Original Article
805
Impact of Sickle Hemoglobinopathies on Pregnancy-Related Venous Thromboembolism Blake Porter, MD1 Nigel S. Key, MBChB, FRCP2 Joseph Biggio, MD1 Alan Tita, MD, PhD1
Victoria Chapman Jauk, MPH1
1 Department of Obstetrics and Gynecology, University of Alabama at
Birmingham, Birmingham, Alabama 2 Department of Medicine, University of North Carolina, North Carolina 3 Department of Medicine, Duke University, Durham, North Carolina
Soheir Adam, MD3
Address for correspondence Blake Porter, MD, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 176F, Room 5328, 619 19th Street South, Birmingham, AL 35249-7333 (e-mail: [email protected]).
Abstract
Keywords
► sickle cell disease ► sickle cell trait ► venous thromboembolism ► pregnancy
Objective The aim of the study is to examine the relationship between sickle cell trait (Hb AS) and other sickle hemoglobinopathies and the risk of thromboembolism during pregnancy or the puerperium. Study Design Retrospective cohort study of African American women receiving prenatal care from 1991 to 2006. Sickle cell status was ascertained by routine hemoglobin electrophoresis. Venous thromboembolism (VTE) was defined as one or more episodes of deep venous and/or pulmonary thromboembolism during pregnancy or the puerperium according to discharge diagnoses based on International Classification of Diseases, Ninth Revision codes. Results Among 22,140 women with hemoglobin (Hb) AA status, 20 women (0.09%) experienced pregnancy-related VTE compared with 3 women (0.15%) of 2,037 women with Hb AS; relative risk (RR) for the association with AS status ¼ 1.6; 95% confidence interval (CI) 0.5 to 5.5. Of 103 women, 3 women (2.9%) with sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-thalassemia) experienced thromboembolism. Compared with women with Hb AA status, the RR ¼ 32.2, 95% CI 9.7 to 107. Conclusion Sickle cell trait may be associated with a modest increase in VTE in the setting of pregnancy; sickle cell disease conditions are strongly associated with this rare but potentially fatal outcome.
The incidence of venous thromboembolism (VTE) is estimated at 0.76 to 1.72 per 1,000 pregnancies.1,2 The risk of VTE is increased approximately 4-fold to 10-fold during pregnancy, compared with nonpregnant women.1–3 VTE, specifically pulmonary embolism, has become the leading cause of pregnancy-related death in developed countries; data from the Center for Disease Control’s National Pregnancy Mortality Surveillance System showed that pulmonary embolism was the most common cause of maternal deaths (accounting for 20%) in the United States.4 Although several factors including sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-
thalassemia) have been associated with increased risk for VTE in pregnancy, the specific impact of sickle cell trait (Hb AS) is poorly understood. Worldwide, there are approximately 283,000 babies born with one of the sickle cell disease conditions each year.5 Sickle cell anemia (Hb SS) is the most common inherited blood disorder in the United States. There are an estimated 80,000 to 100,000 cases of Hb SS in the United States with another 3 million Americans being carriers of the disease.6–8 Sickle cell disease conditions causes chronic activation of the coagulation system,9 including increased circulating tissue factor procoagulant factor, increased
received March 21, 2013 accepted after revision October 16, 2013 published online December 12, 2013
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1361931. ISSN 0735-1631.
Downloaded by: Florida International University. Copyrighted material.
Am J Perinatol 2014;31:805–810.
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy markers of thrombin generation, decreased levels of natural anticoagulant proteins, and evidence of platelet and fibrinolytic system activation.10 Patients with Hb AS experience some of the same biochemical alterations although to a much lesser extent,11 and in nonpregnant patients, Hb AS has been associated with approximately a 2-fold increased risk for VTE compared with wild-type hemoglobin (Hb AA).12 Furthermore, a potential synergy between hormonal contraception and Hb AS has been suggested. Whereas Hb AA women using hormonal contraception experienced a higher overall risk of VTE than Hb AS women with no contraceptive use, Hb AS women using hormonal contraception reportedly had a 12fold increased risk of VTE compared with Hb AA women with no contraception.13 A potential synergy between hormonal contraception and Hb AS was noted, in that the joint effect of the two exposures was considerably greater than the multiplicative effect of each.13 These findings lead one to wonder about the risk of VTE during pregnancy in the setting of Hb AS, a prevalent disease carrier state in African American women. Indeed, few studies have examined the impact of sickle hemoglobinopathies in general on the risk of VTE during pregnancy. Therefore, we compared the risk of VTE during pregnancy in women with Hb AS, Hb AC, or sickle disease conditions (Hb SS, SC, or S,beta-thalassemia) and those with Hb AA.
