Bates 2012

CHEST Online Data Supplement
VTE, Thrombophilia, Antithrombotic

Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines
Shannon M. Bates, MDCM; Ian A. Greer, MD, FCCP;

Saskia Middeldorp, MD, PhD; David L. Veenstra, PharmD, PhD;
Anne-Marie Prabulos, MD; and Per Olav Vandvik, MD, PhD
1
2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American
College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Downloaded From: http://journal.publications.chestnet.org/ on 03/09/2013

Table S1[3.0.1] Systematic Reviews Examining Fetal Safety of Maternal Therapy With Oral Anticoagulants or Aspirin (Methodologic Quality)
Inclusive Duplicate Study List of Studies Characteristics Assessment of Appropriate Methods Assessment of
Literature Selection and (Included and of Included Quality of Used To Combine Likelihood of
Study/Year Intervention Search Data Extraction Excluded) Provided Studies Provided Included Studies Study Findings Publication Bias
Chan et al1/2000 Studies between 1966 and 1997 Yes No No No No Yes No
examining the use of VKAs
and UFH or no anticoagulation
in pregnant women with
mechanical heart valves
Hassouna and Studies between 2000 and 2009 No No No No No Yes No
Allam2/2010 examining the use of VKAs
and UFH or no anticoagulation
in pregnant women with
Askie et al3/2007 Randomized trials (n 5 31) Yes Yes Yes Yes Yes Yes Yes
comparing antiplatelet agents

(low-dose aspirin or dypyridamole)
with either placebo or no
antiplatelet agent in pregnant
women (n 5 32,217) for primary
prevention of preeclampsia.
Aspirin given alone in 27 trials
(n 5 31,678; 98% of women).
Meta-analysis of individual
patient data
Kozer et al4/2002 Controlled studies (n 5 2 case Yes Yes Included studies Yes No Yes No
controlled studies, n 5 5 cohort only
studies, n 5 1 randomized control
study) examining the risk of
maternal exposure to aspirin
during the first trimester of
pregnancy and reported on
congenital malformations

Kozer et al5/2003 Randomized controlled studies Yes Yes Included studies Yes No Yes No
(n 5 38) examining maternal only
exposure to aspirin during
pregnancy and reporting on
seven prespecified outcomes
UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist.
2
Table S2[Section 3.0.1] Systematic Reviews Examining Fetal Safety of Maternal Therapy With Oral Anticoagulants
and Aspirin (Results)
Spontaneous Total Fetal Congenital Fetal Fetal or Neonatal

Anticoagulation Regimen Abortions Wastagea Anomalies Hemorrhage
VKAs throughout with or without heparin at term
Chan et al /2000
1 196/792 (24.7) 266/792 (33.6) 35/549 (6.4)
Hassouna and Allam2/2010 194/833 (23.3) 274/833 (32.9) 21/559 (3.7) Not reported
Heparin in first trimester, then VKAs throughout with or without heparin near term
Heparin use at/before 6 wk
Chan et al1/2000 19/129 (14.7) 21/129 (16.3) 0/108 (0.0) Not reported
Heparin use after 6 wk
Heparin use at unknown time in first trimester
Adjusted-dose heparin
Low-dose heparin
Regimen not specified
No anticoagulation
Nothing
Antiplatelet agent
Nothing or antiplatelet agent
Data are presented as n/N (%). See Table S1 legend for expansion of abbreviation.
a Wastage due to abortions, stillbirths, and neonatal deaths.
3

Table S16Continued
Study/Year Type of Study Participants Intervention Outcomes Follow-up Results Strengths Limitations
No recurrences in
women with no
thrombophilia and a
provoked first VTE
(0/44, 0%; 95% CI,
0%-8.0%); of women
with an idiopathic
first VTE or abnormal
thrombophilia
testing, 3/51
(5.9%; 95% CI, 1.2%-
16.2%) developed
recurrence
Postpartum: 3/122
(2.5%; 95% CI,
0.5%-7.0%)

Retrospective studies
Badaracco Retrospective N 5 30 women Not stated Recurrent VTE Not stated Total: 6/15 (40%; Retrospective, included
et al39/1974 cohort with previous during (95% CI, 16.3%- women with more
study VTE pregnancy 67.7%); distribution than one previous
or postpartum between antepartum VTE, questionnaire
period and postpartum not data, no objective
provided diagnosis
Tengborn Retrospective N 5 72 women with No antepartum Recurrent VTE; Until Antepartum: 5/67 Retrospective, questionnaire
et al40/1989 cohort previous VTE prophylaxis superficial postpartum; (7.5%; 95% CI, data, no objective
study (87 pregnancies; Postpartum: no thrombophlebitis time not 2%-14%) diagnosis, women with
67 pregnancies prophylaxis (not included in stated Postpartum: 2/30 multiple previous
without antepartum (n 5 30) this table) (6.7%; 95% CI, episodes of VTE
prophylaxis) Various anticoagulant 0%-21%) included, some women
regimens, All recurrences with hereditary
including UFH in women with thrombophilia
and dextran previous VTE (anticoagulant inhibitor
(n 5 57) elicited by deficiencies n 5 3;

pregnancy or defective fibrinolysis
OCP use n 5 18), wide range of
postpartum regimens,
potential confounding
by indication
(Continued)
21
Table S16Continued
Pabinger Retrospective N 5 109 women with No antepartum Cumulative 6 wk Antepartum: 8/197 Assessed risk for Retrospective, included
et al41/2005 cohort previous VTE (197 prophylaxis; incidence of postpartum (cumulative full period of women with more than
study pregnancies; 284 inconsistent use recurrent VTE incidence, 6.2%; pregnancy (ie. one previous VTE, not
postpartum periods, of postpartum antepartum 95% CI, including early all VTE objectively
including after prophylaxis, Recurrent VTE 1.6%-10.6%) terminations, diagnosed, potential
terminations, mainly low-dose postpartum No predictive value miscarriages) confounding by
miscarriages, LMWH (details of thrombophilia indication
stillbirths, and not stated) or whether first
live births) episode was
idiopathic

Recurrence risk
in subgroup of
women with first
VTE associated
with OCP use 10%
vs 2.7% if first VTE
not associated with
OCP use (ns)
Postpartum: overall,
15/284 (5.3%;
95% CI, 3.0%-8.6%);
without prophylaxis,
10/187 (5.4%;
95% CI, 2.6%-9.6%);
with prophylaxis,
5/97 (5.2%; 95% CI,
1.7%-11.6%)

(Continued)
22
Table S5[Section 4.0.1, 4.0.5] Prospective Studies of the Effect of Maternal Antithrombotic Therapy on Breast-fed Infants (Clinical Description and Results)
Number Patients Length of Follow-up Presence in Breast

Reference Interventions Analyzed Postdelivery Infant Hemorrhage Milk (%) Effect in Infant Blood Comments
Orme et al6/1977 Warfarin exposure Breast-fed Up to 10 d 0/7 Warfarin, 0/7 Warfarin, 0/7 Warfarin levels measured
during breast- infants, 7/7 by chromatography
feeding (lower limit of detection,
0.08 mmol/L)
McKenna et al7/1983 Warfarin exposure Breast-fed First: 56 d 0/2 Warfarin, 0/2 Elevated PT, 0 /2 Presence of warfarin in
during breast- infants, 2/2 breast milk detected
feeding by spectrophotometry
Second: 130 d
Houwert-de Jong Acenocoumarol Breast-fed Not stated Not reported Acenocoumarol, 0/20 Elevated thrombotest Presence of

et al8/1981 exposure during infants, 7/7 compared with acenocoumarol in
breast-feeding normal range for breast milk detected
age, 0/20 by high-performance
liquid chromatography
(limit of 15 ng/mL)
Fondevila et al9/1989 Acenocoumarol Breast-fed Not stated No predisposition Not reported Mean INR, % PT, % NA
exposure during infants, 7/7 (n 5 4 to perinatal factor II, % factor
breast-feeding mothers) hemorrhaging VII-X not different
complications from control infants
Richter et al10/2001 LMWH exposure Breast-fed Up to 8 d Not reported Detectable anti-Xa Not reported Therapeutic anti-Xa
during breast- infants, 15/15 LMWH levels, LMWH level, 0.5-1.5
feeding 11/15 (range, 0.006- International Units/mL
(maternal-dose 0.037 International 4-6 h postinjection
dalteparin 2,500 Units/mL)
International
Units SC)
Ito et al11/1993 Low-dose aspirin Breast-fed Not reported Not reported Not reported Not reported 0/15 with diarrhea,

exposure during infants, 15/15 drowsiness, or
breast-feeding irritability
INR 5 international normalized ratio; PT 5 prothrombin time. See Table S4 legend for expansion of other abbreviations.
6
Table S6[Section 5.1.1, 5.1.2] Risk of Thromboembolism in Patients Undergoing Assisted Reproductive Technology
Study/Year Type of Study Participants/ Intervention Follow-up Risk of Thromboembolism Strengths/Limitations

12
Mra et al /2004 Retrospective cohort 2,748 IVF cycles IVF cycle and pregnancy Overall: 3/2,748 (0.1%; Strengths:
95% CI, 0%-0.3%); all Precision
internal jugular DVT Directness
In women with severe ovarian Weaknesses:
hyperstimulation: 2/49 Single center
(4.1%; 95% CI, 1.1%-13.7%)
Aurousseau et al13/1995 Retrospective cohort 1,102 IVF procedures; Not stated Overall: 3/1,102 (0.3%; Strengths:
no cases of ovarian 95% CI, 0.1%-0.8%); two Precision
hyperstimulation arterial events and one PE Directness
Weaknesses:
Single center
Duration of follow-up,

methods of investigation,
diagnostic testing strategies
not described
Delvigne et al12/1993 Multicenter retrospective 128 women with ovarian Not stated In women with ovarian Strengths:
cohort hyperstimulation (cases) hyperstimulation: 1/128 Multicenter
(0.8%; 95% CI, 0.1%-4.3%); Directness
cerebral thrombosis Weaknesses:
Imprecision
Unclear whether cases were
consecutive
Duration of follow-up, methods
of investigation, diagnostic
testing strategies not described
17 patients received LMWH
Morris et al14/1995 Prospective cohort 13 women with severe During hospitalization for In women with severe ovarian Strengths:
ovarian hyperstimulation treatment of severe hyperstimulation: 0/13 Directness
ovarian hyperstimulation (0%; 95% CI, 0%-22.8%) Weaknesses:

Imprecision
Short follow-up
(Continued)
7
Table S26[Section 11.2.1] Evidence Profile: Should Aspirin Rather Than No Treatment Be Used for Prevention of Recurrent Pregnancy Loss in Women
Without Thrombophilia?
Quality Assessment Summary of Findings
Anticipated Absolute Effects

Study Event Rates (%) During Pregnancy
Participants Relative Risk Risk Difference

(Studies), Publication Overall Quality Without Effect Without With Aspirin
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence Treatment With Aspirin (95% CI) Treatment (95% CI)
Miscarriage (critical outcome)
202 (1 RCTs), No serious No serious No serious Serious Undetected Moderate due 34/103 (33) 38/99 (38) RR 1.16 300 cases 48 more per 1,000
9 mo risk of bias inconsistency indirectness imprecision to imprecision (0.80-1.69) per 1,000a (from 60 fewer
CI includes to 207 more)

important
benefit
and harm
Major bleeding (critical outcome) antepartum hemorrhageb,c
95,000 (6 RCTs), No serious No serious Serious No serious Undetected Moderate due 219/47,500 (0.5) 335/47,500 (0.7) RR 1.54 15 bleeding 8 more bleeding
3.8-10 y risk of bias inconsistency indirectnessc imprecision to indirectness (1.30-1.82) events events per 1,000
Primary per 1,000d (from 5 more
prevention to 12 more)
cardiovascular
disease
Bibliography: Kaandorp SP, Maritte Goddijn M, van der Post JAM et al. Aspirin combined with low-molecular-weight heparin and aspirin alone in women with recurrent miscarriage. A randomized
placebo-controlled trial: the ALIFE study. New Engl J Med. 2010;29;362:1586-1596. Clark P, Walker ID, Langhorne P, et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized
controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115:4162-4167. Greer IA, Nelson-Piercy C. Low molecular weight heparins
for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106:401-407. See Table S3 and S9 legends for expansion of
abbreviations.
a Baseline risk for miscarriage comes from study event rates in the two available randomized trials by Kaandorp et al and Clark et al.
b Major antenatal nonfatal hemorrhage.

c Rated down for indirectness due to population (primary prevention cardiovascular disease). There were no major bleeding events in the ALIFE Study (personal communication with authors).
d Control group risk estimate for major bleeding events antepartum comes from systematic review by Greer et al.
e Only study identified that compared aspirin to placebo in this population.
50
Table S7[Section 5.1.1, 5.1.2] Risk of Bleeding in Patients Undergoing Transvaginal Oocyte Retrieval
Study/Year Type of Study Participants/ Intervention Follow-up Risk of Bleeding Strengths/Limitations and Comments
Bergh and Lundkvist15/1992 Survey of 12 fertility 10,125 retrievals Varied from clinic Major bleeding: 2/10,125 (0.02%; 95% CI, Strengths:
centers to clinic (1-9 y) 0%-0.1%); intraabdominal bleeding Multicenter
requiring laparotomy Precision
Vaginal bleeding: 33/10,125 (0.3%; 95% CI, Directness
0.2%-0.5%) Weaknesses:
Retrospective definitions and methods
of evaluating outcomes not specified
Ragni et al17/2009 Prospective cohort 150 consecutive 72 h Major bleeding: 0/150 (0%; 95% CI, Strengths:
retrievals 0%-2.4%) Precision
Median blood loss (interquartile range): Directness
72 (2 8 to 162 mL) Methods for detecting blood loss clearly
described
Bennett et al18/1993 Prospective cohort 2,670 consecutive Not stated Major bleeding: 1/2,670 (0.04%; 95% CI, Strengths:
retrievals 0%-0.2%); intraabdominal bleeding with Precision
hypovolemic shock necessitating emergency Directness

laparotomy (1 L hemoperitoneum) Prospective
Abdominal bleeding (nonmajor): 1/2,670 Weaknesses:
(0.04%; 95% CI, 0%-0.2%); trivial Follow-up not described
bleeding with 70 mL blood aspirated Methods for assessment of blood
from the abdominal cavity loss unclear
Vaginal bleeding: 229/2,670 (8.6%; 95% CI,
7.6%-9.7%) . 100 mL, 22/2,670 (0.8%;
95% CI, 0.5%-1.2%)
Requiring local compression, 28/2,670
(1.0%; 95% CI, 0.7%-1.5%)
Dicker et al19/1993 Retrospective 3,656 retrievals Not stated Major bleeding: 3/3,656 (0.08%; 95% CI, Strengths:
0%-0.2%); all intraabdominal; laparotomy Precision
and 4 units of blood required in one Directness
patient; drainage and hemostasis achieved Weaknesses:
laparoscopically in the other two patients. Retrospective
Follow-up not described
Tureck et al20/1993 Retrospective 674 retrievals Not stated Vaginal bleeding: 2/674 (0.3%; 95% CI, Strengths:

