Journal Pre-proof

Low-dose aspirin for preeclampsia prevention: efficacy by ethnicity and race

Mary Catherine TOLCHER, MD, MSc, Haleh SANGI-HAGHPEYKAR, PhD, Hector

MENDEZ-FIGUEROA, MD, Kjersti M. AAGAARD, MD, PhD

PII: S2589-9333(20)30128-2
DOI: https://doi.org/10.1016/j.ajogmf.2020.100184
Reference: AJOGMF 100184

To appear in: American Journal of Obstetrics & Gynecology MFM

Received Date: 5 May 2020

Revised Date: 1 July 2020
Accepted Date: 14 July 2020

Please cite this article as: TOLCHER MC, SANGI-HAGHPEYKAR H, MENDEZ-FIGUEROA H,

AAGAARD KM, Low-dose aspirin for preeclampsia prevention: efficacy by ethnicity and race, American
Journal of Obstetrics & Gynecology MFM (2020), doi: https://doi.org/10.1016/j.ajogmf.2020.100184.

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 |1

Low-dose aspirin for preeclampsia prevention: efficacy by ethnicity and race

Mary Catherine TOLCHER, MD, MSc1, Haleh SANGI-HAGHPEYKAR, PhD1, Hector MENDEZ-

FIGUEROA, MD2, Kjersti M. AAGAARD, MD, PhD*1,3,4

1
Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Baylor College of

Medicine, Houston, TX, United States;

2
Department of Obstetrics, Gynecology, and Reproductive Sciences, McGovern Medical School, The

University of Texas Health Science Center at Houston, Houston, TX, United States;
3
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United

States; and
4
Department of Molecular & Cell Biology, Baylor College of Medicine, Houston, TX, United States

The authors report no conflict of interest.

Financial support: None

Paper presentation information: This work was presented as abstracts #324 and #952 at the 38th

Annual Pregnancy Meeting, January 29-February 3, 2018, Dallas, Texas

*Corresponding author:
Kjersti M. Aagaard, MD, PhD
Baylor College of Medicine
1 Baylor Plaza, Jesse H. Jones Hall, Room 314C
Houston, TX, 77030.
Fax (713) 798-4216
Telephone (713) 798 8467
Email: aagaardt@bcm.edu

Abstract Word Count: 455

Main Text Word Count: 1967

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1 Condensation: Preeclampsia was significantly reduced among low-risk non-Hispanic white women

2 who received aspirin as compared to placebo.

4 Short title: Impact of ethnicity and race on aspirin for preeclampsia prevention

6 A. Why was this study conducted?

7 To determine if the efficacy of aspirin for preeclampsia prevention differs by ethnicity and race in a
8 secondary analysis of randomized controlled trials.
9
10 B. What are the key findings?
11 Low-risk, non-Hispanic white women who received aspirin for the prevention of preeclampsia were
12 the only group who demonstrated a significantly decreased incidence of preeclampsia. This risk
13 persisted after adjustments for compliance and gestational age at onset of therapy.
14
15 C. What does this study add to what is already known?
16 These findings demonstrate variation in efficacy of aspirin for the prevention of preeclampsia by
17 ethnicity and race. When considered in the context of pharmacogenomics, and a high rate of
18 occurrence of preeclampsia among non-Hispanic black women, these findings suggest that future
19 studies may benefit from identifying efficacious preventative measures which would benefit non-white
20 populations.
21
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22 ABSTRACT
23 Background: Low-dose aspirin is recommended for the prevention of preeclampsia among women

24 at high-risk for the disease. Aspirin undergoes polymorphic metabolism, and it is well known that

25 common genetic polymorphisms are related to aspirin intolerance. We hypothesized that efficacy of

26 aspirin prophylaxis may differ by ethnicity and race.

27 Objectives: The aim of the current study is to compare rates of preeclampsia among low- and high-

28 risk women who received aspirin as compared to placebo, stratifying results by ethnicity and race as

29 a first pass approximation of genomic polymorphisms.

30 Study design: This is a secondary analysis of two randomized controlled trials previously performed

31 by the Maternal-Fetal Medicine Units Network; the low-risk aspirin trial and the high-risk aspirin trial.

32 For the low-risk aspirin trial, normotensive, nulliparous women were enrolled between 13 and 26

33 weeks of gestation and randomized to 60 mg aspirin daily or placebo. For the high-risk aspirin trial,

34 women with pregestational insulin-treated diabetes mellitus, chronic hypertension, multiple

35 gestations, or a history of preeclampsia in a previous pregnancy were enrolled between 13 and 26

36 weeks of gestation and randomized to 60 mg aspirin daily or placebo. The primary outcome of our

37 secondary analysis was preeclampsia. Secondary outcomes included gestational age at delivery,

38 preterm delivery, placental abruption, small for gestational age, stillbirth, and neonatal death.