Methods We conducted a population-based retrospective cohort study using data in our obstetric database for births during the 15-year period from 1991 to 2006. The Institutional Review Board of the University of Alabama at Birmingham approved the study. The target population included only African American women because of the extant policy of routine prenatal hemoglobin electrophoresis in this ethnic group.14 Approximately 90% of all the women with hemoglobin electrophoresis results were African American. To reflect the population base primarily served by the health facilities affiliated with our department of obstetrics and gynecology, the study population was further restricted to women with more than one prenatal visit in our system, excluding women who presented for antenatal consults only and those transferred because of complications. Four study groups were identified based on hemoglobin electrophoresis results: women with wild type hemoglobin (Hb AA), those with sickle cell trait (Hb AS), those with hemoglobin C trait (Hb AC), and those with sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-thalassemia). The primary study outcome was VTE defined as 1 or more episodes of clinically apparent deep venous and/or pulmonary thromboembolism during pregnancy or the puerperium. These data on thromboembolism were based on International Classification of Diseases, Ninth Revision (ICD9) codes (15.19, 671.23, 671.33, 671.42, 671.44, 671.54, 673.22, and 673.24) listed in discharge diagnoses corresponding to antepartum or puerperal thromboembolism. Once an ICD-9 code implying VTE was identified, a chart review was performed to ensure that coding information accurately reflected a clinical VTE event. Information regarding a prior American Journal of Perinatology
Vol. 31
No. 9/2014
Porter et al.
history of VTE was determined by patient history and records obtained during routine prenatal care (ICD-9 code V12.51). Data were analyzed using SAS version 9.1 software (SAS, Cary, NC). Descriptive data including means and standard deviations for continuous variables and proportions for categorical variables were computed. These were compared between groups by using t-tests or χ2 tests, and Fisher exact tests, respectively, to compare each group to the AA group. The prevalence of VTE was computed for each group and the relative risks (RRs) and their 95% confidence intervals (CIs) comparing each group to the AA group were also computed.
Results The total study population comprised 24,882 pregnant women: 22,140 (88.98%) AA, 2,037 (8.18%) AS, 602 (2.42%) AC, and 103 (0.41%) with sickle cell disease conditions (SS, SC, or Hb S,betathalassemia). Selected demographic and clinical characteristics of the study population by type of hemoglobinopathy are presented in ►Table 1. Most patient characteristics were not significantly different between each category of hemoglobinopathy and the AA group. However, the AS group had a higher unadjusted prevalence of diabetes while those with the sickle cell disease conditions were more likely to be nulliparous, married, and have hypertensive disease as compared with AA women, but less likely to consume alcohol compared with AA women. Data for the frequency of a prior history of or new onset thromboembolism during pregnancy are presented in ►Table 2. The corresponding incidence of a current or prior history of thromboembolism for women with Hb AA status was 20 (0.09%) compared with 3 (0.15%) for women with Hb AS: RR for the association with AS status ¼ 1.6, 95% CI 0.5 to 5.5, 2 (0.33%) of 602 women with Hb AC: RR ¼ 3.7, 95% CI 0.9, 16, and 3 (2.9%) of 103 women with sickle cell disease conditions RR ¼ 32.2, 95% CI 9.7 to 107. Moreover, when the outcome was restricted to new onset thromboembolism during each pregnancy or postpartum, sickle cell disease conditions (RR, 54; 95% CI 12, 253) were significantly associated with thromboembolism during pregnancy. However, Hb AS (RR, 2.7; 0.6, 13) and Hb AC (RR, 4.6; 0.6, 37) were not significantly associated with thromboembolism during pregnancy. These data are shown in ►Table 3. Not shown, the corresponding risks of VTE (per 1,000) that preceded the index pregnancy or puerperium were 0.54 (12/ 22,132) for Hb AA, 0.49 (1/2,037) for Hb AS, 1.66 (1/601) for Hb AC and 9.80 (1/101) for sickle cell disease conditions.
Discussion This small study indicates that in our cohort of African American women, the increase in VTE, particularly new onset during pregnancy, among women with Hb AS (RR, 2.7; 0.6, 13) or Hb AC (RR, 4.6; 0.6, 37) status as compared with Hb AA women was not statistically significant. However, sickle cell disease conditions including Hb SS, Hb SC, and Hb S,betathalassemia were strongly associated with VTE (RR, 54; 95% CI 12, 253). Given the very small numbers of cases of VTE, we do
Downloaded by: Florida International University. Copyrighted material.
806
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy
Porter et al.