0.1%-1.1%) . 100 mL, one patient Precision
required sutures Directness
Intraabdominal bleeding: 1/674 (0.1%; Weaknesses:
95% CI, 0%-0.8%); expanding broad Retrospective
ligament bleed treated with diagnostic Follow-up not described
laparotomy and observation
(Continued)
9
Table S7Continued
Study/Year Type of Study Participants/ Intervention Follow-up Risk of Bleeding Strengths/Limitations and Comments
21
Govaerts et al /1998 Retrospective 1,500 retrievals At least to Intraabdominal bleeding: 3/1,500 (0.2%; Strengths:
completion 95% CI, 0.1%-0.6%); all three required Precision
of IVF laparoscopy Directness
Weaknesses:
Retrospective
Ludwig et al22/2006 Prospective cohort 1,058 retrievals 2 mo postretrieval Vaginal bleeding: 29/1,049 (2.8%; 95% CI, Strengths:
1.9%-3.9%) Precision
Requiring compression, 28/1,049 Directness
(2.7%; 95% CI, 1.9%-3.9%) Prospective
Requiring tamponade for . 2 h, 1/1,049
(0.1%; 95% CI, 0%-0.5%)
Intraabdominal bleeding: 0/1,049 (0%;

95% CI, 0%-0.4%)
Bodri et al23/2008 Retrospective 4,052 retrievals 2 wk Major bleeding: 1/4,052 (0.02%; 95% CI, Strengths:
0%-0.5%) intraabdominal bleeding Precision
requiring laparotomy and transfusion Directness
Other nonmajor bleeding: 13/4,052 (0.3%; Weaknesses:
95% CI, 0.2%-0.5%); four patients Retrospective
had abdominal bleeding requiring
laparoscopy; in the remaining nine
patients, bleeding resolved spontaneously,
although six were hospitalized
Baber et al24/1988 Retrospective 600 retrievals Not stated Vaginal bleeding: 5/600 (0.8%; 95% CI, Strengths:
0.4%-1.9%); requiring insertion of Precision
vaginal pack (none had significant fall Directness
in hemoglobin level) Weaknesses:
Pelvic hematoma: 3/600 (0.5%; 95% CI, Retrospective
0.2%-1.5%); all managed conservatively
with no drop in hemoglobin level

Overt bleeding: 1/600 (0.2%; 95% CI,
0%-0.9%); 200-mL blood loss
requiring suture
10
Table S8[Section 5.1.1, 5.1.2] Risk of Thrombosis and Bleeding in Patients Receiving Prophylactic Anticoagulation Around the Time of Transvaginal
Oocyte Retrieval
Strengths/Limitations
Study/Year Type of Study Participants/Intervention Follow-up Outcomes Results and Comments
Yinon et al25/2006 Retrospective Twenty-four women considered high risk for Until delivery of embryo Bleeding Bleeding: 0/24 Strengths:
thrombosis undergoing 73 IVF cycles and transfer if pregnancy Thromboembolism (0; 95% CI, 0%-13.8%) Directness
68 oocyte retrieval procedures (five very not achieved. Thromboembolism: Weaknesses:
high risk used a controlled spontaneous 0/24 (0; 95% CI, Imprecision
cycle and surrogacy). Patients received 0%-13.8%) Retrospective
LMWH (0.6-1 mg/kg per d) starting on
the day of GnRH agonist administration
(when GnRH agonist protocols were
used) and on the first day of gonadotropin
administration in the GHrH antagonist
protocol. The last injection of LMWH
was administered 14-15 h prior to oocyte
retrieval and resumed 12 h postprocedure.
Anticoagulation was continued in pregnancy
and stopped after a negative pregnancy
test. Very-high-risk patients received

warfarin aspirin prior to oocyte
retrieval before transitioning to LMWH
postretrieval (unless planned surrogacy).
Qublan et al26/2008 Randomized Eighty-three women with at least three Until delivery. Five women Implantation Bleeding: enoxaparin, Strengths:
trial failed assisted reproduction cycles and in each group were lost success, 3/42 (7.1%; 95% CI, Directness
at least one thrombophilia. to follow-up in the live births, 2.5%-19.0%) Randomized trial
Patients were allocated to enoxaparin LMWH group, and three complications Thrombocytopenia: Weaknesses:
40 mg/d (n 5 42) or placebo (n 5 41) were lost to follow-up in enoxaparin, 2/42 Imprecision
starting on the day of embryo transfer the no-treatment group. (4.8%; 95% CI, Only participants were
and continued until completion of 1.3%-15.8%) blinded For 32% of
pregnancy. Allergic reactions: participants, the
enoxaparin, 1/42 (2.4%; qualifying thrombophilia
95% CI, 0.4%-12.3%) was the MTHFR C677T
mutation, which is not
a risk factor for venous
thrombosis
Criteria for bleeding

and thrombocytopenia
not specified
Bleeding not
specifically reported
for placebo group
Thrombosis not
specifically reported
for either group
(Continued)
11
Table S8Continued
Strengths/Limitations
Study/Year Type of Study Participants/Intervention Follow-up Outcomes Results and Comments
Stern et al27/2003 Randomized, double- One hundred forty-three women with an Until delivery or end Successful Significant bleeding: Strengths:

blind, placebo- autoantibody (either APLA, antinuclear, of pregnancy implantation, heparin and aspirin, Directness
controlled, crossover or anti-b2-glycoprotein I) and at least live births, 0/158 (0; 95% CI, Randomized trial
trial (transfer by 10 prior unsuccessful embryo transfers. bleeding 0%-2.4%) Placebo, 0/142 Double blinding
transfer) Patients were allocated to either UFH 5,000 (0; 95% CI, 0%-2.6%) Weaknesses:
units bid SC and aspirin (158 transfers Criteria for significant
of 296 embryos) or placebo (142 transfers bleeding not reported
of 259 embryos) starting the day of Thrombosis not specifically
embryo transfer until 14 wk gestation reported
or pregnancy failure.
APLA 5 antiphospholipid antibody; GHrH 5 growth-hormone-releasing hormone; GnRH 5 gonadotropin-releasing hormone; MTHFR 5 methylene tetrahydrofolate reductase variant. See Table S1 and
S4 legends for expansion of other abbreviations.

12
Table S9[Section 5.1.1, 5.1.2] Evidence Profile: Prophylactic-Dose LMWH vs No Thromboprophylaxis for Women Who Undergo Assisted Reproductive Therapy
Study Event Rates (%) Anticipated Absolute Effectsb
Participants Overall Relative Risk Difference

(Studies), Risk of Publication Quality of Without Effect Risk Without With LMWH
Follow-up Bias Inconsistency Indirectness Imprecision Bias Evidence Prophylaxisa With LWMH (95% CI) Prophylaxisa (95% CI)
Symptomatic VTE (critical outcome), DVT, and PE
1,953 (6 RCTs), No serious No serious Serious Serious imprecisionc; Undetected Low due to 36/862 (4.2) 15/1,091 (1.4) RR 0.36 Without severe ovarian
27-35 d risk of inconsistency indirectnessa wide CI for indirectness (0.20-0.67) hyperstimulation syndrome
postoperative bias orthopedic control group and imprecision 2 VTE 1 fewer VTE
surgery risk estimates per 1,000d per 1,000
(from 2 fewer
to 0 fewer)

With severe ovarian
hyperstimulation syndrome
40 VTE 26 fewer VTE
per 1,000d per 1,000
(from 32
fewer to
13 fewer)
Major bleed (critical outcome)
5,456 (7 RCTs), No serious No serious Serious c
Serious imprecision ; Undetected Low 2/1,480 (0.14) 6/1,245 (0.48) RR 0.43 30 bleeding 17 fewer bleeding
3 wk-9 mo risk of inconsistency indirectnessa wide CI for (0.11-1.65) events events per
bias orthopedic control group per 1,000d 1,000
surgery risk estimates (from 27 fewer
to 20 more)
Bibliography: Hull RD, et al. Extended out of hospital low molecular weight heparin prophylaxis against deep vein thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med.
2001;135:858-869. RCT 5 randomized controlled trial. See Table S4 and S6 legends for expansion of other abbreviations.
a The population did not include pregnant women. Different doses of LMWH were used, treatment was initiated variably before or after surgery with a duration of 7 days (in hospital). Outcomes were

variably reported, meta-analysis also provides other outcomes such as mortality, asymptomatic DVT, and specific bleed outcomes (wound hematoma, transfusion). Follow-up varied between trials from
3 wk to 9 mo.
b Time frame is 9 mo for all outcomes.
c Imprecise control group risk estimates for bleeding events and for VTE in the subset of women with ovarian hyperstimulation (Tables S6-S8).
d Control group risk for VTE and major bleed come from observational studies of women undergoing assisted reproductive technology (Tables S6-S8).
13
Table S10[Section 6.2.1-6.2.4] Risk Factors for Pregnancy-Associated VTE
Risk Factor Adjusted OR 95% CI
Immobility (strict bed rest for 1 wk in the antepartum period) with BMI 25 kg/m (antenatal risk)
2 62.3 11.5-337.0
Immobility (strict bed rest for 1 wk in the antepartum period) with BMI 25 kg/m2 (postpartum risk) 40.1 8.0-201.5
Factor V Leiden homozygosity 34.4 9.9-120.1
Prothrombin G20210A homozygosity 26.4 1.2-559.3
Previous VTE 24.8 17.1-36
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following vaginal delivery 20.2 6.4-63.5
Postpartum hemorrhage 1,000 mL with surgery 12.0 3.9-36.9
Immobility (strict bed rest for 1 wk in the antepartum period) with BMI , 25 kg/m2 (postpartum risk) 10.8 4.0-28.8
Systemic lupus erythematosus 8.7 5.8-13.0
Factor V Leiden heterozygosity 8.3 5.4-12.7
Immobility (strict bed rest for 1 wk in the antepartum period) with BMI , 25 kg/m (antepartum risk)
2 7.7 3.2-19.0
Blood transfusion 7.6 6.2-9.4
Heart disease 7.1 6.2-8.3
Prothrombin G20210A heterozygosity 6.8 2.5-18.8
Sickle cell disease 6.7 4.4-10.1
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following cesarean section 6.2 2.4-16.2
Preeclampsia with fetal growth restriction 5.8 2.1-16
Multiple pregnancy 4.2 1.8-9.7
BMI . 30 kg/m2 5.3 2.1-13.5
Protein C deficiency 4.8 2.2-10.6
Antithrombin deficiency 4.7 1.3-17.0
Assisted reproductive techniques 4.3 2.0-9.4
Postpartum hemorrhage . 1 L 4.1 2.3-7.3
Fetal growth restriction (gestational age 1 sex-adjusted birth weight , 2.5th percentile) 3.8 1.4-10.2
Smoking (10-30 cigarettes/d prior to or during pregnancy) (postpartum risk) 3.4 2.0-5.5
Protein S deficiency 3.2 1.5-6.9
Preeclampsia 3.1 1.8-5.3
Emergency cesarean section 2.7 1.8-4.1
Anemia 2.6 2.2-2.9
Smoking (10-30 cigarettes/d prior to or during pregnancy) (antepartum risk) 2.1 1.3-3.4
Smoking (5-9 cigarettes/d prior to or during pregnancy) (postpartum risk) 2.0 1.1-3.7
Weight gain . 21 kg (vs 7-21 kg) 1.6 1.1-2.6
Parity . 1 1.5 1.1-1.9
Age . 35 y 1.3 1.0-1.7
Cesarean section (nonemergent) 1.3 0.7-2.2
Data are from Jacobsen et al, Jacobsen et al, Lindqvist et al, Simpson et al, Knight, Roberston et al, and James et al.
16 28 29 30 31 32 33
14

Table S11[6.2.1-6.2.4] Risk Factors for Postpartum VTE
Risk Factor Adjusted OR 95% CIs
Immobility (strict bed rest for 1 wk in the antepartum period) with BMI 25 kg/m 2 40.1 8.0-201.5
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following vaginal delivery 20.2 6.4-63.5
Postpartum hemorrhage 1,000 mL with surgery 12.0 3.9-36.9
Immobility (strict bed rest for 1 wk in the antepartum period) with BMI , 25 kg/m2 10.8 4.0-28.8
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following cesarean section 6.2 2.4-16.2
Preeclampsia with fetal growth restriction 5.8 2.1-16
Postpartum hemorrhage . 1 L 4.1 2.3-7.3
Fetal growth restriction (gestational age 1 sex-adjusted birth weight , 2.5th percentile) 3.8 1.4-10.2
Smoking (10-30 cigarettes/d prior to or during pregnancy) 3.4 2.0-5.5
Preeclampsia 3.1 1.8-5.3
Emergency cesarean section 2.7 1.8-4.1
BMI prepregnancy . 25 kg/m 2 2.4 1.7-3.3
Smoking (5-9 cigarettes/d prior to or during pregnancy) 2.0 1.1-3.7
Cesarean section (nonemergent) 1.3 0.7-2.2
Data are from Jacobsen et al.16
15

Table S12[Section 6.2.1-6.2.4] Evidence Profile: LMWH vs No Thromboprophylaxis for Prevention of VTE in Women Undergoing Cesarean Section
Study Event Rates (%)a Anticipated Absolute Effectsb
Participants Relative Risk Difference

(Studies), Publication Overall Quality Without Effect Risk Without With LMWH
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence Prophylaxis With LWMH (95% CI) Prophylaxisc (95% CI)
Symptomatic VTE (critical outcome), DVT, and PE (only symptomatic PE, not symptomatic DVT, reported separately in meta-analysis) measured at end of follow-up
4,890 (3 RCTs), No serious risk of No serious Serious No serious Undetected Moderate 22/2,445 (0.9) 5/2,445 (0.02) RR 0.29 Low risk
3 wk-9 mo biasc Selective inconsistency indirectness imprecision (0.11-0.73) 5 VTE 3 fewer VTE
outcome general per 1,000d per 1,000
reporting surgery (from 4 fewer
to 1 fewer)
High risk

30 VTE 21 fewer VTE
per 1,000d per 1,000
(from 27
fewer to
9 fewer)
5,456 (7 RCTs), No serious risk No serious Serious No serious Undetected Moderate 37/2,728 (0.14) 74/2,728 (0.48) RR 2.03 20 bleeding 20 more bleeding
3 wk-9 mo of bias inconsistency indirectnesse imprecision (1.37-3.01) events events per
Heterogeneous per 1,000f 1,000 (from
definitions 8 more to
of bleeding 40 more)
events
Bibliography: Mismetti P, Laporte S, Darmon JY, Buchmller A, Decousus H. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg.
2001;88:913-930. Blondon M, Perrier A, Nendaz M, et al. Thromboprophylaxis with low-molecular-weight heparin after cesarean delivery. A decision analysis. Thromb Haemost. 2010;103:129-137.
See Table S3, S4, S6, and S9 legends for expansion of abbreviations.
a The denominators for LMWH and controls were extracted by dividing total no of participants by two.

b Time frame is 9 mo for all outcomes.
c Only five of eight RCTs of LMWH vs placebo/no treatment reported mortality. We did not rate down for risk of bias.
d For source of control group risk estimates see text and Tables S10 and S11.
e Rated down for indirectness due to variable bleeding definitions in trials (bleeding leading to death, transfusion, reoperation, or discontinuation of therapy) measured at end of therapy.
f Control group risk estimate for major bleeding events comes from study by Blondon et al.
16
Table S13Decision and Cost-Effectiveness Analyses/Economic Analyses Study: Methodologic Key Information
Data Sources
Benefits or
Costs and Are Costs Were
All Relevant Time Benefits and Sensitivity
Type of Type of Strategies Perspect. Frame of Probabilities QOL Completely Benefits Analyses
Study/Year Analysis Model Considered? of Analysis Analysis and Rates Costs Measures Specified? Discounted? Performed? Comments
Casele and Cost- Markov No, pharmacol. Health-care Life-time RCT from Published Published Yes Yes, 3% Deterministic Pharmacologic
Grobman34/2006 effective transition prophylaxis payer of cohort different C/E C/E or Yes prophylaxis
state not patient analyses decision Probabilistic not included as
model considered population analysis No a comparator

Costs included: QOL metrics: Moderate
Underlying Not stated uncertainty
disease in baseline
treatment risk and
Treatment effectiveness
complications Satisfactory
quality but
not definitive
given data
uncertainties
as noted by
authors
Quality categorya:
Very good
Good
Satisfactory
Unsatisfactory

QOL 5 quality of life. See Table S9 legend for expansion of other abbreviation.
a Definitions: very good, 90% to 100% of quality items present; good, 80% to 89% of quality items present; satisfactory, 60% to 79% of quality items present; unsatisfactory, , 60% of quality items present.
17
Table S14Decision and Cost-Effectiveness Analyses/Economic Analyses Study: Description of Study
Outcome Measures
Funding Sources Study Conclusions,

and Potential Assessment of
Strategies Target Conflicts of Continued Relevance,
Study/Year Analyzed Populationsa Effectiveness Costb Interest Additional Commentsc
Casele and Pneumatic Pregnant women undergoing QALYs USD 2004 Funding source Pharmacologic
Grobman34/2006 compression cesarean section who were (if any) not prophylaxis not
Results (expected utilities,
vs no not anticoagulated during stated included as a
ICERs, etc)
prophylaxis pregnancy comparator
Delta costs: 1 $ 104 Moderate uncertainty
Delta QALYs: 1 0.00263 in baseline risk and
ICER: 39,545 (range up to effectiveness
200,000 1, depending Satisfactory quality, but
on assumptions) not definitive given
data uncertainties as
noted by authors
ICER 5 incremental cost-effectiveness ratio; QALY 5 quality adjusted life year; USD 5 US dollar.
a Types of patients/multiple subgroups.
b Average wholesale price (eg, Redbook, Bluebook) or average sales price based estimate.
c Quality category definitions: very good, 90% to 100% of quality items present; good, 80% to 89% of quality items present; satisfactory, 60% to 79%
of quality items present; unsatisfactory, , 60% of quality items present.
18

Table S15[Section 7.1.2] Evidence Profile: Should LMWH Rather Than VKAs Be Used for Long-term Treatment of VTE in Pregnant Women?

