematic review and meta-analysis loss unrelated to thrombophilia may be futile,
conducted by Sirico et al. [46] included data and pose an unnecessary risk to the mother
from 22,162 pregnant women, of whom 1320 [38].
(6%) were administered LMWH. Although Fetal safety is of particular concern for all
LMWH-treated patients had a higher risk of drugs administered during pregnancy. Consid-
postpartum hemorrhage, no difference in mean ering that many women who receive enoxa-
blood loss or risk of blood transfusion at deliv- parin treatment during pregnancy are already at
ery was reported. The authors attributed the high risk for poor pregnancy outcome, we did
higher risk for postpartum hemorrhage to not find an incremental fetal risk that was
LMWH usage in spite of there being no differ- attributable to enoxaparin. The risk of congen-
ence in mean blood loss or in risk of blood ital malformations was low and similar to those
transfusion at delivery but noted ‘‘the small reported by Shlomo et al. [50] in a population-
number of women included in the secondary based, retrospective cohort study of maternal
analysis (784 for mean blood loss at delivery, and infant hospital records between 1998 and
883 for blood transfusion) compared to the 2009. Of the 109,473 singleton pregnancies
women included in the primary analysis.’’ reported on, 418 and 572 were exposed to
Moreover, the inclusion of retrospective cohort enoxaparin during the first and third trimesters,
data and the lack of adjustments for con- respectively. Importantly, exposure to enoxa-
founders do impact the generalizability and parin during the first trimester of pregnancy was
conclusions of this study. The increased bleed- not associated with an increased risk of major
ing in enoxaparin-treated patients compared to congenital malformations [adjusted odds ratio
placebo observed in our review, together with (aOR) 1.1, 95% CI 0.8–1.6], while exposure
the findings in the review by Sirico et al. [46], during the third trimester was not associated
supports the practice of assessing risk/benefit with an increased risk of low birth weight, low
Adv Ther
Adv Ther
b Fig.3 Relative risk of pregnancy loss with enoxaparin Only published studies were included, and
compared to a placebo/no treatment or b aspirin. c Relative therefore the review may be limited by publi-
risk of pregnancy loss with enoxaparin ? aspirin com- cation bias. The long-term effect of enoxaparin
pared to aspirin exposure during pregnancy on neurodevelop-
ment requires substantial follow-up and was not
Apgar score, or risk of perinatal mortality. The reported in the included studies. The gray lit-
authors concluded that ‘‘exposure to enoxa- erature was not searched, and very rare adverse
parin during pregnancy was not associated with events may not have been even reported. Stud-
an increased risk of major malformations in ies of pregnant patients with mechanical heart
general or according to organ systems. valves were excluded because these patients
Nonetheless, the risk for specific malformations may have altered enoxaparin pharmacokinetics
cannot be ruled out.’’ and pharmacodynamics, when compared to
In our opinion, the low number of reported pregnant patients without mechanical heart
congenital malformations with enoxaparin in valves and may benefit from a separate system-
the literature has biological plausibility, given atic review. Therefore, the findings of this sys-
that enoxaparin has not been shown to cross tematic review and meta-analysis are not
the placenta in clinical studies that have generalizable to pregnant patients with
directly evaluated whether enoxaparin crosses mechanical valves. Also, given the rarity of
the placenta in vivo [51, 52]. Forestier et al. [51] outcome events, we included both RCT and
studied anti-Xa and anti-IIa activities in mater- observational data, which may present certain
nal and fetal blood after enoxaparin adminis- limitations for analysis.
tration in five cases of medical abortion during
the second trimester (week 23 of gestation); 3 h
after the subcutaneous injection of 7500 anti- CONCLUSION
Xa IU of enoxaparin, anti-Xa and anti-IIa
activities in the five fetuses were not modified In terms of safety, enoxaparin use in pregnancy
compared to controls. Dimitrakakis et al. [52] was associated with a significantly lower
studied the fetal and maternal effects of occurrence of pregnancy loss when compared
enoxaparin 40 mg (4000 IU) in 14 pregnant with control groups and similar rates of bleed-
women and 10 controls due for termination of ing when compared with aspirin; reports of
their pregnancies because of the presence of a thromboembolic events, thrombocytopenia,
major congenital malformation; in the 14 and teratogenicity were rare. The efficacy of
patients receiving drug, no anti-IIa or anti-Xa LMWH for the treatment of VTE is already
activities were observed 3 h post-dose in ultra- established, but evidence for enoxaparin
sound-guided fetal blood samples. specifically remains limited. In light of the
Ideally, the safety and efficacy of enoxaparin adoption of antenatal LMWH into clinical
in pregnancy should be determined in an ade- practice, real-world data and continued phar-
quately powered, randomized, double-blind macovigilance are needed to further inform
controlled trial. This study would, however, treatment guidelines on the clinical benefits
require an exceptionally large number of and risks associated with this form of therapy.
patients given the low number of reported
events. It may also be challenging to conduct a
study because of the large sample size, and ACKNOWLEDGEMENTS
ethical justification for such a trial given that
enoxaparin has become standard of care inter-
nationally and one may argue that clinical Funding. The systematic search and analysis
equipoise does not exist. A more pragmatic assistance was provided by Doctor Evidence and
approach would be to supplement the current funded by Sanofi, including open access and
body of scientific evidence with data from reg- publishing fees.
istry studies and pharmacovigilance reports.
Adv Ther
Medical Writing Assistance. Medical writ- noncommercial use, distribution, and repro-
ing support was provided by Jung Min Han and duction in any medium, provided you give
Saranya Chandrudu of Doctor Evidence with appropriate credit to the original author(s) and
publication support by Angelica Stamegna and the source, provide a link to the Creative
funded by Sanofi. Commons license, and indicate if changes were
made.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
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