807
Hb AA (n ¼ 22,140)
Hb AS (n ¼ 2,037)
p value
Hb AC (n ¼ 602)
p value
Hb SS, SC, S/β (n ¼ 103)
p value
Age, mean SD
21.9 5.6
21.9 5.6
0.986
21.8 5.7
0.736
22.1 5.8
0.642
BMI, mean SD
27.3 9.8
27.0 9.7
0.339
27.2 9.8
0.864
28.4 13.9
0.681
College (%)
3,789 (18.8)
357 (19.3)
0.599
104 (18.6)
0.917
13 (22.0)
0.518
Married (%)
1,773 (8.3)
176 (8.9)
0.316
59 (10.1)
0.113
18 (19.6)
< 0.001
Smoker (%)
3,352 (16.4)
295 (15.8)
0.496
85 (15.2)
0.428
6 (8.5)
0.070
Alcohol (%)
3,322 (16.4)
290 (15.7)
0.461
100 (17.6)
0.413
5 (7.0)
0.034
Drugs (%)
2,144 (10.0)
177 (9.1)
0.167
57 (9.7)
0.809
4 (5.3)
0.167
DM at Del (%)
736 (3.8)
98 (5.5)
0.001
21 (4.0)
0.823
1 (1.2)
0.379
HTN at Del (%)
2,213 (11.4)
224 (12.5)
0.197
50 (9.5)
0.169
23 (27.7)
< 0.001
C-Section (%)
3,423 (17.4)
338 (18.4)
0.267
109 (20.3)
0.074
20 (24.1)
0.107
Nulliparous (%)
14,430 (65.3)
1,339 (65.8)
0.640
393 (65.3)
0.987
78 (75.7)
0.026
Abbreviations: β-thal, beta-thalassemia; BMI, body mass index; C-Section, cesarean section; DM at Del, diabetes mellitus at delivery; Hb, Hemoglobin; HTN at Del, hypertension at delivery. a AA is the comparison group for AS, AC, and SS,SC, S/β b Values are n (%) except where mean SD.
not present multivariable adjusted results, as this would not be valid. VTE in pregnancy and postpartum is a rare event with an incidence of approximately 1/1,000.1,2 Our findings are consistent with other reports associating sickle cell disease conditions with an increased risk of VTE.2,15 However, the strength of association we observed is much higher than the 2.5 to 6.7-fold increase reported in prior studies.2,15 Our results likely overestimate the true magnitude as a result of
the small sample size and our inability to conduct meaningful multivariable adjustments. Furthermore, although not statistically significant, the observed odds ratios and range of values in the 95% CI for sickle cell trait and Hb AC suggest possible associations with VTE and sickle cell trait during pregnancy. If true, this would be supportive of a prior study that associated Hb AS with increased VTE in the setting of hormonal contraception,13 which mimics the biological milieu that exists during pregnancy. Austin et al suggested that
Table 2 Prevalence and relative risk of prior history or new onset thromboembolism during pregnancy or postpartum by type of hemoglobinopathy Hemoglobin status
Prior history or new onset venous thromboembolism Prevalence/1,000
(n/N)
RR
95% CI
Hb AA
0.9
(20/22,140)
1
Referent
Hb AS
1.5
(3/2,037)
1.6
0.5, 5.5
Hb AC
3.3
(2/602)
3.7
0.9, 16
Hb SS, SC, or S/β-thal
29.1
(3/103)
32.2
9.7, 107
Abbreviations: β-thal, beta-thalassemia; CI, confidence interval; Hb, hemoglobin; RR, relative risk.
Table 3 Prevalence and relative risk of new onset thromboembolism during pregnancy or postpartum by type of hemoglobinopathy Hemoglobin status
New onset venous thromboembolism Prevalence/1,000
(n/N)
RR
95% CI
Hb AA
0.4
(8/22,128)
1
Referent
Hb AS
1.0
(2/2,036)
2.7
0.6, 13
Hb AC
1.7
(1/601)
4.6
0.6, 37
Hb SS, SC, or S/β-thal
19.6
(2/102)
54
12, 253
Abbreviations: β-thal, beta-thalassemia; CI, confidence interval; Hb, hemoglobin; RR, relative risk. American Journal of Perinatology
Vol. 31
No. 9/2014
Downloaded by: Florida International University. Copyrighted material.