39 Outcomes were stratified by ethnicity and race (Hispanic, non-Hispanic white, non-Hispanic black, or

40 other).

41 Results: In the low-risk aspirin trial of 3135 women, the risk of preeclampsia was significantly

42 reduced among non-Hispanic white women who received aspirin as compared to non-Hispanic white

43 women who received placebo (relative risk (RR) 0.19, 95% CI 0.06-0.63, P = .007). The risk of

44 preeclampsia was not different comparing aspirin versus placebo groups among the Hispanic, non-

45 Hispanic black, or other ethnicity and race groups. The efficacy among non-Hispanic white women

46 persisted after consideration of compliance and gestational age at randomization (RR 0.07, 95% CI

47 0.009-0.51, P = .009). As noted in the original trial, there was an increased risk of placental abruption
 |3

48 in the aspirin group overall as compared to placebo (P = .025). The risk of stillbirth was significantly

49 increased among non-Hispanic black women who received aspirin as compared to non-Hispanic

50 black women who received placebo (P = .048). In the high-risk aspirin trial of 2539 women, 269 were

51 Hispanic (10.6%), 832 were non-Hispanic white (32.8%), 1426 were non-Hispanic black (56.2%), and

52 12 were categorized as other (0.5%). Stratification by ethnicity and race did not show a decreased

53 incidence of preeclampsia for any of the subgroups (P >.05). Moreover, there was no significant

54 difference in other measured outcomes including preterm delivery <37 weeks, placental abruption,

55 small for gestational age, stillbirth, or neonatal death.

56 Conclusion: The incidence of preeclampsia was significantly reduced among low-risk non-Hispanic

57 white women who received aspirin as compared to placebo, but not overall or among Hispanics or

58 non-Hispanic blacks. Analysis of high-risk women did not demonstrate a difference in the efficacy of

59 aspirin by ethnicity and race.

60

61 Key Words: aspirin, ethnicity, health disparities, preeclampsia, prevention, race

62

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71 INTRODUCTION

72 Preeclampsia is a prevalent pregnancy disorder with significant public health consequences for both

73 mother and infant (e.g. maternal organ dysfunction, fetal growth restriction, and preterm delivery).1

74 Currently, the American College of Gynecologists and Obstetricians (ACOG) and the Society for

75 Maternal-Fetal Medicine recommend low-dose aspirin for the prevention of preeclampsia among

76 women at high-risk for the disease.2 Risk defining criteria include women with a history of

77 preeclampsia, multiple gestations, chronic hypertension, pregestational diabetes, renal disease, or

78 autoimmune disorders.2-4 Low-dose aspirin is not currently recommended for the prevention of

79 preeclampsia in the absence of risk factors.2

80 The recommendation for aspirin prophylaxis for women at high-risk for preeclampsia is based

81 on meta-analyses of randomized trials that revealed a small but significant reduction in preeclampsia

82 with aspirin compared to placebo.5-7 Interestingly, individual randomized controlled trials of women at

83 high-risk for preeclampsia, including a large randomized trial conducted in the United States, showed

84 zero to marginal benefit.8-10 We recently demonstrated a 30% relative risk reduction of recurrent

85 preeclampsia in a contemporary cohort analysis.11 In our study, the relative proportion of Hispanic

86 women experiencing recurrent preeclampsia was lower after implementation of an aspirin guideline

87 while the proportion of non-Hispanic black women was paradoxically higher. Our findings, in addition

88 to known variation in pharmacokinetics of aspirin and other medications by ethnicity and race, led us

89 to question variation in responsiveness to low-dose aspirin for prevention of preeclampsia.12-16

90 In the general medical literature, studies have demonstrated that adequate antiplatelet effects

91 are not achieved in up to 40% of patients receiving aspirin, suggesting that many individuals are

92 aspirin resistant or non-responders.13 The variation in antiplatelet effects of aspirin among individuals

93 seems to vary in a continuous rather than binary spectrum of effectiveness.17 Similarly, aspirin

94 intolerance (adverse effects of aspirin including asthma exacerbation, gastrointestinal bleeding, or

95 urticarial reaction) is known to vary by race and ethnicity, and recent genome wide association

96 studies have linked common polymorphisms in metabolic pathways to both racial and ethnic variation
 |5

97 and aspirin intolerance.18-20 Thus, although low-dose aspirin is not recommended for women at low-

98 risk for the disease, given the potential for varying response to aspirin, there may be subgroups of

99 low-risk women who would benefit from aspirin prophylaxis. A secondary analysis of a multinational

100 randomized trial on aspirin for prevention of preterm preeclampsia among high-risk women did not

101 show an effect by race; however, a higher dose of aspirin was used and only a high-risk group was

102 examined.21 The aim of the current study is to compare rates of preeclampsia among low- and high-

103 risk women who received aspirin as compared to placebo for preeclampsia prevention, stratifying

104 results by ethnicity and race as a first pass approximation of pharmacogenomics. We hypothesized

105 that efficacy of aspirin prophylaxis, as evidenced by occurrence and severity of preeclampsia, may be

106 less in non-Hispanic black women.