Participants Risk Difference

(Studies), Publication Overall Quality Relative Effect Risk With With LMWH
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence With VKA With LMWH (95% CI) VKA (95% CI)
Recurrent symptomatic VTE (critical outcome), DVT, and PE
2,496 (7 RCTs), Serious risk No serious No serious No serious Undetected Moderate due 202/1,231 (16.4) 204/1,265 (16.1) RR 0.62 30 VTE 11 fewer VTE
6 mo of bias inconsistency indirectness imprecision to risk of (0.46-0.84) per 1,000a per 1,000
No studies bias (from 5 fewer
were blinded to 16 fewer)
Major bleeding (critical outcome)
2,727 (8 RCTs), No serious No serious No serious Serious Undetected Moderate 105/1,349 (7.8) 67/1,378 (4.9) RR 0.81 20 bleeding 4 fewer bleeding

6 mo risk of bias inconsistency indirectness imprecision due to (0.55-1.2) events events per
Lack of CI includes imprecision per 1,000c 1,000 (from
blinding not important 9 fewer to 4
seriousb benefit more)
and harm
PTS (important outcome): self-reported leg symptoms and signs
100 (1 RCT), Serious risk No serious Serious No serious Undetected Low due to 31/44 (70.5) 34/56 (60.7) RR 0.85 480 PTS 72 fewer PTS per
not reported of bias inconsistency indirectness imprecision risk of (0.77-0.94) per 1,000d 1,000 (from
Patients and Predictive value bias and 110 fewer to
investigators from 3 mo indirectness 29 fewer)
not blinded to long term
uncertain
Bibliography: Kearon C, Akl EA, Comerato AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-
based clinical practice guidelines. Chest. 2012;141(2)(supp 1):e418S-e494S. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant
treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484-3488. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in
outpatients treated with warfarin. Am J Med. 1998;105:91-99.
Meta-analysis is based on RCTs as referenced in the text of Kearon et al178 in this guideline. Limited to LMWH regimens that used 50% of the acute treatment dose during the extended phase of treat-

ment. PTS 5 postthrombotic syndrome. See Table S1, S3, S4, S6, and S9 legends for expansion of other abbreviations.
a Control group risk estimate for VTE with VKAs comes from cohort study by Prandoni et al, adjusted to 6-mo time frame.
b Outcome less subjective: Borderline decision.
c Control group risk estimate for major bleeding events comes from cohort studies by Prandoni et al and Beyth et al, adjusted to 6-mo time frame.
d Control group risk estimate for PTS comes from observational study of pregnant women (most mild).171
19
Table S16[Section 8.2.2, 8.2.3] Risk of Recurrent VTE in Pregnant Women Without Antepartum Thrombosis Prophylaxis
Prospective studies
Howell RCT N 5 40; n 5 20 No antepartum Bleeding 6 wk Antepartum: RCT, concealment Primary outcome
et al35/1983 in control prophylaxis; Osteopenia postpartum 1 (5%; 95% CI, of allocation was side effects
arm postpartum Recurrent VTE 0.1%-25%) adequate (osteopenia, antenatal
UFH 8,000 Postpartum: 0 bleeding) rather than
bid VTE, no ITT analysis,
mean gestational age
at entry 14 wk (range,
8-37 wk), no objective
diagnosis of first VTE,
no description of
diagnostic techniques

for recurrent DVT
Lao et al36/1985 Prospective N 5 59; 25% women No antepartum Recurrent VTE 6 wk Antepartum: 0
and de Swiet cohort had single previous prophylaxis postpartum Postpartum: 0
et al37/1987 study VTE related to (two protocol
(latter report pregnancy; 39% violations in
provides had single previous which patients
additional VTE during OCP received
data to the use antepartum
first) anticoagulants)
Dextran during
delivery and
heparin or
warfarin for
6 wk postpartum
Brill-Edwards Prospective N 5 125 women No antepartum Recurrent VTE 3 mo Antepartum: Prospective, Inclusion at median
et al38/2000 cohort with one prophylaxis; antepartum postpartum 3/125; 2.4% single episode gestational age of
objectively postpartum Recurrent VTE (95% CI, of prior VTE 15 wk, exclusion of

diagnosed prophylaxis postpartum 0.2%-6.9%) only women with known
previous VTE with warfarin thrombophilia
(Continued)
20
Table S16Continued
No recurrences in
women with no
thrombophilia and a
provoked first VTE
(0/44, 0%; 95% CI,
0%-8.0%); of women
with an idiopathic
first VTE or abnormal
thrombophilia
testing, 3/51
(5.9%; 95% CI, 1.2%-
16.2%) developed
recurrence
Postpartum: 3/122
(2.5%; 95% CI,
0.5%-7.0%)

Badaracco Retrospective N 5 30 women Not stated Recurrent VTE Not stated Total: 6/15 (40%; Retrospective, included
et al39/1974 cohort with previous during (95% CI, 16.3%- women with more
study VTE pregnancy 67.7%); distribution than one previous
or postpartum between antepartum VTE, questionnaire
period and postpartum not data, no objective
provided diagnosis
Tengborn Retrospective N 5 72 women with No antepartum Recurrent VTE; Until Antepartum: 5/67 Retrospective, questionnaire
et al40/1989 cohort previous VTE prophylaxis superficial postpartum; (7.5%; 95% CI, data, no objective
study (87 pregnancies; Postpartum: no thrombophlebitis time not 2%-14%) diagnosis, women with
67 pregnancies prophylaxis (not included in stated Postpartum: 2/30 multiple previous
without antepartum (n 5 30) this table) (6.7%; 95% CI, episodes of VTE
prophylaxis) Various anticoagulant 0%-21%) included, some women
regimens, All recurrences with hereditary
including UFH in women with thrombophilia
and dextran previous VTE (anticoagulant inhibitor
(n 5 57) elicited by deficiencies n 5 3;

pregnancy or defective fibrinolysis
OCP use n 5 18), wide range of
postpartum regimens,
potential confounding
by indication
(Continued)
21
Table S16Continued
Pabinger Retrospective N 5 109 women with No antepartum Cumulative 6 wk Antepartum: 8/197 Assessed risk for Retrospective, included
et al41/2005 cohort previous VTE (197 prophylaxis; incidence of postpartum (cumulative full period of women with more than
study pregnancies; 284 inconsistent use recurrent VTE incidence, 6.2%; pregnancy (ie. one previous VTE, not
postpartum periods, of postpartum antepartum 95% CI, including early all VTE objectively
including after prophylaxis, Recurrent VTE 1.6%-10.6%) terminations, diagnosed, potential
terminations, mainly low-dose postpartum No predictive value miscarriages) confounding by
miscarriages, LMWH (details of thrombophilia indication
stillbirths, and not stated) or whether first
live births) episode was
idiopathic

Recurrence risk
in subgroup of
women with first
VTE associated
with OCP use 10%
vs 2.7% if first VTE
not associated with
OCP use (ns)
Postpartum: overall,
15/284 (5.3%;
95% CI, 3.0%-8.6%);
without prophylaxis,
10/187 (5.4%;
95% CI, 2.6%-9.6%);
with prophylaxis,
5/97 (5.2%; 95% CI,
1.7%-11.6%)

(Continued)
22
Table S16Continued
De Stefano Retrospective N 5 88 women No antepartum Cumulative incidence 6 wk Antepartum: 9/155 Subgroup of Retrospective, included
et al42/2006 cohort with previous prophylaxis; of recurrent VTE postpartum (5.8%; 95% CI, women women with
study VTE (155 120 pregnancies antepartum if delivery 3.0%-10.6%) with first VTE more than one
pregnancies) without postpartum Recurrent VTE after 16 wk Subgroup of women hormonally previous VTE, not
prophylaxis postpartum gestational with and without provoked (ie, all VTE objectively
age thrombophilia: related to diagnosed, potential
7.9% vs 4.2% pregnancy or confounding by
OCP use), 9.5% indication

vs unprovoked,
4.2%, vs transient
nonhormonal
risk factor, 0%
Postpartum: 8.3%
(95% CI,
4.5%-14.6%)
First pregnancy-
related VTE,
15.5% vs first
event-related to
OCP use, 0%,
vs unprovoked,
3.1%, vs transient
nonhormonal
risk factor, 7.1%
ns 5 not significant; OCP 5 oral contraception. See Table S1, S4, and S9 for expansion of other abbreviations.

23
Table S17[Section 8.2.2, 8.2.3] Risk of Symptomatic Recurrent VTE and Bleeding in Pregnant Women Receiving Antepartum Thrombosis Prophylaxis: RCTs
Study/Year Type of Study Participants Intervention Control Outcomes Follow-up Results Strengths Limitations
Howell RCT N 5 40; n 5 20 Antepartum No antepartum Bleeding 6 wk Recurrent VTE Concealment Primary outcome
et al35/1983 in prophylaxis prophylaxis UFH prophylaxis Osteopenia postpartum Intervention arm: of allocation was side effects
arm 10,000 units Postpartum Recurrent Antepartum, 0/20 adequate (osteopenia, antenatal
bid starting at UFH 8,000 VTE Postpartum, 0/20 bleeding) rather than
enrollment (mean, units bid Control arm: antepartum, VTE, no ITT analysis,
14 wk; range, 1/20 (5%; 95% CI, mean gestational age
8-37 wk) 0.1%-25%); postpartum, at entry 16 wk
Postpartum UFH 0/20 (0%; 95% CI, (range 8-37 wk), no
8,000 units bid 0%-16.8%); estimate objective diagnosis
for 6 wk of effect size, RR 0.33 of first VTE, no
(95% CI, 0.01-7.72) description of
Bleeding diagnostic techniques
Intervention arm, of recurrence

2/20 (10%; 95% CI,
1.24%-31.7%); control
arm, 0/20 (0%, 95% CI,
0%-16.8%); estimate
of effect size, RR 5.00
(95% CI, 0.26-98.00)
Gates RCT N 5 16 Enoxaparin 40 mg Placebo (1 mL Symptomatic 6 mo Recurrent VTE Adequate Pilot study, too small to
et al43/2004 started from saline) confirmed postpartum Intervention arm: concealment draw any conclusions,
antenatal VTE antepartum, 0/8 (0.0%; of allocation recruitment at all
recruitment Symptomatic 95% CI, 0.0%-36.9%); Adequate gestational ages,
until 6 wk osteoporotic postpartum, 0/8 (0.0%; blinding of the majority . 20 wk,
postpartum fractures 95% CI, 0.0%-36.9%) patients and some crossover
Control arm: antepartum, caregivers between groups
0/8 (0.0%; 95% CI, postpartum
0.0%-36.9%); postpartum,
1/8 (12.5%; 95% CI,
3.1%-52.7%); estimate

of effect size, RR 0.33
(95% CI, 0.02-7.14)
Bleeding: none reported
(Continued)
24
Table S17Continued
Study/Year Type of Study Participants Intervention Control Outcomes Follow-up Results Strengths Limitations
Pettil RCT n 5 102 women Antepartum dalteparin Antepartum UFH Recurrent 6 wk Recurrent VTE Concealment Not blinded
et al44/1994 with previous once daily at bid SC starting VTE postpartum Dalteparin arm: 0/48 of allocation
proximal VTE starting dose of at 7,500 Bleeding UFH arm: 0/54 safety, adequate,
or previous 5,000 International International episodes any bleeding objectively

distal VTE Units (, 85 kg) or Units, then complication confirmed
and protein S 7,500 International dose adjusted Dalteparin arm: 9/50 previous
and protein Units (. 85 kg), to maintain (18%; 95% CI, VTE
C deficiency, then dose adjusted aPTT 5-15 s 7.0%-29%)
activated protein C to maintain above upper UFH arm: 35/55
resistance, or anti-Xa levels . 0.20 limit of normal (64%; 95% CI,
associated with units/mL 3 h after 51%-77%)
pregnancy or OCP injection
use (three women
with VTE during
current pregnancy
excluded)
aPTT 5 activated partial thromboplastin time. See Table S1, S3, S4, S16 for expansion of other abbreviations.