Table 1 Demographic and clinical characteristics of the study populationa,b
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy both hormonal contraception and Hb AS have a procoagulant effect, and that there may be synergy between the two. They postulated that the joint effect of hormonal contraception and Hb AS is considerably greater than the multiplicative effect of each. Given the increases in both estrogen and progesterone during pregnancy, one would expect to see a similar increase in VTE in Hb AS pregnancies.13 Sickle trait has also been associated with increased VTE outside of the pregnant state (without regard to hormonal contraception).12 On the one hand, our small study sample size may explain the failure to demonstrate a significant increase in pregnancy-related VTE in women with Hb AS. Given that the incidence of VTE in pregnancy was estimated at 0.09% for women with Hb AA, and 0.15% for those with Hb AS, approximately 110,000 women would be needed to demonstrate a RR of 1.67 with 80% power and a type I error rate of 5%. On the other hand, however, one recent study reported no association between Hb AS and VTE during pregnancy and postpartum.16 However, this study was even smaller than this study and given the previously mentioned rarity of VTE, their results are certainly subject to the limitations of a smaller sample size. Similar to our findings for Hb AS, the results further suggest the hypothesis that Hb AC may be associated with an increase in VTE during pregnancy given adequate sample size. This is the only study we are aware of that has examined the impact of the hemoglobin AC genotype vis-à-vis VTE during pregnancy. Whereas our findings may be more supportive of observations in the setting of hormonal contraception, differences between VTE in pregnancy and VTE in the setting of hormonal contraception must be considered. While estrogen and progesterone are increased in both states, the levels are different between the pregnant state and hormonal contraceptive use.17,18 Second, hemostasis and the coagulation cascade are profoundly altered during pregnancy with adaptation that favors clot formation. The extrinsic and intrinsic pathways are upregulated and almost all clotting factors are increased in pregnancy.17,19 While the complexities of coagulation during pregnancy are only partially understood, increased serum estrogen and progesterone levels seen with hormonal contraception are only slightly altered compared with the vast shift in the hemostatic changes that occur during pregnancy. In summary, our data must be interpreted with caution. The prevalence of VTE in the Hb AA group (0.9%) was similar to previously published studies1,2 providing some reassurance regarding the validity of our findings. However, the implications of these findings must be tempered by the acknowledged study limitations particularly the small sample size and lack of adjustments. Moreover, the use of ICD-9 codes to detect the incidence VTE in pregnancy is problematic and ICD-9 codes specific to pregnancy may underestimate the true incidence.20 Similarly, the use of discharge data and ICD-9 codes may underestimate the incidence of postpartum VTE occurring in the outpatient setting.21 Additional studies are needed to confirm the impact of Hb AS and AC on VTE risk during pregnancy before specific directed interventions are considered. Given the rarity of American Journal of Perinatology
Vol. 31
No. 9/2014
Porter et al.
the outcome, multicenter studies may be better suited to cumulate the needed numbers and prospective ascertainment may be preferable to overcome bias. In the meantime, these patients should be stratified and managed during pregnancy according to individual risk factors for VTE, including body mass index and prior VTE history. For patients with Hb SS, it would prudent to consider them a high-risk group given the underlying pathophysiology and accumulating literature.
Acknowledgments There are no disclosures. The authors have received no financial support for the work being published.
References 1 Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ
2
3
4
5 6
7
8 9
10
11
12
13
14
15
III. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143(10):697–706 James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194(5):1311–1315 Lindqvist P, Dahlbäck B, Marŝál K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999;94(4): 595–599 Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance—United States, 1991–1999. MMWR Surveill Summ 2003;52(2):1–8 Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010;115(22):4331–4336 Section on Hematology/Oncology Committee on Genetics; American Academy of Pediatrics. Health supervision for children with sickle cell disease. Pediatrics 2002;109(3):526–535 Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell disease in the United States: national and state estimates. Am J Hematol 2010;85(1): 77–78 Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med 2010;38(4, Suppl)S512–S521 Rickles FR, O’Leary DS. Role of coagulation system in pathophysiology of sickle cell disease. Arch Intern Med 1974;133(4): 635–641 Key NS, Slungaard A, Dandelet L, et al. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 1998;91(11):4216–4223 Westerman MP, Green D, Gilman-Sachs A, et al. Coagulation changes in individuals with sickle cell trait. Am J Hematol 2002; 69(2):89–94 Austin H, Key NS, Benson JM, et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007;110(3): 908–912 Austin H, Lally C, Benson JM, Whitsett C, Hooper WC, Key NS. Hormonal contraception, sickle cell trait, and risk for venous thromboembolism among African American women. Am J Obstet Gynecol 2009;200(6):e1–e3 Tita AT, Biggio JR, Chapman V, Neely C, Rouse DJ. Perinatal and maternal outcomes in women with sickle or hemoglobin C trait. Obstet Gynecol 2007;110(5):1113–1119 Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008;199(2):e1–e5
Downloaded by: Florida International University. Copyrighted material.
808
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy
Porter et al.
19 O’Riordan MN, Higgins JR. Haemostasis in normal and abnormal
increased VTE risk in pregnancy and the postpartum? PLoS ONE 2013;8(5):e64141 17 Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 2009;114(6):1326–1331 18 Mishell DR Jr, Thorneycroft IH, Nakamura RM, Nagata Y, Stone SC. Serum estradiol in women ingesting combination oral contraceptive steroids. Am J Obstet Gynecol 1972;114(7):923–928
pregnancy. Best Pract Res Clin Obstet Gynaecol 2003;17(3): 385–396 20 White RH, Brickner LA, Scannell KA. ICD-9-CM codes poorly indentified venous thromboembolism during pregnancy. J Clin Epidemiol 2004;57(9):985–988 21 Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007;167(14):1471–1475
Downloaded by: Florida International University. Copyrighted material.