107

108 METHODS

109 Study design, subjects, and database characteristics

110 This is a secondary analysis of two randomized controlled trials previously performed by the

111 Maternal-Fetal Medicine Units (MFMU) Network; the low-risk aspirin (LRA) study and the high-risk

112 aspirin (HRA) study.8,9 For the LRA study, normotensive, nulliparous women were enrolled between

113 13 and 26 weeks of gestation and randomized to aspirin 60 mg daily or placebo.9 For the HRA study,

114 women with pregestational insulin-treated diabetes mellitus, chronic hypertension, multiple

115 gestations, or a history of preeclampsia in a previous pregnancy were enrolled between 13 and 26

116 weeks of gestation and randomized to aspirin 60 mg daily or placebo.8 Given the use of publicly

117 available, de-identified datasets, this work did not constitute human subjects research and an

118 Institutional Review Board (IRB) approval was deemed to not be required and IRB exemption was

119 granted. Subjects were initially consented under the index study IRBs, including permission for future

120 use of de-identified data.8,9

121

122 Outcome measures and data analysis

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123 The primary outcome of this secondary analysis was the diagnosis of preeclampsia. Outcomes were

124 stratified by ethnicity and race (Hispanic, non-Hispanic white, non-Hispanic black, or other).

125 Multivariate analyses including adjustments for compliance (≥50% of tablets taken) and gestational

126 age at randomization (continuous variable) were performed for the primary outcome. In both studies,

127 compliance was determined by direct questioning of trial participants and tablets counts.8,9 A priori

128 defined secondary outcomes in this analysis included gestational age at delivery, preterm delivery,

129 placental abruption, small for gestational age (SGA), stillbirth, and neonatal death. Continuous

130 variables were compared using the two-sample t-test if parametric or Wilcoxon Rank Sum if

131 nonparametric. Categorical or binary variables were compared using chi-square or Fisher’s Exact

132 Test as appropriate. Relative risk (RR) and 95% CI were calculated for each outcome. All analyses

133 were performed in SAS statistical software (version 9.4). P <.05 was considered statistically

134 significant in both unadjusted and adjusted analyses.

135

136 RESULTS

137 The LRA study included 3135 women; 1570 were assigned to aspirin and 1565 to placebo. The study

138 included 1561 non-Hispanic black (50.0%), 558 non-Hispanic white (17.8%), 988 Hispanic (31.5%),

139 and 28 “other” (0.9%) women, and there was no difference between ethnicity and race comparing the

140 aspirin and placebo groups (P = .895) (Figure 1A). The risk of preeclampsia was significantly reduced

141 among non-Hispanic white women who received aspirin as compared to non-Hispanic white women

142 who received placebo (1.2% versus 6.2%, RR 0.19, 95% CI 0.06-0.63, P = .007) but not among the

143 Hispanic, non-Hispanic black, or other ethnicity and race groups (Figure 2). When analyses were

144 limited to women with high compliance (≥50% of tablets taken) and adjusted for gestational age at

145 randomization, the reduction in preeclampsia among non-Hispanic white women in the aspirin group

146 as compared to placebo persisted (aRR 0.07, 95% CI 0.009-0.51, P = .009); there was no difference

147 among the other high compliance groups after adjustments for gestational age (Hispanic aRR 1.01,
 |7

148 95% CI 0.58-1.77, P = 0.97; non-Hispanic black (aRR 0.72, 95% CI 0.46-1.12, P = 014). As noted in

149 the original trial, there was an increased risk of placental abruption in the aspirin group overall as

150 compared to placebo (0.8% versus 0.1%, P = .025). The risk of stillbirth was significantly increased

151 among non-Hispanic black women who received aspirin as compared to non-Hispanic black women

152 who received placebo (1.5% versus 0.4%, P = .048).

153 The HRA study included 2503 women; 1254 were assigned to aspirin and 1249 to placebo. Of

154 the cohort, 1426 were non-Hispanic black (56.2%), 832 were non-Hispanic white (32.8%), 269 were

155 Hispanic (10.6%), and 12 were categorized as other (0.5%), and there was no difference between

156 ethnicity and race comparing the aspirin and placebo groups (P = .546) (Figure 1B). Stratification by

157 ethnicity and race did not show a decreased incidence of preeclampsia comparing aspirin and

158 placebo for any of the subgroups (P >.05) (Figure 3). Moreover, there were no significant differences

159 in other measured outcomes including preterm delivery <37 weeks, placental abruption, SGA,

160 stillbirth, or neonatal death.