25
Table S18[8.2.2, 8.2.3] Risk of Recurrent VTE in Pregnant Women Receiving Antepartum Thrombosis Prophylaxis: Observational Studies
Prospective studies
Blombck Prospective 25 women with Dalteparin weight- Recurrent VTE 6 wk Antepartum Objective Uncontrolled, 14 women
et al45/1998 cohort previous VTE adjusted starting Anti-Xa levels postpartum recurrent VTE: diagnosis were recruited in the
study dose, then adjusted 0/25 (0%; of first VTE second trimester of
to target anti-Xa 95% CI, pregnancy, 3 women
levels of 0.20- 0%-13.7%) did not complete the
0.40 units/mL 3 h study and were
postinjection withdrawn from
the analysis
Brennand Prospective 16 women with Enoxaparin 40 mg Anti-Xa levels Not stated Antepartum: 0/14 Pharmacodynamic study
et al46/1999 cohort an indication once daily; Recurrent VTE (0%; 95% CI,
study for thrombosis postpartum reported in 0%-23.2%)
prophylaxis during not stated the article Postpartum: 1/14
pregnancy; 14 (7.1%; 95% CI,
had a history of 0.2%-34%)
previous VTE

Bauersachs Prospective 810 pregnant Antepartum clinical Symptomatic Not stated Low-risk group: Uncontrolled, included
et al47/2007 cohort women at surveillance; recurrent 0/49 (95% CI, women with multiple
management increased intermediate- and VTE, clinically 0%-7.3%) episodes of VTE,
study risk for VTE; high-dose dalteparin relevant High-risk group: includes women
225 with according to risk bleeding, 2/338 (0.6%; without history of
previous stratification based on serious 95% CI, 0.0%-2.1%) VTE, data in this table
VTE history (see legend) bleeding Very-high-risk group: deduced from article
Women with previous 2/104 (1.9%;
VTE/total: low-risk 95% CI,
group, 49/225; 0.2%-6.8%)
high-risk group,
339/469; very-high-risk
group, 104/116
Dargaud Prospective 286 pregnant Antepartum clinical Symptomatic Not stated, No antenatal LMWH Uncontrolled, may have
et al48/2009 cohort women at surveillance; enoxaparin recurrent VTE, likely 8 wk (risk score , 3): included women with
management increased risk 40 mg once daily bleeding, HIT, postpartum 0/25 (95% CI, multiple episodes of
study for VTE; 183 (60 mg in BMI symptomatic 0%-13.7%) VTE, included women
with previous . 35 kg/m2) starting in osteoporosis, LMWH start in third without history of

VTE the third trimester or serious urticarial trimester (risk score VTE, data in this table
starting early in rash related to 3-5): antepartum, deduced from article
pregnancy according heparin 0/89 (0%; 95% CI,
to a risk score (see 0%-4.1%);
legend); all in addition postpartum, 1/89
to class 2 stockings (1.1%; 95% CI,
0.0%-6.1%)
(Continued)
26
Table S18Continued
No antenatal LWMH, LMWH throughout
n 5 25 pregnancy (risk
Start LMWH in third score 6):
trimester, n 5 89 antepartum,
LMWH throughout 0/69 (0%; 95% CI,
pregnancy, n 5 69 0%-5.2%);
postpartum, 1/69
(1.5%; 95% CI,
0.0%-7.8%)
Bleeding: one

postpartum
hemorrhage
in a woman not
receiving LMWH
Folkeringa Prospective 55 women from Adjusted-dose UFH or Fetal loss Not stated Not stated whether Uncontrolled, may have
et al49/2007 cohort families with LMWH before 16 wk of Symptomatic antepartum or included women with
study antithrombin, gestation and after 36 wk recurrent VTE postpartum: 2/19 multiple episodes of
protein C, and of gestation, with VKAs reported in the (10.5%; 95% CI, VTE, included women
protein S deficiency; in between or adjusted- article 1.3%-33.1%) without history of
22 with a history dose LMWH No major bleeding VTE, data in this table
of VTE. throughout pregnancy reported deduced from article
19 women received
thrombosis
prophylaxis during
pregnancy; 18 were
antithrombin,
protein C, or
protein S deficient

(Continued)
27
Table S18Continued
Rozanski Prospective 90 pregnant women Antepartum clinical Symptomatic Not stated Previous provoked Uncontrolled, abstract
et al50/2009 cohort at increased risk surveillance in women recurrent VTE, clinical only, definition of
management for VTE with previous provoked VTE surveillance: provoked vs idiopathic
study VTE (major risk factor), antepartum previous VTE unclear
n 5 30; 37 pregnancies recurrent VTE,
Dalteparin (dose not 1/37 (2.7%; 95%
stated) in women with CI, 0.5%-13.8%);
previous idiopathic postpartum, 0/36
VTE n 5 60; Previous idiopathic
99 pregnancies VTE, dalteparin:
antepartum,
recurrent VTE
3/99 (3.0%; 95%
CI, 1.0%-8.5%);
postpartum, 0/96

Major bleeding: None
Tengborn Retrospective 72 women with Antepartum: UFH 5,000 Recurrent VTE, Until postpartum, Antepartum: 3/20 Retrospective,
et al40/1989 cohort previous VTE, International Units superficial time not stated (15%, 95% CI, questionnaire data,
study 87 pregnancies; bid (n 5 11), 10,000 thrombophlebitis 0%-31%); two no objective diagnosis,
20 pregnancies International Units (not included occurring in women with multiple
with antepartum bid (n 5 1), 12,500 in this table) lowest UFH dose; previous episodes of
prophylaxis International Units one in woman VTE included, some
bid (n 5 2), aPTT-based with antithrombin women with hereditary
(n 5 2), Unknown deficiency who thrombophilia
regimen (n 5 1) had aPTT-adjusted (anticoagulant inhibitor
UFH started at median dose UFH deficiencies, n 5 3;
of 16th (range, before Postpartum: 2/57 defective fibrinolysis,
conception-30 wk) (3.5%; 95% CI, n 5 18), potential
gestational age 0.4%-12.1%) confounding by
Postpartum: UFH, dose despite prophylaxis indication
not stated (n 5 13); All recurrences in

dextran, dose not women with
stated (n 5 42); UFH previous VTE
and dextran (n 5 1); elicited by
UFH and antithrombin pregnancy or
concentrate (n 5 1) OCP use
(Continued)
28
Table S18Continued
Sanson Systematic review 486 pregnancies Several doses and types Adverse Not stated 3/149 (2%; 95% CI, Review of small case
et al51/1999 of published from 21 reports; of LMWH; low-dose pregnancy 0.7-5.6%) had series and ad hoc
cohort studies 149 pregnancies defined as , 75 anti-Xa events; adverse phlebitis; 2 had identified cohorts,
and cohorts from in women with units/kg; intermediate fetal/neonatal thrombophilia; potential for publication
international previous VTE dose defined as 75-150 events 1 had APLAs; and reporting bias,
interest group anti-Xa units/kg; high Secondary: VTE, 1 low-dose; 2 risk per dose LMWH
dose defined as . 150 thrombocytopenia, intermediate-dose cannot be calculated
anti-Xa units/kg osteoporosis, from the published
hemorrhagic data, diagnostic criteria
episodes first and recurrent VTE

not stated, number
of previous VTE not
stated
Lepercq Retrospective 604 women with Several doses and Maternal safety, Antepartum recurrence, Primary outcome safety
et al52/2001 cohort 649 pregnancies indications of pregnancy n 5 5 (denominator rather than recurrent
study enoxaparin outcome, unclear), all in women VTE
thrombosis neonatal who had had previous Denominator of women
prophylaxis in safety, VTE VTE in current with history of VTE
574 cases recurrence pregnancy while cannot be extracted
taking 40 mg from the article, unclear
Postpartum whether recurrences
recurrence, are real recurrences or
n53 extensions from recent
acute VTE, diagnostic
criteria first and
recurrent VTE not
stated, number of
previous VTE not stated

(Continued)
29
Table S18Continued
Pabinger Retrospective Unknown number Antepartum UFH Cumulative 6 wk Antepartum: 0/87 Assessed risk Included women with
et al41/2005 cohort of women with 5,000 bid or low-dose incidence of postpartum (0%; 95% CI, of full more than one previous
study previous VTE enoxaparin or dalteparin recurrent VTE 0%-4.1%) period of VTE, not all VTE
who had 87 (dose not stated); antepartum, Postpartum: overall, pregnancy objectively diagnosed,

pregnancies inconsistent use of recurrent VTE 15/284 (5.3%; (ie, including potential confounding
with antepartum postpartum prophylaxis, postpartum 95% CI, 3.0%-8.6%); early by indication
prophylaxis mainly low-dose LMWH without prophylaxis, terminations,
284 postpartum (details not stated) 10/187 (5.3%; miscarriages)
periods, including 95% CI, 2.6%-9.6%);
after terminations, with prophylaxis,
miscarriages, 5/97 (5.2%; 95% CI,
stillbirths, and 1.7%-11.6%)
live births
Bauersachs et al47: Risk stratification for women with previous VTE: (1) low-risk patients, prior secondary VTE (not associated with thrombophilia, pregnancy, oral contraception); (2) high-risk patients, prior
VTE and thrombophilia, prior idiopathic VTE, prior VTE during pregnancy or oral contraception, recurrent secondary VTE; (3) very-high-risk patients, antithrombin deficiency and prior VTE, antiphospho-
lipid syndrome and prior VTE or arterial thromboembolism, acute VTE in current pregnancy after day 11. Dargaud et al48: Risk stratification using an individual risk score, see Table 1 in original publication.
HIT 5 heparin-induced thombocytopenia. See Table S1, S4, S8, S16, and S17 legends for expansion of other abbreviations.

30
Table S19[Section 8.2.2, 8.2.3] Antepartum and Postpartum Prevention of VTE With Prophylactic-Dose LMWH vs No Prophylaxis in Pregnant Women
With Prior VTE


Follow up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence Prophylaxis With LWMH (95% CI) Prophylaxis (95% CI)

Symptomatic VTE (critical outcome), DVT and PE
1,953 (6 RCTs), No serious No serious Serious Serious Undetected Low due 36/862 (4.2) 15/1,091 (1.4) RR 0.36 Low risk (transient risk factor)
27-35 d risk of inconsistency indirectnessa imprecisionb to indirectness (0.20-0.67) 20 VTE 13 fewer VTE
postoperative bias orthopedic Wide CI for and imprecision per 1,000c per 1,000 (from
surgery control group 16 fewer to
risk estimates 7 fewer)
Intermediate and high risk
(pregnancy or estrogen related,
idiopathic, or multiple prior VTE
but discontinued VKA)
40 VTE 26 fewer VTE
per 1,000c per 1,000 (from
32 fewer to
13 fewer)
(Continued)

31
Table S19Continued


Follow up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence Prophylaxis With LWMH (95% CI) Prophylaxis (95% CI)
Major bleed (critical outcome) d
5,456 (7 RCTs), No serious No serious Serious Serious Undetected Low due 2/1,480 6/1,245 (0.48) RR 0.43 Antepartum period
3 wk-9 mo risk of inconsistency indirectnessa imprecision CI to indirectness (0.14) (0.11-1.65) 5 bleeding 3 fewer bleeding
bias orthopedic includes benefit and imprecision events events per 1,000

surgery and harm per 1,000e (from 4 fewer
to 3 more)
Postpartum period
20 bleeding 11 fewer bleeding
events events per 1,000
per 1,000e (from 18 fewer
to 13 more)
Hull RD et al. Extended out of hospital low molecular weight heparin prophylaxis against deep vein thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med. 2001;135:
858-869. Greer IA, Nelson-Piercy C. Low molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood.
2005;106:401-407. See Table S3, S4, S6, S9 legends for expansion of abbreviations.
a Population is indirect; the population did not include pregnant women. Different doses of LMWH were used, treatment was initiated variably before or after surgery with a duration of 7 days (in hospi-
tal). Outcomes variably reported. Meta-analysis also provides other outcomes, such as mortality, asymptomatic DVT, and specific bleed outcomes (wound hematoma, transfusion). Follow-up varied among
trials from 3 wk to 9 mo.
b Baseline risk estimates for VTE in the antepartum and postpartum period come from studies summarized in Table S16. Quality of evidence is rated down because of imprecision in these risk estimates.
We consider the distribution of VTE antepartum and postpartum to be equal.

cBaseline risk estimates for VTE in the antepartum and postpartum period come from studies summarized in Table S16. We consider the distribution of VTE antepartum and postpartum to be equal.
d Defined nonfatal maternal hemorrhage (according to section 1.0) as a symptomatic bleeding complication noted during pregnancy or within 6 weeks postpartum that involved bleeding into a critical site,

bleeding causing a fall in hemoglobin level of 2 g/dL or more, and bleeding leading to transfusion of 2 units of whole blood or red cells.
e Baseline risk estimate for major maternal hemorrhage comes from a systematic review by Greer et al.38
32
Table S20[Section 9.2.1-9.2.4] Evidence Profile: Antepartum and Postpartum Prophylactic-Dose LMWH vs No Thromboprophylaxis for Pregnant Women
With a Known Thrombophilia

Antepartum and Postpartum (Different
Study Event Rates (%) Risk Estimates for Bleeding Events)
Participants Relative Risk

(Studies), Publication Overall Quality Without Effect Without Risk Difference With
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence Prophylaxis With LWMH (95% CI) Prophylaxis LMWH (95% CI)
Symptomatic VTE (critical outcome), DVT, and PE
1,953 (6 RCTs), No serious No serious Serious Serious Undetected Low due to 36/862 (4.2) 15/1,091 (1.4) RR 0.36 Positive family history VTE and
27-35 d risk of inconsistency indirectnessa imprecisionb indirectness (0.20-0.67) heterozygous factor V Leiden or
postoperative bias orthopedic Wide CI for and imprecision prothrombin 202010A
surgery control 15 VTE 10 fewer VTE per 1,000

group risk per 1,000c (from 12 fewer to
estimates 5 fewer)
Positive family history VTE and
antithrombin, protein C or
protein S deficiency
20 VTE 13 fewer VTE per 1,000
per 1,000c (from 16 fewer to
6 fewer)
Positive family history VTE and
homozygous factor V Leiden or
prothrombin 20210A
70 VTE 47 fewer VTE per 1,000
per 1,000c (from 56 fewer to
21 fewer)
No family history of VTE but
homozygous factor V Leiden or
prothrombin 20210A

20 VTE per 13 fewer VTE per 1,000
1,000c (from 16 fewer to
6 fewer)
(Continued)
33
Table S20Continued

Antepartum and Postpartum (Different
Study Event Rates (%) Risk Estimates for Bleeding Events)
Participants Relative Risk

(Studies), Publication Overall Quality Without Effect Without Risk Difference With
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence Prophylaxis With LWMH (95% CI) Prophylaxis LMWH (95% CI)

5,456 (7 RCTs), No serious No serious Serious Serious Undetected Low due to 2/1,480 (0.14) 6/1,245 (0.48) RR 0.43 Antepartum period
3 wk-9 mo risk of inconsistency indirectness imprecision indirectness (0.11-1.65) 5 bleeding 3 fewer bleeding events
bias orthopedic CI includes and events per 1,000 (from 4
surgery benefit and imprecision per 1,000d fewer to 3 more)
harm
Postpartum period
20 bleeding 11 fewer bleeding events
events per per 1,000 (from 18
1,000d fewer to 13 more)
Bibliography: Hull RD, et al. Extended out of hospital low molecular weight heparin prophylaxis against deep vein thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med.
2001;135:858-869. Greer IA, Nelson-Piercy C. Low molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.
Blood. 2005;106:401-407. See Table S3, S4, S6, and S9 legends for expansion of abbreviations.
a The population did not include pregnant women. Different doses of LMWH were used, treatment was initiated variably before or after surgery with a duration of 7 days in hospital and 25 days out
of hospital. Outcomes were variably reported.

b Imprecision in baseline risk estimates for all thrombophilias (see Table S22) results in imprecise anticipated absolute effects.
c Baseline risk estimate for VTE comes from observational studies summarized in Table S22. Our antepartum risk estimate is based on assumed equal distribution of antepartum and postpartum VTE events
based on data from observational studies (I. A. Greer, MD, personal communication, November 8, 2010).
d Baseline risk estimate for major bleeding events antepartum and postpartum come from systematic review by Greer.