16 Pintova S, Cohen HW, Billett HH. Sickle cell trait: is there an
809
American Journal of Perinatology
Vol. 31
No. 9/2014
805
Impact of Sickle Hemoglobinopathies on Pregnancy-Related Venous Thromboembolism Blake Porter, MD1 Nigel S. Key, MBChB, FRCP2 Joseph Biggio, MD1 Alan Tita, MD, PhD1
Victoria Chapman Jauk, MPH1
1 Department of Obstetrics and Gynecology, University of Alabama at
Birmingham, Birmingham, Alabama 2 Department of Medicine, University of North Carolina, North Carolina 3 Department of Medicine, Duke University, Durham, North Carolina
Soheir Adam, MD3
Address for correspondence Blake Porter, MD, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 176F, Room 5328, 619 19th Street South, Birmingham, AL 35249-7333 (e-mail: [email protected]).
Abstract
Keywords
► sickle cell disease ► sickle cell trait ► venous thromboembolism ► pregnancy
Objective The aim of the study is to examine the relationship between sickle cell trait (Hb AS) and other sickle hemoglobinopathies and the risk of thromboembolism during pregnancy or the puerperium. Study Design Retrospective cohort study of African American women receiving prenatal care from 1991 to 2006. Sickle cell status was ascertained by routine hemoglobin electrophoresis. Venous thromboembolism (VTE) was defined as one or more episodes of deep venous and/or pulmonary thromboembolism during pregnancy or the puerperium according to discharge diagnoses based on International Classification of Diseases, Ninth Revision codes. Results Among 22,140 women with hemoglobin (Hb) AA status, 20 women (0.09%) experienced pregnancy-related VTE compared with 3 women (0.15%) of 2,037 women with Hb AS; relative risk (RR) for the association with AS status ¼ 1.6; 95% confidence interval (CI) 0.5 to 5.5. Of 103 women, 3 women (2.9%) with sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-thalassemia) experienced thromboembolism. Compared with women with Hb AA status, the RR ¼ 32.2, 95% CI 9.7 to 107. Conclusion Sickle cell trait may be associated with a modest increase in VTE in the setting of pregnancy; sickle cell disease conditions are strongly associated with this rare but potentially fatal outcome.
The incidence of venous thromboembolism (VTE) is estimated at 0.76 to 1.72 per 1,000 pregnancies.1,2 The risk of VTE is increased approximately 4-fold to 10-fold during pregnancy, compared with nonpregnant women.1–3 VTE, specifically pulmonary embolism, has become the leading cause of pregnancy-related death in developed countries; data from the Center for Disease Control’s National Pregnancy Mortality Surveillance System showed that pulmonary embolism was the most common cause of maternal deaths (accounting for 20%) in the United States.4 Although several factors including sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-
thalassemia) have been associated with increased risk for VTE in pregnancy, the specific impact of sickle cell trait (Hb AS) is poorly understood. Worldwide, there are approximately 283,000 babies born with one of the sickle cell disease conditions each year.5 Sickle cell anemia (Hb SS) is the most common inherited blood disorder in the United States. There are an estimated 80,000 to 100,000 cases of Hb SS in the United States with another 3 million Americans being carriers of the disease.6–8 Sickle cell disease conditions causes chronic activation of the coagulation system,9 including increased circulating tissue factor procoagulant factor, increased
received March 21, 2013 accepted after revision October 16, 2013 published online December 12, 2013
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1361931. ISSN 0735-1631.
Downloaded by: Florida International University. Copyrighted material.
Am J Perinatol 2014;31:805–810.
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy markers of thrombin generation, decreased levels of natural anticoagulant proteins, and evidence of platelet and fibrinolytic system activation.10 Patients with Hb AS experience some of the same biochemical alterations although to a much lesser extent,11 and in nonpregnant patients, Hb AS has been associated with approximately a 2-fold increased risk for VTE compared with wild-type hemoglobin (Hb AA).12 Furthermore, a potential synergy between hormonal contraception and Hb AS has been suggested. Whereas Hb AA women using hormonal contraception experienced a higher overall risk of VTE than Hb AS women with no contraceptive use, Hb AS women using hormonal contraception reportedly had a 12fold increased risk of VTE compared with Hb AA women with no contraception.13 A potential synergy between hormonal contraception and Hb AS was noted, in that the joint effect of the two exposures was considerably greater than the multiplicative effect of each.13 These findings lead one to wonder about the risk of VTE during pregnancy in the setting of Hb AS, a prevalent disease carrier state in African American women. Indeed, few studies have examined the impact of sickle hemoglobinopathies in general on the risk of VTE during pregnancy. Therefore, we compared the risk of VTE during pregnancy in women with Hb AS, Hb AC, or sickle disease conditions (Hb SS, SC, or S,beta-thalassemia) and those with Hb AA.