161

162 COMMENT

163 Principal Findings

164 The main findings of the current analysis of a previously published randomized controlled trial of

165 aspirin versus placebo for preeclampsia prevention among low-risk women (LRA study) included a

166 significantly reduced incidence of preeclampsia among non-Hispanic white women who received

167 aspirin, but not overall or among Hispanics or non-Hispanic blacks. The protective effect of aspirin

168 among non-Hispanic white women persisted after compliance and gestational age were considered.

169 As noted in the original trial, the incidence of placental abruption was higher in the aspirin group in the

170 LRA study9; however, there was no significant difference in this outcome in the HRA study, and

171 placental abruption is an imprecise and difficult outcome to measure given the clinical nature of the

172 diagnosis. In addition, we observed that the relative risk of stillbirth was higher in the aspirin group in
 |8

173 the LRA study for the non-Hispanic black women subgroup. A similar analysis of the HRA study

174 showed no significant reduction in preeclampsia or other outcomes for any of the ethnic and racial

175 subgroups.

176

177 Results

178 We sought to examine the question of impact of ethnicity and race on aspirin efficacy after our recent

179 retrospective cohort study showed a significant decrease in recurrent preeclampsia in our population

180 with a disproportionate lack of effect among non-Hispanic black women.11 We hypothesized that the

181 lack of effect in the non-Hispanic black population, who made up more than 50% of the MFMU index

182 study populations, may explain the lack of overall efficacy in the MFMU randomized trials.8,9 Our

183 findings presented here recapitulate our prior observations,11 and add to a growing body of evidence

184 suggesting that since aspirin undergoes polymorphic metabolism, both adverse reactions and efficacy

185 may have significant variation by virtue of common genetic variants retained in distinct racial and

186 ethnic populations and their admixtures. In the advent of growing concerns over health disparities, it

187 is noteworthy that both the current study and our prior analyses suggest that non-Hispanic black

188 women show a disproportionate lack of efficacy of aspirin for the prevention of recurrent

189 preeclampsia. Given the well documented higher rate of occurrence of preeclampsia in this

190 population, our findings are of important clinical significance.

191

192 Clinical Implications

193 Aspirin resistance (or non-response) refers to a lack of reduction in platelet production of

194 thromboxane A2 and resultant platelet activation and aggregation.22 Typically, response to aspirin is

195 assessed by laboratory tests of thromboxane-dependent platelet function and has been described in

196 the context of secondary prevention of cardiovascular disease including coronary artery disease and

197 stroke.23,24 The exact mechanism of aspirin resistance is an area of ongoing study; however,

198 pharmacogenetics studies over the last decade have evaluated several polymorphisms considered to
 |9

199 potentially influence the antiplatelet effect of aspirin including the impact of ethnicity and race.14,25,26

200 Gene polymorphisms have also been linked to aspirin intolerance in asthmatics as well as risk of

201 aspirin-induced gastrointestinal bleeding.27,28 In one study of predictors of non-responders to aspirin

202 and clopidogrel among patients with ischemic stroke, African American race was a risk factor for non-

203 response to clopidogrel but for non-response to aspirin.29 A recently published cohort study examined

204 the impact of implementing the ACOG endorsed guidelines for aspirin therapy among pregnant

205 women with chronic hypertension in a population of majority non-Hispanic black women and failed to

206 observe a significant decrease in superimposed preeclampsia, small for gestational age, or preterm

207 delivery.30 This study further supports our hypothesis that non-Hispanic at-risk black women may be

208 either resistant or unresponsive to aspirin, or require a higher dose of aspirin for prevention of

209 preeclampsia. The underlying biological mechanism of these observations is unknown, but we

210 speculate that it is likely multifactorial and would include clinical factors (such as medical

211 comorbidities), biochemical and cellular factors (such as altered pharmacodynamics), and genetic

212 mechanisms (such as polymorphisms or pharmacogenomics). The lack of findings of difference in

213 efficacy by ethnicity and race among the high-risk cohort is unclear, but may similarly reflect the

214 pharmacodynamics of prevention, manifesting clinically as a higher requisite dose among higher risk

215 women to achieve equivalence of efficacy in prevention. National recommendations continue to

216 support the use of low-dose aspirin prophylaxis (81 mg/day) for all women at high-risk for