34
Table S21[Section 10.2.3. 10.2.4] Randomized Trials and Observational Studies of the Prevention of Complications in Pregnant Women With Thrombophilia:
Clinical Description and Results
Number Patients Length of Pregnancy Fetal Growth Placental Maternal

Study/Year Intervention Analyzed Follow-up Loss (%) Restriction (%) Preeclampsia (%) Abruption (%) Bleeding (%) Comments
Randomized trials
Thrombophilia-APLA
Aspirin vs placebo
Cowchock and Aspirin 81 mg/d Aspirin 5 11 Pregnancy loss Aspirin 5 1/11 Aspirin 5 0/10 NR NR NR
Reece53/1997 or delivery (9.1)
Usual care Usual 5 8 Usual 5 0/8 Usual 5 1/8 (12.5)
RR 2.25 RR 0.27
(0.10-49.04) (0.01-5.92)
Tulppala Aspirin 50 mg/d Aspirin 5 6 Pregnancy loss Aspirin 5 5/6 (83) NR NR NR NR Pregnancy losses
et al54/1997 or delivery include: ASA
Placebo Placebo 5 6 Placebo 5 3/6 1/6 5 blighted
(50.0) ovum; control

3/6 5 blighted
RR 1.20
ovum or
(0.48-2.99)
ectopic
pregnancy
Pattison Aspirin 75 mg/d Aspirin 5 20/25 Pregnancy loss Aspirin 5 4/20 Aspirin 5 1/16 Aspirin 5 3/20 NR Aspirin 5 9/20 All bleeding
et al55/2000 (80.0%) or delivery (20.0) (6.2) (15.0) (45.0) events minor
Placebo Placebo 5 20/25 Placebo 5 3/20 Placebo 5 4/17 Placebo 5 3/20 Placebo 5 7/20
(80.0%) (15.0) (23.5) (15.0) (35.0)
RR 1.33 RR 0.27 RR 1.00 RR 1.29
(0.34-5.21) (0.03- 2.13) (0.23- 4.37) (0.6-2.72)
UFH 1 aspirin vs aspirin alone
Rai et al56/1997 UFH 5,000 units UFH 1 Pregnancy loss UFH 1 UFH 1 UFH 1 NR NR
SC bid 1 aspirin aspirin 5 45/45 or delivery aspirin 5 13/45 aspirin 5 3/32 aspirin 5 0/32
75 mg/d (28.9) (9.4) (0.0)
Aspirin 75 mg/d Aspirin 5 45/45 Aspirin 5 26/45 Aspirin 5 1/19 Aspirin 5 1/19
(57.8) (5.3) (2.2)

RR 0.50 RR 1.78 RR 0.33
(0.30- 0.84) (0.20-15.93) (0.01-7.92)
Goel et al57/2006 UFH 5,000 UFH 1 Pregnancy loss Overall: UFH 1 UFH 1 NR No major
International aspirin 5 33/33 or delivery UFH 1 aspirin 5 2/28 aspirin 5 0/28 bleeding
Units SC bid 1 (100%) aspirin 5 5/33 (15) (0) due to
aspirin 80 mg/d (15.2) heparin
(Continued)
35
Table S21Continued

Aspirin 80 mg/d Aspirin 5 39/39 Aspirin 5 15/39 Aspirin 5 1/24 Aspirin 5 2/24
(100%) (38.5) (4.2) (8.3)
RR 0.39
(0.16-0.97)
First trimester
loss:
UFH 1
aspirin 5 4/33
(12.1)
Aspirin 5 13/39
(33.3)
Kutteh58/1996 UFH 5,000 units UFH 1 Pregnancy loss UFH 1 UFH 1 aspirin UFH 1 NR UFH 1 All bleeding
SC bid adjusted aspirin 5 25/25 or delivery aspirin 5 5/25 5 3/20 (15.0) aspirin 5 2/20 aspirin 5 3/20 events

to attain 6 h (20.0) (10.0) (15.05) considered
postinjection minor
aPTT at 1.2-1.5
times baseline 1
aspirin 81 mg/d
Aspirin 81 mg/d Aspirin 5 25/25 Aspirin 5 14/25 Aspirin 5 1/11 Aspirin 5 1/11 Aspirin 5 1/11
(56.0) (9.1) (9.1) (9.1)
RR 0.36 RR 1.65 RR 1.10 RR 1.65
(0.15- 0.84) (0.19-14.03) (0.11-10.81) (0.19- 14.03)
LMWH 1 aspirin vs aspirin alone
Farquharson LMWH 5,000 LMWH 1 Pregnancy loss LMWH 1 NR NR NR NR
et al59/2002 units/d SC until aspirin 5 51/51 or delivery aspirin 5 11/51
delivery 1 (21.6)
aspirin 75 mg/d
Aspirin 75 mg/d Aspirin 5 47/47 Aspirin 5 13/47
(27.6)
RR 0.78

(0.39- 1.57)
Laskin LMWH 5,000 LMWH 1 Pregnancy loss LMWH 1 LMWH 1 NR NR NR Early losses not
et al60/2009 International aspirin 5 22/22 or delivery aspirin 5 5/22 aspirin 5 3/17 stratified by
Units SC daily (100%) (22.7) (17.6) thrombophilia
until delivery 1 type
aspirin 81 mg/d
(Continued)
36
Table S21Continued

Aspirin 81 mg/d Aspirin 5 20/20 Aspirin 5 5/20 Aspirin 5 6/15 (40)
(100%) (25.0) (IUGR numbers
include one
twin who was
stillborn)
RR 0.91
(0.31-2.68)
LMWH 1 aspirin vs UFH 1 aspirin
Stephenson Aspirin 81 mg/d LMWH 1 Pregnancy loss LMWH 1 NR LMWH 1 NR NR
et al61/2004 starting prior to aspirin 5 14/14 or delivery aspirin 5 4/13 aspirin 5 1/9
conception 1 (100.0) (30.7) (11.1)
LMWH luteal
phase or first

trimester dalteparin
2,500 International
Units SC once
daily; second
trimester dalteparin
5,000 International
Units SC once
daily; third trimester
dalteparin 7,500
International Units
SC once daily
Aspirin 81 mg/d UFH 1 UFH 1 UFH 1
starting prior to aspirin 5 14/14 aspirin 5 9/13 aspirin 5 0/4
conception 1 UFH (100.0) (69.2) (0.0)
luteal phase or first
trimester 5,000
units SC bid;
second trimester

7,500 units SC bid;
third trimester
10,000 units SC bid
RR 0.44 RR 3.00
(0.18-1.08) (0.13-67.52)
(Continued)
37
Table S21Continued

Hereditary thrombophilia
LMWH vs aspirin
Gris et al62/2004 LMWH (enoxaparin LMWH 5 80/80 Pregnancy loss LMWH 5 11/80 LMWH 5 7/71 LMWH 5 4/71 NR NR
40 mg/d SC) 1 or delivery (13.7) (9.9) (5.6)
folic acid 5 mg/d
Aspirin 100 mg/d 1 Aspirin 5 80/80 Aspirin 5 57/80 Aspirin 5 7/23 Aspirin 5 3/23
folic acid 5 mg/d (71.2) (30.4) (13)
RR 0.19 RR 0.32 RR 1.33
(0.11- 0.34) (0.13-0.83) (4.77-0.69)
Observational Studies
ThrombophiliaAPLA

Noble Aspirin 81 mg daily LMWH 1 2 wk LMWH 1 LMWH 1 LMWH 1 NR LMWH 1 All bleeding
et al63/2005 starting prior to aspirin 5 25/25 postdelivery aspirin 5 4/25 aspirin 5 1/21 aspirin 5 0/21 aspirin 5 3/25 events
conception 1 (16.0) (4.8) (0) (12.0) classified
LMWH as minor
(enoxaparin
40 mg/d SC)
Aspirin 81 mg daily UFH 1 aspirin UFH 1 UFH 1 UFH 1 UFH 1
starting prior to 5 25/25 aspirin 5 5/25 aspirin 5 1/20 aspirin 5 0/20 aspirin 5 2/25
conception 1 UFH (20.0) (5.0) (0) (5.0)
(5,000-6,000 units
SC bid, depending
on weight)
RR 0.80 RR 0.95 RR 1.00 RR 1.5
(0.24-2.64) (0.06-14.22) (0.02-48.53) (0.27-8.22)
UFH higher dose 1 aspirin vs UFH lower dose 1 aspirin
Kutteh and UFH 5,000 units SC UFH higher Pregnancy loss UFH higher NR NR NR NR
Ermel64/1996 bid adjusted to dose 1 or delivery dose 1

maintain aPTT at aspirin 5 25/25 aspirin 5 5/25
1.2-1.5 3 baseline (20.0)
(higher dose) 1
aspirin 81 mg/d
(Continued)
38
Table S21Continued

UFH 5,000 units SC UFH lower UFH lower
bid adjusted to dose 1 dose 1
maintain aPTT aspirin 5 25/25 aspirin 5 6/25
at upper limit of (24.0)
normal (lower
dose) 1 aspirin
81 mg/d
RR 0.83
(0.29-2.38)
LMWH vs control
Carp LMWH LMWH 5 37/37 Pregnancy loss LMWH 5 11/37 NR LMWH 5 2/26 NR NR
et al65/2003 (enoxaparin (100%) or delivery (29.7) (7.6)

40 mg/d SC)
Retrospective Control 5 48/48 Control 5 27/48 Control 5 1/21
control (no (100%) (56.3) (4.8)
prophylaxis)
RR 1.89 RR 2.00
(1.09-3.29) (0.19-0.72)
LMWH vs control (untreated)
Leduc LMWH (dalteparin) LMWH 5 13/13 Chart review Data on LMWH LMWH OR Data on placental No major OR: the probability
et al66/2007 varied between (100%) 1994-2001 pregnancy OR 0.81 0.92 Aspirin abruption not bleeding or of developing
3,500 and 7,500 loss not OR 0.87 stratified by maternal an obstetric
International stratified by treatment mortality complication
Units SC bid treatment reported despite
Aspirin 80 mg/d Aspirin 5 11/11 Aspirin OR 0.88 prophylactic
(100%) therapy
(interpreted
to mean the
odds of

complication
compared
with no
treatment)
(Continued)
39
Table S21Continued

LMWH 1 aspirin vs control (untreated)
Leduc LMWH (dalteparin) LMWH 1 Chart review NR LMWH 1 LMWH 1 NR NR OR: the probability
et al66/2007 varied between aspirin 5 26/26 1994-2001 aspirin aspirin of developing
3500 IU SC and (100%) OR 0.70 OR 0.80 an obstetric
7500 IU SC bid 1 complication
aspirin 80 mg/d despite
LMWH (dalteparin) LMWH 5 13/13 LMWH LMWH prophylactic
varied between (100%) OR 0.81 OR 0.92 therapy
3500 and 7,500 (interpreted
International to mean the

Units SC bid odds of
complication
compared
with no
treatment)
Aspirin vs control (untreated)
Leduc LMWH (dalteparin) LMWH 1 Chart review NR LMWH 1 LMWH 1 NR NR OR: the probability
et al66/2007 varied between aspirin 5 26/26 1994-2001 aspirin aspirin of developing
3,500 and 7,500 (100%) OR 0.70 OR 0.80 an obstetric
International complication
Units SC bid 1 despite
aspirin 80 mg/d prophylactic
Aspirin 80 mg/d Aspirin 5 11/11 Aspirin 0.88 Aspirin 0.87 therapy
(100%) (interpreted
to mean the
odds of
complication
compared

with no
treatment)
ASA 5 acetylsalicyclic acid; IUGR 5 intrauterine growth restriction; NR 5 not reported. See Table S1, S3, S4, S8, S9, and S17 legends for expansion of other abbreviations.
40
Table S22[Section 10.2.3, 10.2.4] Randomized Trials and Observational Studies of the Prevention of Complications in Pregnant Women With Thrombophilia:
Methodologic Quality
Randomized Trials
Study/Year Intervention Study Design Randomize Concealed Blinding Lost to Follow-up Analysis Comments
Thrombophilia-APLA
Aspirin vs placebo
Cowchock Aspirin 81 mg/d RCT, PN Patients: PN Aspirin 5 0/11 ITT Population: pregnant women
et al53/1997 Usual care multicenter Caregivers: PN Usual care 5 0/9 with APLA and either 0 (10/19
Data Collectors: PN patients) or 1 (9/19 patients) prior
Adjudicators: PN spontaneous abortion. Women
Data Analysts: PN with thrombosis history or lupus
excluded.
No definition of usual care.
Tulppala Aspirin 50 mg/d RCT, single PY Patients: CY Aspirin 5 0/6 ITT Population: subgroup of 66 pregnant
et al54/1997 Placebo center Caregivers: PY Placebo 5 0/6 women with three to eight
Data Collectors: PY consecutive losses: 12 pregnant

Adjudicators: PN women with APLA of whom two
Data Analysts: PN had blighted ova (one in each
treatment arm), and two had
ectopic pregnancies (placebo group).
Pattison Aspirin 75 mg/d RCT, single CY Patients: CY Aspirin 5 5/25 Not ITT Population: pregnant women with
et al55/2000 Placebo center Caregivers: CY Placebo 5 5/25 APLA and three or more fetal
Data Collectors: CY (5 postrandomization losses. Women with thrombosis
Adjudicators: PN exclusions from each history or lupus excluded.
Data Analysts: PN treatment arm) Ten exclusions after randomization
because of inappropriate inclusion.
Randomization not balanced for
mean gravidity and number
of first trimester losses
(both favoring aspirin).
UFH 1 aspirin vs aspirin alone
Rai et al56/1997 UFH 5,000 units RCT, single PN Patients: CN UFH 1 ITT Population: pregnant women with
SC bid 1 center Caregivers: aspirin 5 0/45 APLA and three or more

aspirin 75 mg/d CN Data Collectors: Aspirin 5 0/45 consecutive miscarriages.
Aspirin 75 mg/d PN Adjudicators: PN Women with prior thrombosis
Data Analysts: PN or lupus excluded.
Treatment stopped at 34 wk or
miscarriage.
(Continued)
41
Table S22Continued
Randomized Trials
Goel et al57/2006 UFH 5,000 RCT, NR Patients: DN UFH 1 ITT Population: pregnant women with
International multicenter Caregivers: DN aspirin 5 0/39 APLA (anticardiolipin) with two
Units SC bid 1 Data Collectors: PN Aspirin 5 0/33 or more first or second trimester
aspirin 80 mg/d Adjudicators: PN miscarriages.
Aspirin 80 mg/d Data Analysts: PN Treatment discontinued at 36 wk
gestation.
Kutteh58/1996 UFH 5,000 units RCT, single Quasi-randomized Patients: DN UFH 1 No Population: pregnant women with
SC bid adjusted center Caregivers: DN aspirin 5 0/25 APLA and three or more
to attain 6 h Data Collectors: PN Aspirin 5 0/25 consecutive miscarriages
postinjection Adjudicators: PN (women with NSI or lupus

aPTT at 1.2-1.5 Data Analysts: PN excluded).
times baseline 1 Alternate assignment of treatment.
aspirin 81 mg/d USPSTF rating of evidence
Aspirin 81 mg/d is II-1.
LMWH 1 aspirin vs aspirin alone
Farquharson LMWH 5,000 units/d RCT, single CY Patients: CN LMWH 5 0/51 ITT Population: pregnant women with
et al59/2002 SC until delivery 1 center Caregivers: CN Aspirin 5 0/47 APLA and at least three
aspirin 75 mg/d Data Collectors: CN consecutive losses or two losses
Aspirin 75 mg/d Adjudicators: CN with fetal death after 10 wk.
Data Analysts: CN
Laskin LMWH 5,000 Open label, Not NR Patients: DN LMWH 1 ITT Population: pregnant women with
et al60/2009 International Units RCT, single Caregivers: DN aspirin 5 0/22 APLA or inherited thrombophilia
SC daily until center Data Collectors: PN (0%) or ANA (only APLA able to be
delivery 1 aspirin Adjudicators: PN Aspirin 5 0/20 (0%) considered here) with two or
81 mg/d Data Analysts: PN more unexplained consecutive
Aspirin 81 mg/d pregnancy losses prior to 32 wk.
Treatment with LMWH

stopped at 35 wk
or delivery.
(Continued)
42
Table S22Continued
Randomized Trials
Stephenson Aspirin 81 mg/d starting Open-label, CY Patients: CN In patients who Unclear Population: women with
et al61/2004 prior to conception RCT, single Caregivers: CN became whether APLA and recurrent
1 LMWH (luteal center Data Collectors: CN pregnant: ITT losses.
phase or first trimester Adjudicators: PN LMWH 1 Patients randomized prior to
dalteparin 2,500 Data Analysts: PN aspirin 5 0/13 conception (one patient in
International Units UFH 1 each group did not become
SC once daily; second aspirin 5 0/13 pregnant during study).
trimester dalteparin Hereditary thrombophilia.
5,000 International
Units SC once daily;
third trimester

dalteparin 7,500
International Units
SC once daily)
Aspirin 81 mg/d starting
prior to conception 1
UFH (luteal phase or
first trimester 5,000
units SC bid; second
trimester 7,500 units
SC bid; third trimester
10,000 units SC bid)
Hereditary thromphilia
LMWH vs aspirin alone
Gris et al62/2004 LMWH (enoxaparin RCT CY Patients: CN 14/174 (8%) lost Unclear Population: women with factor V
40 mg/d SC) and Caregivers: CN prior to whether Leiden, prothrombin gene
folic acid 5 mg/d Data Collectors: PN allocation ITT mutation, or protein S deficiency
Aspirin 100 mg/d and Adjudicators: PN LMWH 5 0/80 and a single loss after 10 wk.