Methods We conducted a population-based retrospective cohort study using data in our obstetric database for births during the 15-year period from 1991 to 2006. The Institutional Review Board of the University of Alabama at Birmingham approved the study. The target population included only African American women because of the extant policy of routine prenatal hemoglobin electrophoresis in this ethnic group.14 Approximately 90% of all the women with hemoglobin electrophoresis results were African American. To reflect the population base primarily served by the health facilities affiliated with our department of obstetrics and gynecology, the study population was further restricted to women with more than one prenatal visit in our system, excluding women who presented for antenatal consults only and those transferred because of complications. Four study groups were identified based on hemoglobin electrophoresis results: women with wild type hemoglobin (Hb AA), those with sickle cell trait (Hb AS), those with hemoglobin C trait (Hb AC), and those with sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-thalassemia). The primary study outcome was VTE defined as 1 or more episodes of clinically apparent deep venous and/or pulmonary thromboembolism during pregnancy or the puerperium. These data on thromboembolism were based on International Classification of Diseases, Ninth Revision (ICD9) codes (15.19, 671.23, 671.33, 671.42, 671.44, 671.54, 673.22, and 673.24) listed in discharge diagnoses corresponding to antepartum or puerperal thromboembolism. Once an ICD-9 code implying VTE was identified, a chart review was performed to ensure that coding information accurately reflected a clinical VTE event. Information regarding a prior American Journal of Perinatology
Vol. 31
No. 9/2014
Porter et al.
history of VTE was determined by patient history and records obtained during routine prenatal care (ICD-9 code V12.51). Data were analyzed using SAS version 9.1 software (SAS, Cary, NC). Descriptive data including means and standard deviations for continuous variables and proportions for categorical variables were computed. These were compared between groups by using t-tests or χ2 tests, and Fisher exact tests, respectively, to compare each group to the AA group. The prevalence of VTE was computed for each group and the relative risks (RRs) and their 95% confidence intervals (CIs) comparing each group to the AA group were also computed.
Results The total study population comprised 24,882 pregnant women: 22,140 (88.98%) AA, 2,037 (8.18%) AS, 602 (2.42%) AC, and 103 (0.41%) with sickle cell disease conditions (SS, SC, or Hb S,betathalassemia). Selected demographic and clinical characteristics of the study population by type of hemoglobinopathy are presented in ►Table 1. Most patient characteristics were not significantly different between each category of hemoglobinopathy and the AA group. However, the AS group had a higher unadjusted prevalence of diabetes while those with the sickle cell disease conditions were more likely to be nulliparous, married, and have hypertensive disease as compared with AA women, but less likely to consume alcohol compared with AA women. Data for the frequency of a prior history of or new onset thromboembolism during pregnancy are presented in ►Table 2. The corresponding incidence of a current or prior history of thromboembolism for women with Hb AA status was 20 (0.09%) compared with 3 (0.15%) for women with Hb AS: RR for the association with AS status ¼ 1.6, 95% CI 0.5 to 5.5, 2 (0.33%) of 602 women with Hb AC: RR ¼ 3.7, 95% CI 0.9, 16, and 3 (2.9%) of 103 women with sickle cell disease conditions RR ¼ 32.2, 95% CI 9.7 to 107. Moreover, when the outcome was restricted to new onset thromboembolism during each pregnancy or postpartum, sickle cell disease conditions (RR, 54; 95% CI 12, 253) were significantly associated with thromboembolism during pregnancy. However, Hb AS (RR, 2.7; 0.6, 13) and Hb AC (RR, 4.6; 0.6, 37) were not significantly associated with thromboembolism during pregnancy. These data are shown in ►Table 3. Not shown, the corresponding risks of VTE (per 1,000) that preceded the index pregnancy or puerperium were 0.54 (12/ 22,132) for Hb AA, 0.49 (1/2,037) for Hb AS, 1.66 (1/601) for Hb AC and 9.80 (1/101) for sickle cell disease conditions.
Discussion This small study indicates that in our cohort of African American women, the increase in VTE, particularly new onset during pregnancy, among women with Hb AS (RR, 2.7; 0.6, 13) or Hb AC (RR, 4.6; 0.6, 37) status as compared with Hb AA women was not statistically significant. However, sickle cell disease conditions including Hb SS, Hb SC, and Hb S,betathalassemia were strongly associated with VTE (RR, 54; 95% CI 12, 253). Given the very small numbers of cases of VTE, we do
Downloaded by: Florida International University. Copyrighted material.
806
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy
Porter et al.