217 preeclampsia.2

218

219 Research Implications

220 A recently published study of pregnant women at high-risk for preeclampsia found a high rate of

221 variable and indeterminate aspirin response based on platelet function testing.31 According to a meta-

222 analysis of randomized trials, there is a dose-response effect of aspirin as increasing dosages of

223 aspirin were associated with greater risk reduction in preeclampsia, severe preeclampsia, and fetal

224 growth restriction.32 The highest dose reported in this meta-analysis was 150 mg, and a 150 mg
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225 dosage was used in a randomized trial published following this meta-analysis.33 Important to note is

226 that in both of the trials that we analyzed, the dose of aspirin utilized was 60 mg which differs from the

227 currently available and recommended low-dose of 81 mg in the United States. Future studies should

228 examine if higher doses are effect modifiers among non-responders, including stratified analyses by

229 ethnicity and race. Our results differ from that of Poon et al who found no evidence of heterogeneity in

230 aspirin effect by ethnicity or race in their secondary analysis of a randomized trial.21 We believe our

231 findings could be explained by the difference in aspirin dose, racial heterogeneity of the study

232 population, or clinical characteristics of the population defined as high-risk. To this latter point, Poon

233 et al employed a screening algorithm which included biomarkers not widely used in practice to define

234 their “high-risk” study population.

235

236 Strengths and Limitations

237 To our knowledge, this study is one of the first to address the question of varying efficacy of aspirin

238 prophylaxis by ethnicity and race in a pregnant population subjected to a randomized controlled study

239 design. Our study is limited by the retrospective nature of a secondary analysis which was not initially

240 powered to address the hypothesis being tested. Nevertheless, given that significance was observed,

241 the studies were adequately powered for this secondary analysis. Moreover, the results of our study

242 are strengthened by the fact that the index studies were large, multicenter randomized controlled

243 trials. Women of ethnic and racial groups other than Hispanic, non-Hispanic white, and non-Hispanic

244 black were largely underrepresented in the studies examined and conclusions regarding efficacy

245 cannot be made in these other populations. We defined high compliance as taking half or more of

246 tablets as the HRA study did not find a difference in the incidence of preeclampsia based on the

247 percentage of tablets taken (50% versus 80%). However, one secondary analysis found that

248 compliance ≥90% was associated with lower rates of preterm preeclampsia.34 Finally, responsiveness

249 to aspirin could be affected by factors other than ethnicity and race including measureable genetic

250 polymorphisms which do not vary in accordance with race nor ethnicity, other medication or drug use,
 | 11

251 aspirin dosage, non-compliance,34 or timing of initiation during pregnancy.26,35,36 Further, subgroup

252 analyses suffer from loss of randomization and should be interpreted with caution and considered

253 exploratory. Although we explored the impact of compliance and gestational age at randomization,

254 the impact of gestational age at initiation (particularly <16 weeks versus >16 weeks) and the dose of

255 aspirin are areas of ongoing debate that require further study.35,37,38

256

257 Conclusions

258 When considered with our previously published and recent work,11 these findings presented are of

259 clinical significance and collectively suggest that broad, unselective use of aspirin among low-risk

260 women is not currently supported by data or national recommendations with demonstrated potential

261 benefit only among few women. Our findings of a substantial improvement in efficacy of aspirin for

262 preventing preeclampsia among low risk non-Hispanic white women support future exploration of the

263 pharmacogenetics of aspirin metabolism and the potential impact of genomics-driven aspirin

264 resistance on preeclampsia prevention.