folic acid 5 mg/d Data Analysts: PN Aspirin 5 0/80 Women with other hereditary
thrombophilia, lupus, APLA,
or prior thrombosis were
excluded.
(Continued)
43
Table S22Continued
Effectively
Blinded
Intervention/Control Intervention/Control Assessment
Study/Year Intervention Study Design Setting Similar? Time Frame Similar? Adjustment of Outcome Lost to Follow-up Comments
Noble et al63/2005 Aspirin 81 mg/d Prospective Very Identical All relevant No LMWH 1 Population: women with
starting prior to cohort, variables aspirin 5 0/25 APLA and three or more
conception 1 two center UFH 1 aspirin pregnancy losses before
LMWH (enoxaparin 5 0/25 20 wk.
40 mg/d SC) Treatment regimen based
Aspirin 81 mg/d starting on enrolling center.
prior to conception 1 LMWH stopped 3 wk before
UFH (5,000-6,000 estimated due date or 5 d

units SC bid, prior to scheduled
depending on weight) induction or
cesarean section.
UFH discontinued with
spontaneous labor.
UFH higher dose 1 aspirin vs UFH lower dose 1 aspirin
Kutteh and UFH 5,000 units Prospective Very Close All relevant No UFH (higher Population: pregnant women
Ermel64/1996 SC bid adjusted cohort, variables dose) 1 with APLA and at least
to maintain aPTT single center aspirin 5 0/25 three consecutive
at 1.2 to 1.5 times UFH (lower miscarriages. Women
baseline (higher dose) 1 with NSI or lupus
dose) 1 aspirin aspirin 5 0/25 excluded.
81 mg/d Alternate assignment of
UFH 5,000 units SC treatments.
bid adjusted to
maintain aPTT at
upper limit of normal

(lower dose) 1
aspirin 81 mg/d
(Continued)
44
Table S22Continued
Effectively
Blinded
Intervention/Control Intervention/Control Assessment
Study/Year Intervention Study Design Setting Similar? Time Frame Similar? Adjustment of Outcome Lost to Follow-up Comments
LMWH vs control
Carp et al65/2003 LMWH (enoxaparin Prospective Very Close Most No LMWH 5 0/37 Population: women with
40 mg/d SC) cohort, Control 5 0/48 hereditary thrombophilia
Retrospective single center and three or more
control consecutive losses in
(no prophylaxis) first or second trimesters.
Patients were excluded if
prior thrombosis or APLA.
Controls were women

retrieved from a
database, matched
for number of
miscarriages, maternal
age, and time taken
to conceive.
LMWH 1 aspirin vs aspirin vs LMWH
66
Leduc et al /2007 LMWH (dalteparin) Retrospective Very Identical Some: use No LMWH 1 Population: women who
varied between cohort, single of LMWH aspirin 5 0/26 received antithrombotic
3,500 and 7,500 center or ASA and Aspirin 5 0/11 prophylaxis during
International Units gestation age LMWH 5 0/13 pregnancy between 1997
SC bid 1 aspirin and 2001 or a history
80 mg/d of previous pregnancy
Aspirin 80 mg/d complicated by severe
LMWH (dalteparin) preeclampsia, placental
varied between abruption, fetal growth
3,500 and 7,500 restriction, second or
International third trimester fetal loss,

Units SC bid and associated hereditary
thrombophilia. Excluded if
previous thromboembolic
disorder or APLA.
ANA 5 antinuclear antibody; CY 5 certain yes; DN 5 definite no; NSI 5 nonspecific inhibitor; PN 5 probable no; PY 5 probable yes. See Table S1, S4, S8, S9, and legends S17 for expansion of other
abbreviations.
45
Table S23[Section 10.2.1,10.2.3] Evidence Profile: Should UFH Plus Aspirin or Aspirin Alone Be Used for Pregnant Women With APLA and Recurrent Pregnancy
Loss?
Study Event Rates (%) Anticipated Absolute Effectsa
Participants Overall With Relative Risk Difference

(Studies), Publication Quality of With UFH 1 Effect Risk With With Addition of
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias Evidence Aspirinb Aspirin (95% CI) Aspirinb UFH (95% CI)
Pregnancy loss (critical outcome)

212 (3 RCTs), Serious risk of No serious No serious No serious Undetected Moderate 55/109 (50) 23/103 (22) RR 0.44 500 pregnancy 283 fewer pregnancy
not bias inconsistency indirectness imprecision due to risk (0.30-0.66) losses losses per 1,000
reported Issues of of bias per 1,000 (from 172 fewer
randomization, to 353 fewer)
allocation
concealment,
and blinding
IUGR (critical outcome) estimated fetal weight , 10th percentile for gestational age
134 (3 RCTs), Serious risk No serious No serious Very serious Undetected Very low due 3/54 (5.6) 8/80 (10) RR 1.71 56 IUGR 39 more IUGR
not of bias inconsistency indirectness imprecision to risk of (0.48-6.17) per 1,000 per 1,000 (from
reported Issues of CI includes bias and 29 fewer to
randomization, important imprecision 287 more)
allocation benefit and
concealment, harm
and blinding
(Continued)

46
Table S23Continued
Study Event Rates (%) Anticipated Absolute Effectsa
Participants Overall With Relative Risk Difference

(Studies), Publication Quality of With UFH 1 Effect Risk With With Addition of
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias Evidence Aspirinb Aspirin (95% CI) Aspirinb UFH (95% CI)
Preeclampsia (critical outcome) not clearly defined

134 (3 RCTs), Serious risk of No serious No serious Serious Undetected Low due to 4/54 (7.4) 2/80 (2.5) RR 0.43 74 preeclampsia 42 fewer
not bias inconsistency indirectness imprecision risk of (0.09-2.08) per 1,000 preeclampsia per
reported Issues of CI includes bias and 1,000 (from 67
randomization, important imprecision fewer to 80 more)
allocation benefit and
concealment, harm
and blinding
Major Bleeding (critical outcome) not reportedc
Bibliography: Data from unpublished meta-analysis based on three trials: Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is
superior to low-dose aspirin alone. Am J Obstet Gynecol. 1996;174:1584-1589. Rai R, Cohen H, Dave M, et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with
recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;314:253-257. Goel N, Tuli A, Choudhry R. The role of aspirin versus aspirin and heparin in cases
of recurrent abortions with raised anticardiolipin antibodies. Med Sci Monit. 2006(3):CR132-CR136. PO Vandvik, MD, personal communication, October 2010. See Table S1, S3, S9, and S21 legends for
expansion of abbreviation.
a Time frame is 9 mo for all outcomes.
b Estimates for baseline risk with aspirin comes from the meta-analysis of three trials.
c Although a patient important outcome defined as in 1, none of the three trials reported major bleeding events.

47
Table S24[Section 11.1.1] Evidence Profile: Should Aspirin Rather Than No Treatment Be Used for Prevention of Preeclampsia in Women Without Thrombophilia?


(Studies), Publication Quality of Without Effect Risk Without With LMWH
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias Evidence Prophylaxis With LWMH (95% CI) Prophylaxis (95% CI)
Preeclampsia (critical outcome) defined as proteinuric preeclampsia in Cochrane systematic review
32,590 No serious Serious No serious No serious Undetected Moderate 1,292/16,194 1,081/16,396 RR 0.83 Low risk for preeclampsia
(43 RCTs,) risk of bias inconsistencya indirectness imprecision due to (8) (6.6) (0.77-0.89)
not reported Variability I2 5 46, Benefit even inconsistency 60 cases 10 fewer per 1,000
across trials P , .001 at lower per 1,000b (from 14 fewer
but not end of CI to 7 fewer)
considered High risk for preeclampsia

to introduce
210 38 fewer per 1,000
bias
per 1,000b (from 46 fewer
to 23 fewer)
Major bleed (critical outcome)c
95,000 No serious risk No serious Serious No serious Undetected Moderate 219/47,500 335/47,500 RR 1.54 15 bleeding 8 more bleeding
(6 RCTs), of bias inconsistency indirectnessd imprecision due to (0.5) (0.7) (1.30-1.82) events events per 1,000
3.8-10 y Primary indirectness per 1,000e (from 5 more to
prevention 12 more)
cardiovascular
disease
Bibliography: Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007;(2):CD004659. Greer IA,
Nelson-Piercy C. Low molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106:401-407.
See Table S3, S4, and S9 legends for expansion of abbreviations.
a Heterogeneity might be related to different types and doses of antiplatelet agents, the lack of placebo in the control group in many of the trials, different populations of pregnant women concerning risk
of preeclampsia, and effect of treatment.

b Control group risk estimate for preeclampsia is based on control event rates in studies included in subgroup analyses in the meta-analysis. High risk was defined in the systematic review as women who
either were normotensive or had chronic hypertension without superimposed preeclampsia at trial entry and were classified as being at high risk if they had one or more of the following: previous severe

preeclampsia, diabetes, chronic hypertension, renal disease, or autoimmune disease.
c Major antenatal maternal hemorrhage.
d Rated down for indirectness due to population (people included in trials of primary prevention cardiovascular disease). The Cochrane review does not report the effects of antiplatelet therapy on major
bleeding events in pregnant women.

e Control group risk estimate for major bleeding events antepartum from systematic review by Greer et al.
48
Table S25[Section 11.2.1] Evidence Profile: Should LMWH and Aspirin Rather Than No Treatment Be Used for Prevention of Recurrent Pregnancy Loss in
Women Without Thrombophilia?


(Studies), Publication Quality of Without With LMWH Effect Risk Without With LMWH and
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias Evidence Treatment and Aspirin (95% CI) Treatment Aspirin (95% CI)
294 (2 RCTs), 9 mo No serious No serious No serious Serious Undetected Moderate due 62/250 (25.2) 62/244 (25.4) RR 1.01 300 cases 3 more per 1,000
risk of bias inconsistency indirectness imprecision to imprecision (0.84-1.38) per 1,000a (from 48 fewer

important
benefit and
harm
294 (1 RCT), 9 mo No serious No serious No serious Serious Undetected Moderate due 10/147 (6.8) 10/147 (6.8) RR 1.00 15 bleeding 0 more bleeding
risk of bias inconsistency indirectness imprecision to imprecision (0.42-2.33) events per events per 1,000
CI includes 1,000c (from 9 fewer to
benefit and 20 more)
harm
Bibliography: Greer IA, Nelson-Piercy C. Low molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood.
2005;106:401-407. Data from an unpublished meta-analysisd of two RCTs by Kaandorp SP, Maritte Goddijn M, van der Post JAM, et al. Aspirin combined with low-molecular-weight heparin and aspirin
alone in women with recurrent miscarriage. A randomized placebo-controlled trial: the ALIFE study. N Engl J Med. 2010;29:1586-1596 and Clark P, Walker ID, Langhorne P, et al. SPIN (Scottish Pregnancy
Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115:4162-4167. See Table S3, S4,
and S9 legends for expansion of abbreviations.
a Control group risk for miscarriage comes from study event rates in the two available randomized trials by Kaandorp and Clark.
b Bleeding outcomes variably reported in the two trials. We use data from Clark et al on serious adverse events and antepartum hemorrhage to generate both relative risks and baseline risks for anticipated

absolute effects. Kaandorp et al reported nose bleed, GI problem, hematuria, and bleeding gums. There were no major bleeding events (S. Middeldorp, MD, personal communication, October 2010).
c Control group risk estimate for major bleeding events antepartum comes from systematic review by Greer et al.
d Meta-analysis performed in RevMan version 5 with fixed-effects model for heterogeneity.
49
Table S26[Section 11.2.1] Evidence Profile: Should Aspirin Rather Than No Treatment Be Used for Prevention of Recurrent Pregnancy Loss in Women
Without Thrombophilia?