807
Hb AA (n ¼ 22,140)
Hb AS (n ¼ 2,037)
p value
Hb AC (n ¼ 602)
p value
Hb SS, SC, S/β (n ¼ 103)
p value
Age, mean SD
21.9 5.6
21.9 5.6
0.986
21.8 5.7
0.736
22.1 5.8
0.642
BMI, mean SD
27.3 9.8
27.0 9.7
0.339
27.2 9.8
0.864
28.4 13.9
0.681
College (%)
3,789 (18.8)
357 (19.3)
0.599
104 (18.6)
0.917
13 (22.0)
0.518
Married (%)
1,773 (8.3)
176 (8.9)
0.316
59 (10.1)
0.113
18 (19.6)
< 0.001
Smoker (%)
3,352 (16.4)
295 (15.8)
0.496
85 (15.2)
0.428
6 (8.5)
0.070
Alcohol (%)
3,322 (16.4)
290 (15.7)
0.461
100 (17.6)
0.413
5 (7.0)
0.034
Drugs (%)
2,144 (10.0)
177 (9.1)
0.167
57 (9.7)
0.809
4 (5.3)
0.167
DM at Del (%)
736 (3.8)
98 (5.5)
0.001
21 (4.0)
0.823
1 (1.2)
0.379
HTN at Del (%)
2,213 (11.4)
224 (12.5)
0.197
50 (9.5)
0.169
23 (27.7)
< 0.001
C-Section (%)
3,423 (17.4)
338 (18.4)
0.267
109 (20.3)
0.074
20 (24.1)
0.107
Nulliparous (%)
14,430 (65.3)
1,339 (65.8)
0.640
393 (65.3)
0.987
78 (75.7)
0.026
Abbreviations: β-thal, beta-thalassemia; BMI, body mass index; C-Section, cesarean section; DM at Del, diabetes mellitus at delivery; Hb, Hemoglobin; HTN at Del, hypertension at delivery. a AA is the comparison group for AS, AC, and SS,SC, S/β b Values are n (%) except where mean SD.
not present multivariable adjusted results, as this would not be valid. VTE in pregnancy and postpartum is a rare event with an incidence of approximately 1/1,000.1,2 Our findings are consistent with other reports associating sickle cell disease conditions with an increased risk of VTE.2,15 However, the strength of association we observed is much higher than the 2.5 to 6.7-fold increase reported in prior studies.2,15 Our results likely overestimate the true magnitude as a result of
the small sample size and our inability to conduct meaningful multivariable adjustments. Furthermore, although not statistically significant, the observed odds ratios and range of values in the 95% CI for sickle cell trait and Hb AC suggest possible associations with VTE and sickle cell trait during pregnancy. If true, this would be supportive of a prior study that associated Hb AS with increased VTE in the setting of hormonal contraception,13 which mimics the biological milieu that exists during pregnancy. Austin et al suggested that
Table 2 Prevalence and relative risk of prior history or new onset thromboembolism during pregnancy or postpartum by type of hemoglobinopathy Hemoglobin status
Prior history or new onset venous thromboembolism Prevalence/1,000
(n/N)
RR
95% CI
Hb AA
0.9
(20/22,140)
1
Referent
Hb AS
1.5
(3/2,037)
1.6
0.5, 5.5
Hb AC
3.3
(2/602)
3.7
0.9, 16
Hb SS, SC, or S/β-thal
29.1
(3/103)
32.2
9.7, 107
Abbreviations: β-thal, beta-thalassemia; CI, confidence interval; Hb, hemoglobin; RR, relative risk.
Table 3 Prevalence and relative risk of new onset thromboembolism during pregnancy or postpartum by type of hemoglobinopathy Hemoglobin status
New onset venous thromboembolism Prevalence/1,000
(n/N)
RR
95% CI
Hb AA
0.4
(8/22,128)
1
Referent
Hb AS
1.0
(2/2,036)
2.7
0.6, 13
Hb AC
1.7
(1/601)
4.6
0.6, 37
Hb SS, SC, or S/β-thal
19.6
(2/102)
54
12, 253
Abbreviations: β-thal, beta-thalassemia; CI, confidence interval; Hb, hemoglobin; RR, relative risk. American Journal of Perinatology
Vol. 31
No. 9/2014
Downloaded by: Florida International University. Copyrighted material.