265

266
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267 REFERENCES

268 1. Bokslag A, van Weissenbruch M, Mol BW, de Groot CJ. Preeclampsia; short and long-term
269 consequences for mother and neonate. Early Hum Dev 2016;102:47-50.
270 2. ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet Gynecol
271 2018;132:e44-e52.
272 3. LeFevre ML, Force USPST. Low-dose aspirin use for the prevention of morbidity and mortality
273 from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med
274 2014;161:819-26.
275 4. https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/low-
276 dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-
277 medication. Accessed June 25, 2020.
278 5. Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose
279 aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for
280 the U.S. Preventive Services Task Force. Ann Intern Med 2014;160:695-703.
281 6. Xu TT, Zhou F, Deng CY, Huang GQ, Li JK, Wang XD. Low-Dose Aspirin for Preventing
282 Preeclampsia and Its Complications: A Meta-Analysis. J Clin Hypertens (Greenwich) 2015;17:567-73.
283 7. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, Group PC. Antiplatelet agents for
284 prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1791-8.
285 8. Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high
286 risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine
287 Units. N Engl J Med 1998;338:701-5.
288 9. Sibai BM, Caritis SN, Thom E, et al. Prevention of preeclampsia with low-dose aspirin in
289 healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development
290 Network of Maternal-Fetal Medicine Units. N Engl J Med 1993;329:1213-8.
291 10. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-
292 eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in
293 Pregnancy) Collaborative Group. Lancet 1994;343:619-29.
294 11. Tolcher MC, Chu DM, Hollier LM, et al. Impact of USPSTF recommendations for aspirin for
295 prevention of recurrent preeclampsia. Am J Obstet Gynecol 2017;217:365 e1- e8.
296 12. Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance: a comprehensive
297 systematic review. Br J Clin Pharmacol 2008;66:222-32.
298 13. Vasudeva K, Chaurasia P, Singh S, Munshi A. Genetic Signatures in Ischemic Stroke: Focus
299 on Aspirin Resistance. CNS Neurol Disord Drug Targets 2017;16:974-82.
300 14. Wurtz M, Kristensen SD, Hvas AM, Grove EL. Pharmacogenetics of the antiplatelet effect of
301 aspirin. Curr Pharm Des 2012;18:5294-308.
302 15. Wurtz M, Lordkipanidze M, Grove EL. Pharmacogenomics in cardiovascular disease: focus on
303 aspirin and ADP receptor antagonists. J Thromb Haemost 2013;11:1627-39.
304 16. Weng Z, Li X, Li Y, Lin J, Peng F, Niu W. The association of four common polymorphisms from
305 four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity: a meta-analysis.
306 PLoS One 2013;8:e78093.
307 17. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006;367:606-17.
308 18. Shiotani A, Murao T, Fujita Y, et al. Novel single nucleotide polymorphism markers for low
309 dose aspirin-associated small bowel bleeding. PLoS One 2013;8:e84244.
310 19. Kim JM, Park BL, Park SM, et al. Association analysis of N-acetyl transferase-2
311 polymorphisms with aspirin intolerance among asthmatics. Pharmacogenomics 2010;11:951-8.
312 20. Agundez JA, Martinez C, Perez-Sala D, Carballo M, Torres MJ, Garcia-Martin E.
313 Pharmacogenomics in aspirin intolerance. Curr Drug Metab 2009;10:998-1008.
314 21. Poon LC, Wright D, Rolnik DL, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial:
315 effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their
316 characteristics and medical and obstetrical history. Am J Obstet Gynecol 2017;217:585 e1- e5.
 | 13

317 22. Floyd CN, Goodman T, Becker S, et al. Increased platelet expression of glycoprotein IIIa
318 following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects. Br J Clin Pharmacol
319 2014;78:320-8.
320 23. Floyd CN, Ferro A. Mechanisms of aspirin resistance. Pharmacol Ther 2014;141:69-78.
321 24. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin "resistance" and risk of
322 cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008;336:195-8.
323 25. Momary KM, Shapiro NL, Brace LD, et al. Influence of cyclooxygenase-1 genotype on ex vivo
324 aspirin response in patients at risk for stroke. Cerebrovasc Dis 2009;27:585-93.
325 26. Fitzgerald R, Pirmohamed M. Aspirin resistance: effect of clinical, biochemical and genetic
326 factors. Pharmacol Ther 2011;130:213-25.
327 27. Kim SH, Sanak M, Park HS. Genetics of hypersensitivity to aspirin and nonsteroidal anti-
328 inflammatory drugs. Immunol Allergy Clin North Am 2013;33:177-94.
329 28. Shiotani A, Fujita Y, Nishio K. Low-Dose Aspirin-Associated Upper and Mid Gastrointestinal
330 Tract Damage and Gene Polymorphism. Curr Pharm Des 2015;21:5066-72.
331 29. Fong J, Cheng-Ching E, Hussain MS, Katzan I, Gupta R. Predictors of biochemical aspirin and
332 clopidogrel resistance in patients with ischemic stroke. J Stroke Cerebrovasc Dis 2011;20:227-30.
333 30. Banala C, Moreno S, Cruz Y, et al. Impact of the ACOG guideline regarding low-dose aspirin
334 for prevention of superimposed preeclampsia in women with chronic hypertension. Am J Obstet
335 Gynecol 2020.
336 31. Navaratnam K, Alfirevic A, Jorgensen A, Alfirevic Z. Aspirin non-responsiveness in pregnant
337 women at high-risk of pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2018;221:144-50.
338 32. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on
339 the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am
340 J Obstet Gynecol 2017;216:110-20 e6.
341 33. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus Placebo in Pregnancies at High Risk for
342 Preterm Preeclampsia. N Engl J Med 2017;377:613-22.
343 34. Wright D, Poon LC, Rolnik DL, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial:
344 influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. Am J
345 Obstet Gynecol 2017;217:685 e1- e5.
346 35. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks' gestation
347 for preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol
348 2017;216:121-8 e2.
349 36. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth
350 restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010;116:402-14.
351 37. Seidler AL, Askie L, Ray JG. Optimal aspirin dosing for preeclampsia prevention. Am J Obstet
352 Gynecol 2018.
353 38. Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term
354 preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol 2018;218:287-93 e1.
355