Participants Relative Risk Risk Difference

(Studies), Publication Overall Quality Without Effect Without With Aspirin
Follow-up Risk of Bias Inconsistency Indirectness Imprecision Bias of Evidence Treatment With Aspirin (95% CI) Treatment (95% CI)
202 (1 RCTs), No serious No serious No serious Serious Undetected Moderate due 34/103 (33) 38/99 (38) RR 1.16 300 cases 48 more per 1,000
9 mo risk of bias inconsistency indirectness imprecision to imprecision (0.80-1.69) per 1,000a (from 60 fewer

important
benefit
and harm
95,000 (6 RCTs), No serious No serious Serious No serious Undetected Moderate due 219/47,500 (0.5) 335/47,500 (0.7) RR 1.54 15 bleeding 8 more bleeding
3.8-10 y risk of bias inconsistency indirectnessc imprecision to indirectness (1.30-1.82) events events per 1,000
Primary per 1,000d (from 5 more
prevention to 12 more)
cardiovascular
disease
Bibliography: Kaandorp SP, Maritte Goddijn M, van der Post JAM et al. Aspirin combined with low-molecular-weight heparin and aspirin alone in women with recurrent miscarriage. A randomized
placebo-controlled trial: the ALIFE study. New Engl J Med. 2010;29;362:1586-1596. Clark P, Walker ID, Langhorne P, et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized
controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115:4162-4167. Greer IA, Nelson-Piercy C. Low molecular weight heparins
for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106:401-407. See Table S3 and S9 legends for expansion of
abbreviations.
a Baseline risk for miscarriage comes from study event rates in the two available randomized trials by Kaandorp et al and Clark et al.
b Major antenatal nonfatal hemorrhage.

c Rated down for indirectness due to population (primary prevention cardiovascular disease). There were no major bleeding events in the ALIFE Study (personal communication with authors).
d Control group risk estimate for major bleeding events antepartum comes from systematic review by Greer et al.
e Only study identified that compared aspirin to placebo in this population.
50
Table S27[Section 12.1.1-12.1.3] Systematic Reviews Examining Maternal and Fetal Safety of Anticoagulant Regimens in Pregnant Women With Mechanical
Heart Valves (Methodologic Quality)
List of Studies Appropriate

Inclusive Duplicate Study (Included and Characteristics of Methods Used to Assessment of
Literature Selection and Excluded) Included Studies Assessment of Quality Combine Study Likelihood of
Study/Year Intervention Search Data Extraction Provided Provided of Included Studies Findings Publication Bias
Chan et al1/2000 Studies between 1966 and Yes No No No No Yes No
1997 examining the use
of VKAs and UFH or
no anticoagulation in
pregnant women with

Hassouna and Allam2/2010 Studies between 2000 and No Bi No No No Yes No
2009 examining the use
of VKAs and UFH or
no anticoagulation in
pregnant women with
James et al67/2006 Studies between 1966 and No No No Yes No N/A No
2006 involving pregnant
women with mechanical
heart valves receiving
LMWH
Oran et al68/2004 Studies between 1989 and Yes No No Yes No N/A No
2004 involving pregnant
women with mechanical
heart valves who received
heparin

See Table S1 and S4 legends for expansion of abbreviations.
51
Table S28[Section 12.1.1-12.1.3] Antithrombotic Therapy in Pregnant Women With Mechanical Heart ValvesMaternal Outcomes (Clinical
Description and Results)
Maternal Maternal Maternal

Number of Intracranial Extracranial Systemic
Patients and Maternal Bleeding events, Bleeding events, Thromboembolism,
Country, Study/Year Pregnancies Population Treatment Regimens Deaths, n/N (%) n/N (%) n/N (%) n/N (%)
Cohort studies with comparator groups
Iran, retrospective, 110 women Pregnant women Regimen 1 warfarin Regimen 1, Regimen 1, Regimen 1, 0/142 (0.0) Regimen 1, 6/142 (3.1)
Khamooshi 196 pregnancies with mechanical throughout pregnancy; 5/142 (3.5) 0/142 (0.0) (3 valve thrombosis,
et al69/2007 heart valves INR checked monthly 3 embolism)
Valve type and kept 2.5-3.5
Tilting: 98 Regimen 2 SC UFH for Regimen 2, Regimen 2, Regimen 2, 2/54 (3.7) Regimen 2, 9/54 (16.7)
Bileaflet: 98 the first trimester, 2/54 (3.7) 0/54 (0.0) (2 vaginal bleeding (7 valve thrombosis,
Valve position warfarin until week 36, events treated 2 embolism)
Aortic: 26 then UFH for remainder conservatively)
Mitral: 128 of pregnancy; aPTT
Aortic and kept 2 times control

mitral: 42
No fatal No major GI or major
maternal obstetrical bleeding
bleeding events
events
Korea, retrospective, 25 women Pregnant women Regimen 1 coumarin Regimen 1, Regimen 1, Regimen 1, 0/23 (0.0) Regimen 1, 2/8 (25.0)
Lee et al70/2007 31 pregnancies with mechanical and aspirin throughout 0/8 (0) 0/8 (0.0) (1 valve thrombosis,
heart valves pregnancy with 1 TIA)
Valve position target INR 2.5-3.5, then
Aortic: 4 nadroparin 7,500 units
Mitral: 21 SC q12h for 2 wk
Double valve before due date
replacement: 5 Regimen 2 nadroparin Regimen 2, Regimen 2, Regimen 2, 023 (0.0) Regimen 2, 3/23 (13.0)
7,500 units SC q12h 0/23 (0) 0/23 (0.0) (2 valve thrombosis,
until week 12, then 1 TIA)
coumarins until week
38 when nadroparin
resumed.

Aspirin 100 mg/d
throughout pregnancy
No fatal No maternal major GI
maternal or major obstetrical
bleeding bleeding events
events
(Continued)
52
Table S28Continued

New Zealand, 31 women Pregnant women Regimen 1 predominantly Regimen 1, Regimen 1, Unable to separate Regimen 1, 0/13 (0)
retrospective audit, 47 pregnancies with mechanical warfarin and aspirin 0/13 (0.0) 0/13 (0.0) by regimen
McLintock et al71/2009 heart valves (100-150 mg) throughout Maternal major
Valve type with enoxaparin GI bleeding events:
Starr-Edwards: 12 (1 mg/kg SC q12h) 0/47 (1 minor
Tilting disc or and aspirin substituted hematemesis with
bileaflet: 19 between weeks 6 and enoxaparin)
Valve position 12 and at 34 and 36 wk Maternal major
Mitral:14 gestation obstetrical bleeding
Aortic: 4 Regimen 2 enoxaparin Regimen 2, Regimen 2, events: 19/47 Regimen 2, 5/34 (14.7)

Mitral and (1 mg/kg SC q12h) and 0/34 (0.0) 0/34 (0.0) (2 abruptions and (1 valve thrombosis,
aortic: 13 aspirin (100-150 mg) 1 antepartum 4 TIA, 3/5 associated
predominantly hemorrhage with with noncompliance,
In both regimens, No fatal enoxaparin; 2 events postpartum)
enoxaparin monitored maternal 1 additional
by anti-Xa levels every bleeding abruption during IV
3-7 d; dose adjusted to events UFH around
attain a target predose delivery; 1 additional
level: 0.4-0.7 minor antepartum
International Units/mL hemorrhage with
enoxaparin; 6 primary
postpartum
hemorrhages and
9 secondary
postpartum
hemorrhages)
Major bleeding from
other site: 1/47

(rectus sheath and
epistaxis with IV
UFH around delivery)
(Continued)
53
Table S28Continued

Single-group cohort studies
Norway, retrospective, 11 women Pregnant women Therapeutic doses of 0/12 (0.0) 0/12 (0.0) 4/12 (33.3) 2/12 (16.7) (both
Abildgaard 12 pregnancies with mechanical LMWH q12h throughout 1 subject who No maternal major associated with
et al72/2009 heart valves pregnancy. Aspirin died suddenly GI bleeding events subtherapeutic
Valve position 75 mg/d recommended at 11 wk with Maternal major dosing of LMWH)
Mitral: 4 but discontinued 1 wk no autopsy obstetrical bleeding Maternal ischemic
Aortic: 6 before expected delivery evidence of events: 4 (all stroke: 1
Aortic and date bleeding or postpartum or Maternal nonstroke

mitral: 2 Doses adjusted to attain thrombosis postcesarean section) systemic
peak anti-Xa level of excluded from embolism: 0
0.7-1.2 units/mL analysis Maternal valve
No maternal thrombosis: 1
fatal bleeding
events reported
Japan, retrospective, 12 women Pregnant women Substitution of warfarin 1/16 (6.3) (death 2/16 (12.5) 7/16 (43.8) 3/16 (13.8)
Kawamata 16 pregnancies with mechanical with UFH starting of mother and No maternal major Maternal ischemic
et al73/2007 heart valves between 6-13 wk fetus during GI bleeding events stroke: 0
Valve position and until term replacement Maternal major No maternal nonstroke
Mitral: 7 Doses adjusted to maintain of thrombosed obstetrical bleeding systemic
Aortic: 2 aPTT levels 2-3 times valve) events: 7 (4 perinatal embolism: 0
Tricuspid: 7 control (between 20,000 No fatal maternal bleeding, 3 subchorionic Maternal valve
and 30,000 International bleeding events bleeding events) thrombosis: 2
Units/d)
(Continued)

54
Table S28Continued

England, prospective, 11 women Pregnant women Dalteparin 100 International 0/12 (0.0) Not reported 6/12 (50.0) (3 minor, 1/12 (8.3) (associated
Quinn et al74/2009 12 pregnancies with mechanical Units/kg q12h (8) or No maternal epistaxis, placental with subtherapeutic
heart valves enoxaparin 1 mg/kg q12h fetal bleeding hematoma, secondary anti-Xa levels)
Valve position (4) 1 aspirin 81 mg/d events reported postpartum hemorrhage; No maternal ischemic
Mitral: 4 LMWH doses adjusted to 3 major as below) stroke reported.
Aortic: 2 attain an anti-Xa level No maternal major No maternal nonstroke
Aortic and mitral: 3 1.0-1.2 units/mL GI bleeding events systemic embolism
Systemic right reported reported.
atrioventricular Maternal major Maternal valve

valve: 2 obstetrical bleeding thrombosis: 1
events: 3 (antepartum
hemorrhage with
placenta previa,
persistent cervical
hematoma and vaginal
bleeding leading to
cesarean section,
postpartum hemorrhage)
Canada, prospective, 17 women Pregnant women LMWH SC q12h. 1/23 (4.3) (fatal 0/23 (0.0) 3/23 (13.0) (2 minor 1/23 (4.3)
Yinon et al75/2009 23 pregnancies with mechanical Low-dose aspirin TIA/valve postpartum and 1 major Maternal ischemic
heart valves (81 mg/d) administered thrombosis) bleeding events as below) stroke: 1
Valve position to all patients No fatal maternal No major maternal Maternal nonstroke
Mitral: 14 LWMH dose adjusted to bleeding events GI bleeding events systemic
Aortic: 8 maintain 4 h postinjection Major maternal obstetrical embolism: 0
Aortic and mitral: 1 anti-Xa level 1-1.2 bleeding events: 1/23 Maternal valve
International Units/mL (large uterine hematoma thrombosis: 1

postcesarean section
requiring transfusion)
(Continued)
55
Table S28Continued

Systematic reviews
Canada, Chan1/2000 976 women Studies between Overall: Overall: Overall major bleeding
1,234 1966 and 1997 25/854 (2.9%) 0/1234 (0.0) events: 31/1234 (2.5)
pregnancies involving (25 at delivery, 6 outside
pregnant delivery); unable to
women with separate by regimen
mechanical or specific location
heart valves Regimen 1 oral Regimen 1, Regimen 1,
Valve type anticoagulants 10/561 (1.8) 31/788 (3.9)
Cage and ball: 433 throughout pregnancy
Single-tilting Regimen 2 substitution of Regimen 2, Regimen 2,
disc: 356 UFH in the first trimester 7/167, (4.2) 21/229 (9.2)

Bileaflet: 62 either at or before 6 wk,
Other: 20 after 6 wk, or at unknown
Heterograft: 1 time in the first trimester
Unknown: 104 Regimen 3 UFH Regimen 3, 3/20 Regimen 3, 7/21 (33.3)
Position throughout pregnancy- (15.0) Adjusted-dose
Mitral: 647 adjusted dose or low Adjusted-dose UFH: 4/16 (25.0)
Aortic: 202 dose ( 15,000 units/d) UFH: Low-dose UFH:
Tricuspid: 1 1/15 (6.7) 3/5 (60.0)
. 1 valve: 126 Low-dose UFH:
Valve position 2/5 (40)
Mitral: 647 Regimen 4 no anticoagulants, Regimen 4, 5/106, Regimen 4, 26/107
Aortic: 202 including use of (4.7) Nothing: (24.3) Nothing:
Tricuspid: 1 antiplatelet agents alone 2/3, (5.4) 6/38 (15.8)
. 1 valve: 126 Antiplatelet: Antiplatelet:
Total: 976 3/69 (4.3) 20/69 (29)
Fatal maternal Maternal ischemic
bleeding stroke: 0
events: 2 Maternal nonstroke

systemic
embolism: 0
Maternal valve
thrombosis:
17 [all fatal]
(Continued)
56
Table S28Continued

United States, 76 pregnancies Studies between Conversion to LMWH prior 3/76 (3.9) 1/76 (1.3) 6/76 (7.9) (4 minor bleeding 17/76 (22.4)
James et al67/2006 1966 and 2006 to pregnancy or by the Fatal maternal (1 intracranial events [2 hematomas, Maternal ischemic
involving end of first trimester bleeding events: bleed during 1 subchorionic hematoma, stroke: 2
pregnant women LMWH 1 (1 intracranial conversion 1 delayed broad ligament Maternal nonstroke
with mechanical Enoxaparin: 32 bleed during to warfarin hematoma] and 2 major systemic

heart valves Nadroparin: 20 conversion to postdelivery) bleeding events as below) embolism:
receiving LMWH Dalteparin: 13 warfarin No major maternal 2 (myocardial
Valve type Tinzaparin: 2 postdelivery) GI bleeding events infarction)
Cage and ball: 4 Reviparin: 1 Major maternal obstetrical Maternal valve
Single-tilting disc: 2 Unknown: 8 bleeding events: thrombosis:
Bileaflet: 8 Addition of low-dose aspirin: 2 (1 peripartum hemor- 13 (2 fatal)
Sorin: 1 13 Varying regimens rhage
Unknown: 61 ranging from a fixed requiring transfusion,
Valve position subtherapeutic dose 1 delayed postpartum
Mitral: 24 to weight-adjusted hemorrhage requiring
Aortic: 12 therapeutic doses transfusion)
Bjork-Shiley: 2 Monitoring of anti-factor
Unknown: 40 Xa levels: 43. The minimum
value for the target ranges
was 0.5, and the maximum
was 1.2.
(Continued)

57
Table S28Continued

United States, 75 women Studies between 1989 Cases were included 1/81 (1.2) 1/81 (1.2) 3/81 (3.7) 10/81 (12.3)
Oran et al68/2004 81 pregnancies and 2004 involving if LMWH was received Fatal maternal (intracranial Anti-Xa-adjusted LMWH: Anti-Xa-adjusted
pregnant women during pregnancy bleeding events: bleed 3 mo 2 (hematomas at cesarean LMWH: 1 (valve
with mechanical irrespective of this type, 1 (intracranial postpartum incision) thrombosis)
heart valves who dose and duration and bleed 3 mo with no Fixed-dose LMWH: Fixed-dose LMWH:
received LMWH administration of different postpartum with monitoring 1 (peripartum 9 (6 valve
Valve position anticoagulant regimens no monitoring of INRs) hemorrhage) thrombosis,

Mitral: 44 other than LMWH during of INRs) No major maternal 2 cerebrovascular
Aortic: 8 the same pregnancy. GI bleeding events accidents,
Mitral and Conversion to LMWH occurred Major maternal 1 embolism)
aortic: 5 1 mo before conception in obstetrical bleeding Maternal ischemic
Unknown: 18 2 women; in the remainder, events: 1 (peripartum) stroke: 2
conversion to LMWH Maternal nonstroke
occurred during pregnancy embolism (type not
LMWH use during second reported): 1
half of first trimester and Maternal valve
at term: 21 LMWH thrombosis:
throughout pregnancy: 60. 7 (8.64%)
LMWH Enoxaparin:
35 Nadroparin: 21 Daltaparin:
11 Tinzaparin: 3 Reviparin:
1 Unknown: 10
Dose adjusted to
therapeutic anti-Xa level:
51 Fixed dose: 30

(Continued)
58
Table S28Continued

Egypt, Hassouna 892 women Studies published Overall: Not reported Overall: Overall: 77/1343 (5.7)
and Allam2/2009 1,231 between 16/974, (1.6) 65/1343 (4.8)
pregnancies January 2000 and Regimen 1 VKAs throughout Regimen 1, Regimen 1, Regimen 1,
September 2009 pregnancy with and 7/605 (1.1) 35/833 (4.2) 24/833 (2.9%)
involving pregnant without UFH or LMWH

women with substitution near term
mechanical heart Regimen 2 UFH or LMWH Regimen 2, Regimen 2, Regimen 2,
valves who substitution during the 4/236 (1.7) 11/322 (3.4) 23/322 (7.2%)
received defined first trimester and near
anticoagulant term
regimens Regimen 3 UFH or LMWH Regimen 3, Regimen 3, Regimen 3,
Valve type throughout pregnancy 5/107 (4.7) 17/157 (10.8) 21/157 (13.4%)
Cage and ball: 134 Regimen 4 Regimen 4, Regimen 4, Regimen 4,
Tilting disc: 382 no anticoagulants 0/26 (0) 2/31 (6.4) 9/31 (29%)
Bileaflet: 341 Fatal maternal Major maternal Maternal ischemic
Undefined: 256 fatal bleeding GI bleeding events: stroke and
Valve position events: 2 not reported nonstroke systemic
Mitral: 671 Fatal maternal Maternal major embolism: 26
Aortic: 141 thrombosis: 8 obstetrical bleeding Maternal valve
Mitral and events: 55 (occurred thrombosis: 51
aortic: 147 1 147 at delivery)
Tricuspid: 7
TIA 5 transient ischemic attack. See Tables S1, S4, and S17 for expansion of other abbreviations.