Table 1 Demographic and clinical characteristics of the study populationa,b
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy both hormonal contraception and Hb AS have a procoagulant effect, and that there may be synergy between the two. They postulated that the joint effect of hormonal contraception and Hb AS is considerably greater than the multiplicative effect of each. Given the increases in both estrogen and progesterone during pregnancy, one would expect to see a similar increase in VTE in Hb AS pregnancies.13 Sickle trait has also been associated with increased VTE outside of the pregnant state (without regard to hormonal contraception).12 On the one hand, our small study sample size may explain the failure to demonstrate a significant increase in pregnancy-related VTE in women with Hb AS. Given that the incidence of VTE in pregnancy was estimated at 0.09% for women with Hb AA, and 0.15% for those with Hb AS, approximately 110,000 women would be needed to demonstrate a RR of 1.67 with 80% power and a type I error rate of 5%. On the other hand, however, one recent study reported no association between Hb AS and VTE during pregnancy and postpartum.16 However, this study was even smaller than this study and given the previously mentioned rarity of VTE, their results are certainly subject to the limitations of a smaller sample size. Similar to our findings for Hb AS, the results further suggest the hypothesis that Hb AC may be associated with an increase in VTE during pregnancy given adequate sample size. This is the only study we are aware of that has examined the impact of the hemoglobin AC genotype vis-à-vis VTE during pregnancy. Whereas our findings may be more supportive of observations in the setting of hormonal contraception, differences between VTE in pregnancy and VTE in the setting of hormonal contraception must be considered. While estrogen and progesterone are increased in both states, the levels are different between the pregnant state and hormonal contraceptive use.17,18 Second, hemostasis and the coagulation cascade are profoundly altered during pregnancy with adaptation that favors clot formation. The extrinsic and intrinsic pathways are upregulated and almost all clotting factors are increased in pregnancy.17,19 While the complexities of coagulation during pregnancy are only partially understood, increased serum estrogen and progesterone levels seen with hormonal contraception are only slightly altered compared with the vast shift in the hemostatic changes that occur during pregnancy. In summary, our data must be interpreted with caution. The prevalence of VTE in the Hb AA group (0.9%) was similar to previously published studies1,2 providing some reassurance regarding the validity of our findings. However, the implications of these findings must be tempered by the acknowledged study limitations particularly the small sample size and lack of adjustments. Moreover, the use of ICD-9 codes to detect the incidence VTE in pregnancy is problematic and ICD-9 codes specific to pregnancy may underestimate the true incidence.20 Similarly, the use of discharge data and ICD-9 codes may underestimate the incidence of postpartum VTE occurring in the outpatient setting.21 Additional studies are needed to confirm the impact of Hb AS and AC on VTE risk during pregnancy before specific directed interventions are considered. Given the rarity of American Journal of Perinatology
Vol. 31
No. 9/2014
Porter et al.
the outcome, multicenter studies may be better suited to cumulate the needed numbers and prospective ascertainment may be preferable to overcome bias. In the meantime, these patients should be stratified and managed during pregnancy according to individual risk factors for VTE, including body mass index and prior VTE history. For patients with Hb SS, it would prudent to consider them a high-risk group given the underlying pathophysiology and accumulating literature.
Acknowledgments There are no disclosures. The authors have received no financial support for the work being published.
References 1 Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ
2
3
4
5 6
7
8 9
10
11
12
13
14
15
III. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143(10):697–706 James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194(5):1311–1315 Lindqvist P, Dahlbäck B, Marŝál K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999;94(4): 595–599 Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance—United States, 1991–1999. MMWR Surveill Summ 2003;52(2):1–8 Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010;115(22):4331–4336 Section on Hematology/Oncology Committee on Genetics; American Academy of Pediatrics. Health supervision for children with sickle cell disease. Pediatrics 2002;109(3):526–535 Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell disease in the United States: national and state estimates. Am J Hematol 2010;85(1): 77–78 Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med 2010;38(4, Suppl)S512–S521 Rickles FR, O’Leary DS. Role of coagulation system in pathophysiology of sickle cell disease. Arch Intern Med 1974;133(4): 635–641 Key NS, Slungaard A, Dandelet L, et al. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 1998;91(11):4216–4223 Westerman MP, Green D, Gilman-Sachs A, et al. Coagulation changes in individuals with sickle cell trait. Am J Hematol 2002; 69(2):89–94 Austin H, Key NS, Benson JM, et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007;110(3): 908–912 Austin H, Lally C, Benson JM, Whitsett C, Hooper WC, Key NS. Hormonal contraception, sickle cell trait, and risk for venous thromboembolism among African American women. Am J Obstet Gynecol 2009;200(6):e1–e3 Tita AT, Biggio JR, Chapman V, Neely C, Rouse DJ. Perinatal and maternal outcomes in women with sickle or hemoglobin C trait. Obstet Gynecol 2007;110(5):1113–1119 Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008;199(2):e1–e5
Downloaded by: Florida International University. Copyrighted material.
808
Sickle Hemoglobinopathies and Thromboembolism in Pregnancy
Porter et al.
19 O’Riordan MN, Higgins JR. Haemostasis in normal and abnormal
increased VTE risk in pregnancy and the postpartum? PLoS ONE 2013;8(5):e64141 17 Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 2009;114(6):1326–1331 18 Mishell DR Jr, Thorneycroft IH, Nakamura RM, Nagata Y, Stone SC. Serum estradiol in women ingesting combination oral contraceptive steroids. Am J Obstet Gynecol 1972;114(7):923–928
pregnancy. Best Pract Res Clin Obstet Gynaecol 2003;17(3): 385–396 20 White RH, Brickner LA, Scannell KA. ICD-9-CM codes poorly indentified venous thromboembolism during pregnancy. J Clin Epidemiol 2004;57(9):985–988 21 Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007;167(14):1471–1475
Downloaded by: Florida International University. Copyrighted material.
16 Pintova S, Cohen HW, Billett HH. Sickle cell trait: is there an
809
American Journal of Perinatology
Vol. 31
No. 9/2014