356

357

358

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360 Table 1. Outcomes by ethnicity/race among low-risk women receiving aspirin or placebo for
361 preeclampsia prevention, n = 2985. Hispanic, n = 998; non-Hispanic white, n = 558; non-Hispanic
362 black, n = 1561; other, n = 28.
†
Outcome Aspirin group Placebo group P value RR (95% CI) P value
n = 1485 n = 1500
Preeclampsia, n (%) 69 (4.7%) 94 (6.3%) 0.07 0.74 (0.55-1.01) 0.052
Hispanic 23 (4.9%) 26 (5.4%) 0.90 (0.52-1.56) 0.716
Non-Hispanic white 3 (1.2%) 17 (6.2%) 0.19 (0.06-0.63) 0.007
Non-Hispanic black 42 (5.7%) 50 (6.8%) 0.83 (0.56-1.23) 0.347
Other 1 (9.1%) 1 (7.7%) 1.18 (0.08-16.78) 0.900
GA at delivery, mean (SD) 38.6 (3.2) 38.8 (2.9) -- -- 0.427
Hispanic 38.8 (2.8) 39.0 (2.4) 0.177
Non-Hispanic white 39.1 (2.6) 39.1 (2.3) 0.429
Non-Hispanic black 38.4 (3.6) 38.5 (3.3) 0.905
Other 38.6 (1.5) 39.5 (2.6) 0.089
Preterm delivery*, n (%) 157 (10.6%) 146 (9.7%) 0.89 1.09 (0.88-1.34) 0.45
Hispanic 47 (10.0%) 33 (6.9%) 1.45 (0.95-2.23) 0.09
Non-Hispanic white 17 (6.6%) 23 (8.4%) 0.78 (0.43-1.42) 0.42
Non-Hispanic black 93 (12.5%) 89 (12.2%) 1.03 (0.78-1.35) 0.84
Other 0 1 (7.7%) -- --
Abruption, n (%) 11 (0.8%) 2 (0.1%) 0.88 5.56 (1.24-25.06) 0.025
Hispanic 2 (0.4%) 0 -- --
Non-Hispanic white 5 (2.0%) 0 -- --
Non-Hispanic black 4 (0.6%) 2 (0.3%) 1.98 (0.36-10.79) 0.428
Other 0 0 -- --
SGA infant, n (%) 73 (5.0%) 90 (6.1%) 0.49 0.82 (0.61-1.11) 0.203
Hispanic 15 (3.2%) 23 (4.8%) 0.67 (0.35-1.26) 0.212
Non-Hispanic white 12 (4.7%) 10 (3.7%) 1.27 (0.56-2.90) 0.563
Non-Hispanic black 45 (6.2%) 56 (7.7%) 0.80 (0.55-1.16) 0.237
Other 1 (9.1%) 1 (7.7%) 1.18 (0.08-16.78) 0.902
Stillbirth, n (%) 13 (0.9%) 5 (0.3%) 0.25 2.62 (0.94-7.35) 0.066
Hispanic 1 (0.2%) 1 (0.2%) 1.03 (0.06-13.34) 0.986
Non-Hispanic white 1 (0.4%) 1 (0.4%) 1.05 (0.07-16.64) 0.974
Non-Hispanic black 11 (1.5%) 3 (0.4%) 3.61 (1.01-12.89) 0.048
Other 0 0 -- --
Neonatal death, n (%) 4 (0.3%) 7 (0.5%) 0.89 0.58 (0.17-1.97) 0.379
Hispanic 2 (0.4%) 2 (0.4%) 1.03 (0.15-7.25) 0.979
Non-Hispanic white 0 1 (0.4%) -- --
Non-Hispanic black 2 (0.3%) 4 (0.6%) 0.49 (0.09-2.68) 0.413
Other 0 -- -- --
363 Abbreviations: GA, gestational age; SGA, small for gestational age