59
Table S29[Section 12.1.1-12.1.3] Antithrombotic Therapy in Pregnant Women With Mechanical Heart ValvesFetal and Neonatal Outcomes
(Clinical Description and Results)
Fetal and/or Total Early Late

Number of Congenital Neonatal Pregnancy Pregnancy Pregnancy
Country, Patients and Malformations, Hemorrhage, Loss, Loss, Loss,
Study/Year Pregnancies Population Treatment Regimens n/N (%) n/N (%) n/N (%) n/N (%) n/N (%) Neonatal Death
Cohort studies with comparator groups
Iran, 110 women Pregnant women Regimen 1 warfarin Regimen 1, Not reported Regimen 1, Regimen 1, Regimen 1, Unable to
retrospective, 196 pregnancies with throughout 7/142 (4.9) 71/142 66/142 5/142 (3.5) separate
Khamooshi mechanical pregnancy; INR (50) (46.5) neonatal
et al75/2007 heart valves checked monthly deaths from
Valve type and kept 2.5-3.5 premature

Tilting: 98 Regimen 2 SC Regimen 2, Regimen 2, Regimen 2, Regimen 2, births
Bileaflet: 98 UFH for the 1/54 (1.9) 10/54 8/54 2 /54 (3.7)
Valve position first trimester, (18.5) (14.8)
Aortic: 26 warfarin until
Mitral: 128 week 36, then
Aortic and UFH for
mitral: 42 remainder
of pregnancy;
aPTT kept
2 times
control
Malformations
included
hydrocephalus
(2), stabismus (3),
telebrachydactyly
(1), nasal
hypoplasia (1)

(Continued)
60
Table S29Continued

Korea, 25 women Pregnant women Regimen 1 coumarin Regimen 1, Not reported Regimen 1, Not Not specified Not specified
retrospective, 31 pregnancies with and aspirin 1/23 (3.2) 4/8 (50) specified
Lee mechanical throughout (hydrocephalus) (1 loss was
et al73/2007 heart valves pregnancy with associated

Valve position target INR 2.5-3.5, with
Aortic: 4 then nadroparin maternal
Mitral: 21 7,500 units SC valve
Double valve q12h for 2 wk thrombosis)
replacement: 5 before due date
Regimen 2 nadroparin Regimen 2, Regimen 2,
7,500 units SC q12 0/8 (0.0) 2/23 (8.7)
until week 12, (1 loss was
then coumarins associated
until week 38 with
when nadroparin maternal
resumed valve
Aspirin 100 mg/d thrombosis)
throughout
pregnancy
(Continued)

61
Table S29Continued

New Zealand, 31 women Pregnant women Regimen 1 Regimen 1, Regimen 1, Regimens 1 Regimens 1 Regimen 1, Regimen 1,
retrospective, 47 pregnancies with predominantly 3/13 (23.1) 2/13 (15.3) and 2, and 2, 2/13 (15.3) 2/13 (15.3)
McLintock mechanical warfarin and (warfarin (fetal 11/47 8/47 (fetal (warfarin
et al71/2009 heart valves aspirin embyropathy, intracerebral (23.4) (17.0) intracerebral embryopathy,
Valve type (100-150 mg) hydrocephalus, hemorrhage hemorrhage complex
Starr- throughout with cardiac resulting in resulting in congenital
Edwards: 12 enoxaparin (1 mg/kg anomalies) stillbirth) stillbirth) heart
Tilting disc or SC q12h) and disease)

bileaflet: 19 aspirin substituted
Valve position between weeks 6
Mitral:14 and 12 and at
Aortic: 4 34-36 wk gestation
Mitral and Regimen 2 enoxaparin Regimen 2, Regimen 2, Regimen 2, Regimen 2,
aortic: 13 (1 mg/kg SC 0/34 (0.0) 0/34 (0.0) 1/34 (2.9) 0/34 (0/0)
q12h) and aspirin
(100-150 mg)
predominantly
In both regimens,
enoxaparin
monitored
by anti-Xa levels
every 3-7 d; dose
adjusted to attain
a target predose
level: 0.4-0.7
International

Units/mL
(Continued)
62
Table S29Continued

Single-group cohort studies
Norway, 11 women Pregnant women Therapeutic doses 1/12 (8.3) (patent Not reported 0/12 (0.0) 0/12 0/12 (0.0) 0/12 (0.0)
retrospective, 12 pregnancies with of LMWH q12h ductus (0.0%)
Abildgaard mechanical throughout arteriosus)
et al72/2009 heart valves pregnancy
Valve position Aspirin 75 mg/d
Mitral: 4 recommended but
Aortic: 6 discontinued 1 wk

Aortic and before expected
mitral: 2 delivery date
Doses adjusted
to attain peak
anti-Xa level of
0.7-1.2 units/mL
Japan, 12 women Pregnant women Substitution of 1/16 (6.3) 2/16 (12.5) 5/16 (31.3) 4/16 (25) 1/16 (8.3) 2/16 (12.5)
retrospective, 16 pregnancies with warfarin with (hydrocephalus) (intraventricular (intrauterine (see under
Kawamata mechanical UFH starting hemorrhage, fetal death Fetal
et al73/2007 heart valves between 6 and intraventricular during and/or
Valve position 13 wk and until and pulmonary extracorporeal Neonatal
Mitral: 7 term hemorrhage) circulation) Hemorrhage)
Aortic: 2 Doses adjusted to
Tricuspid: 7 maintain aPTT levels
2-3 times control
(between 20,000
and 30,000
International

Units/d)
(Continued)
63
Table S29Continued

England, 11 women Pregnant women Dalteparin 100 Not reported Not reported 1/12 (8.3) 0/12 (0.0) 1/12 (8.3) 0/12 (0.0)
prospective, 12 pregnancies with International
Quinn mechanical Units/kg q12h
et al74/2009 heart valves (8) or enoxaparin
Valve position 1 mg/kg q12h
Mitral: 4 (4) 1 aspirin 81 mg/d
Aortic :2 Doses adjusted

Aortic and to attain an
mitral: 3 anti-Xa level
Systemic 1.0-1.2 units/mL
right
atrioventricular
valve: 2
Canada, 17 women Pregnant LMWH SC q12h 0/23 (0.0) Not reported Total 2/23 (8.7) 2/23 (8.7) 1/12 (4.3)
prospective, 23 pregnancies women with Low-dose aspirin pregnancy
Yinon mechanical (81 mg/d) loss:
et al75/2009 heart valves administered 4 (17.4)
Valve position to all patients
Mitral: 14 LWMH dose adjusted
Aortic: 8 to maintain 4 h
Aortic and postinjection
mitral: 1 anti-Xa level 1-1.2
International
Units/mL

(Continued)
64
Table S29Continued

Systematic reviews
Canada, Chan 976 women Studies between Regimen 1 oral Regimen 1, Not reported Regimen 1, Regimen 1, Not specified Not specified
et al1/2000 1,234 1966-1997 anticoagulants 35/549 (6.4) 266/792 196/792
pregnancies involving throughout (33.6%) (24.7)
pregnant pregnancy
women with Regimen 2 substitution Regimen 2, Regimen 2, Regimen 2,
mechanical of UFH in the first 6/174 (3.4) 61/230 (26.5) 57/230
heart valves: trimester either 6 wk: 0/108 (0) 6 wk: 21/129 (24.8)

Valve type at or before 6 wk, . 6 wk: 4/36 (11.1) (16.3) 6 w:
Cage and after 6 wk, or at Unknown: . 6 wk: 20/56 19/129
ball: 433 unknown time 2/30 (6.7) (35.37) (14.7)
Single-tilting in the first trimester Unknown: . 6 wk:
disc: 356 20/45 19/56
Bileaflet: 62 (44.4) (33.9)
Other: 20 Unknown:
Heterograft: 1 19/45
Unknown: 104 (42.2)
Position Regimen 3 UFH Regimen 3, Regimen 3, Regimen 3,
Mitral: 647 throughout 0/12 (0) 9/21 (42.9) 5/21
Aortic: 202 pregnancy, adjusted Adjusted dose: Adjusted (23.8)
Tricuspid: 1 dose, or low dose 0/12 (0) dose: Adjusted
. 1 valve: 126 ( 15,000 units/d) Low dose: 0/5 (0) 7/16 dose:
Valve position (43.8) 4/16 (25)
Mitral: 647 Low-dose: Low-dose:
Aortic: 202 2/5 (40) 1/5 (20)
Tricuspid: 1

. 1 valve: 126
Total: 976
(Continued)
65
Table S29Continued

Regimen 4, no Regimen 4, Regimen 4, Regimen 4,
anticoagulants, 3/92 (3.3) 20/102 10/102
including use of Nothing: (19.6) (9.8)
antiplatelet agents 2/33 (6.1) Nothing: Nothing:
alone Antiplatelet: 7/35 (20) 2/35 (5.7)
1/59 (1.7) Antiplatelet: Antiplatelet:

Malformations 13/67 8/67
include (19.4) (11.9)
warfarin
embryopathy
(29), CNS
abnormalities
(4), cleft lip and
cleft palate (4),
left ventricular
hypoplasia (1),
corneal leukoma
(1), bilateral hand
polydactyly (1),
single kidney-
toe-finger
deformity (1)
(Continued)

66
Table S29Continued

United States, 76 pregnancies Studies between Conversion to LMWH 0/76 (0.0) Not reported 12 (15.8) 8/76 (10.5) 2/76 (2.6) Not reported
James 1966 and prior to pregnancy Additional 2
et al67/2006 2006 or by the end of demises
involving first trimester secondary
pregnant LMWH to fatal
women Enoxaparin: 32 maternal
with Nadroparin: 20 valve
mechanical Dalteparin: 13 thrombosis
heart valves Tinzaparin: 2 Not included
receiving Reviparin: 1 elective
LMWH Unknown: 8 termination
Valve type Addition of low-dose at 14 wk
Cage and aspirin: 13

ball: 4 Varying regimens
Single-tilting ranging from a
disc: 2 fixed subtherapeutic
Bileaflet: 8 dose to weight-
Sorin: 1 adjusted therapeutic
Unknown: 61 doses
Valve position Monitoring of anti-factor
Mitral: 24 Xa levels: 43 The
Aortic: 12 minimum value for
Bjork-Shiley: 2 the target ranges was
Unknown: 40 0.5 and the maximum
was 1.2
United States, 75 women Studies between Cases were included 1/81 (1.2) Not reported 9/81 (11.1) 6/81 (7.4) 3/81 (3.7) Not reported
Oran 81 pregnancies 1989 and if LMWH was (hydrocephalus, Anti-Xa Anti-Xa Anti-Xa
et al68/2004 2004 involving received during LMWH adjusted adjusted adjusted
pregnant pregnancy received dose: dose: dose:
women irrespective during first 3/81 (3.7) 3/81 (3.7) 0/81 (0.0)
with of this type, dose, trimester, Fixed dose: Fixed dose: Fixed dose:

mechanical and duration and warfarin 4/81 (4.9) 3/81 (3.7) 1/81 (1.2)
heart valves administration of subsequent Unknown: Unknown:
who received different anticoagulant to that) 2/81 (3.7) 2/81 (3.7)
LMWH regimens other than
LMWH during the
same pregnancy
(Continued)
67
Table S29Continued

Valve position Conversion to Not
Mitral: 44 LMWH occurred included:
Aortic: 8 1 mo before 1 first
Mitral and conception in trimester
aortic: 5 2 women; elective
Unknown: 18 in the remainder, termination
conversion to LMWH

occurred during
pregnancy
LMWH use during
second half of first
trimester and
at term: 21
LMWH throughout
pregnancy: 60
LMWH enoxaparin: 35
Nadroparin: 21
Daltaparin: 11
Tinzaparin: 3
Reviparin: 1
Unknown: 10
Dose adjusted to
therapeutic anti-Xa
level: 51
Fixed dose: 30

(Continued)
68
Table S29Continued

Egypt, 892 women Studies published Overall Not reported Overall Overall Not specified Not reported
Hassouna 1,231 between 22/942 (2.3) 403/1343 272/1343
and pregnancies January (30) (20.2)
Allam2/2009 2000- Regimen 1 VKAs Regimen 1 Regimen 1 Regimen 1
September throughout 21/559 (3.7) 274/833 194/833
2009 involving pregnancy with (32.9) (23.3)
pregnant and without
women UFH or LMWH
with substitution
mechanical near term
heart valves Regimen 2 UFH Regimen 2 Regimen 2 Regimen 2
who received or LMWH 1/258 (0.4) 64/322 42/322

defined substitution (19.9) (13)
anticoagulant during the first
regimens trimester and
Valve type near term
Cage and Regimen 3 UFH Regimen 3 Regimen 3 Regimen 3
ball: 134 or LMWH 0/96 (0) 61/157 34/157
Tilting disc: 382 throughout (38.8) (21.6)
Bileaflet: 341 pregnancy
Undefined: 256 Regimen 4 Regimen 4 Regimen 4 Regimen 4
Valve position no anticoagulants 0/27 (0) 4/31 2/31
Mitral: 671 Includes (12.9) (12.9)
Aortic: 141 hydrocephalus
Mitral and aortic: (4), nasal
147 1 147 hypoplasia,
Tricuspid: 7 epiphyseal
stippling (7)
strabismus (3),
mental

retardation
(2), cleft lip/
palate (2),
telebrachydactyly
(1), and other (3)
and denote additional data referring to the number of late losses two of 76 (2.6). See Tables S1, S4, and S17 for expansion of abbreviations.
69
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CHEST Online Data Supplement

VTE, Thrombophilia, Antithrombotic

Shannon M. Bates, MDCM; Ian A. Greer, MD, FCCP;

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Spontaneous Total Fetal Congenital Fetal Fetal or Neonatal

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Number Patients Length of Follow-up Presence in Breast

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Study/Year Type of Study Participants/ Intervention Follow-up Risk of Thromboembolism Strengths/Limitations

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Quality Assessment Summary of Findings

Anticipated Absolute Effects

Participants Relative Risk Risk Difference

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b Major antenatal nonfatal hemorrhage.

College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

e Only study identified that compared aspirin to placebo in this population.

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Quality Assessment Summary of Findings

Study Event Rates (%) Anticipated Absolute Effectsb

Participants Overall Relative Risk Difference

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Risk Factor Adjusted OR 95% CI

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Risk Factor Adjusted OR 95% CIs

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Quality Assessment Summary of Findings

Study Event Rates (%)a Anticipated Absolute Effectsb

Participants Relative Risk Difference

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Funding Sources Study Conclusions,

of quality items present; unsatisfactory, , 60% of quality items present.

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Quality Assessment Summary of Findings

Anticipated Absolute Effects

Participants Risk Difference

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

b Outcome less subjective: Borderline decision.

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College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Downloaded From: http://journal.publications.chestnet.org/ on 03/09/2013

College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300

Downloaded From: http://journal.publications.chestnet.org/ on 03/09/2013

College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300