364 * Preterm delivery considered <37 weeks

365 † Test of interaction between ethnicity and aspirin use for each outcome

366

367

368

369
 | 15

370 Table 2. Outcomes by ethnicity/race among high-risk women receiving aspirin or placebo for
371 preeclampsia prevention, n = 2503. Hispanic, n = 269; non-Hispanic white, n = 832; non-Hispanic
372 black, n = 1426; other, n = 12.
†
Outcome Aspirin group Placebo group P value RR (95% CI) P value
n = 1254 n = 1249
Preeclampsia, n (%) 231 (18.4%) 254 (20.3%) 0.48 0.91 (0.77-1.06) 0.23
Hispanic 21 (16.7%) 25 (18.4%) 0.91 (0.54-1.54) 0.72
Non-Hispanic white 73 (18.5%) 92 (22.0%) 0.84 (0.64-1.11) 0.22
Non-Hispanic black 136 (18.7%) 137 (19.9%) 0.94 (0.76-1.17) 0.58
Other 1 (14.3%) 0 -- --
GA at delivery, mean (SD) 36.2 (3.9) 35.9 (4.4) -- -- 0.43
Hispanic 36.2 (3.5) 35.8 (4.0) -- -- 0.28
Non-Hispanic white 36.3 (3.8) 35.8 (4.3) 0.23
Non-Hispanic black 36.2 (4.1) 36.0 (4.6) 0.82
Other 37.4 (2.0) 39.6 (0.9) 0.10
Preterm delivery*, n (%) 502 (40.0%) 532 (42.6%) 0.26 0.94 (0.86-1.03) 0.19
Hispanic 51 (40.5%) 64 (47.1%) 0.86 (0.65-1.13) 0.29
Non-Hispanic white 165 (41.8%) 195 (46.5%) 0.90 (0.76-1.05) 0.17
Non-Hispanic black 284 (39.1%) 273 (39.6%) 0.99 (0.87-1.12) 0.85
Other 2 (28.6%) 0 -- --
Abruption, n (%) 15 (1.2%) 22 (1.8%) 0.62 0.68 (0.35-1.30) 0.24
Hispanic 1 (0.8%) 2 (1.5%) 0.55 (0.05-5.87) 0.61
Non-Hispanic white 5 (1.3%) 6 (1.5%) 0.88 (0.27-2.87) 0.84
Non-Hispanic black 9 (1.3%) 14 (2.1%) 0.61 (0.27-1.40) 0.24
Other -- 0 -- --
SGA infant, n (%) 101 (8.1%) 92 (7.4%) 0.47 1.09 (0.83-1.43) 0.55
Hispanic 7 (5.6%) 7 (5.2%) 1.09 (0.39-3.01) 0.87
Non-Hispanic white 30 (7.6%) 25 (6.1%) 1.26 (0.75-2.10) 0.38
Non-Hispanic black 64 (8.9%) 60 (8.8%) 1.08 (0.72-1.41) 0.96
Other 0 0 -- --
Stillbirth, n (%) 21 (1.7%) 32 (2.6%) 0.76 0.65 (0.38-1.13) 0.12
Hispanic 1 (0.8%) 3 (2.2%) 0.36 (0.04-3.41) 0.37
Non-Hispanic white 5 (1.3%) 7 (1.7%) 0.76 (0.24-2.37) 0.63
Non-Hispanic black 15 (2.1%) 21 (3.1%) 0.68 (0.35-1.30) 0.24
Other 0 1 (20%) -- --
Neonatal death, n (%) 21 (1.7%) 23 (1.8%) 0.28 0.91 (0.51-1.63) 0.75
Hispanic 3 (2.4%) 3 (2.2%) 1.08 (0.22-5.25) 0.92
Non-Hispanic white 6 (1.5%) 4 (1.0%) 1.59 (0.45-5.58) 0.47
Non-Hispanic black 12 (1.7%) 16 (2.3%) 0.71 (0.34-1.49) 0.37
Other 0 0 -- --
373 Abbreviations: GA, gestational age; SGA, small for gestational age

374 * Preterm delivery considered <37 weeks

375 † Test of interaction between ethnicity and aspirin use for each outcome

376

377

378
 | 16

379 Figure Legends

380 Figure 1. Ethnic and racial makeup of study participants from index randomized trials. A. Low-risk

381 aspirin (LRA) study for preeclampsia prevention. B. High-risk aspirin (HRA) study for preeclampsia

382 prevention.

383 Figure 2. Forest plot of outcomes by ethnicity and race, low-risk aspirin (LRA) study. Efficacy of ASA

384 for prevention among subjects at low-risk for the occurrence of preeclampsia was observed to be

385 significant only among non-Hispanic white, and not among non-Hispanic black nor Hispanic.

386 Figure 3. Forest plot of outcomes by ethnicity and race, high-risk aspirin (HRA) study. There was no

387 significant impact of ASA in prevention of preeclampsia among subjects at high-risk risk, including

388 when stratified by race or ethnicity.

389
 American Journal of
Obstetrics & Gynecology
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Manuscript title: Low-dose aspirin for preeclampsia prevention: efficacy by ethnicity and race

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