Preventing Preeclampsia with Low-Dose Aspirin: Critical Policy Review

Abstract

Administering of Low-Dose Aspirin to prevent Preeclampsia Statement of the Problem, Significance, Scope, and Burden In spite of studies evaluating the effectiveness of low-dose aspirin as a prevention of preeclampsia, the evidence is insufficient to inform stakeholders on the policies to put in place to facilitate the efficiency of the administration of the drug. The current review of literature examines alternative policy interventions that would determine how healthcare systems globally use low-dose aspirin to treat preeclampsia. Scope and Burden of Preeclampsia Preeclampsia affects pregnant women and is the leading cause of morbidity and mortality for mothers and babies in the United States and globally. In particular, the health condition increases the risk of preterm delivery raising the risk of death resulting from pregnancy. Preeclampsia causes high blood pressure among pregnant women and is associated with high levels of protein in the urine. Women with chronic high blood pressure, history of preeclampsia, type I or type II diabetes, or kidney disease are at a high risk of preeclampsia. The epidemiology of preeclampsia is 5-8% of all births and the rate has increase by 25% in the United States in the past two decades (5,6). Consequently, the care of pregnant women in consideration of the prevention of preeclampsia is critical in the healthcare system. While there are risk factors indicating a high likelihood of pregnant women developing preeclampsia, the condition could affect any woman during pregnancy and postpartum (4). In the United States, racial and ethnic minorities are disproportionately affected by preeclampsia. Studies have found that the most clinical method for preventing preeclampsia is the administration of low-dose aspirin to pregnant women (1,5,8). This approach could save lives and increase the quality of health for the mothers and babies globally. While the administering of low-dose aspirin has a significant reduction in the exposure of pregnant women to preeclampsia, the difference is small. The critical policy question for researchers and policy-makers is how they intend to administer low-dose aspirin in the most efficient manner (7). Determining how the health of mothers responds differently to women in different categories would shed light on the policies healthcare organizations and systems should make justified by primary research. Moreover, determining the effects of the treatment on the health outcomes pregnant women and babies would indicate the need to research and develop alternative treatments for preeclampsia. The impact of preeclampsia on pregnant mothers and babies is a key reason to consider the policies on the use of low-dose aspirin for prevention. Critical Literature Review Policy Interventions Effective interventions for preeclampsia could save the lives of mothers and babies and lead to healthy deliveries. The administration of low-dose aspirin is the best-known intervention for the prevention of preeclampsia among pregnant women in the globally. The studies included in this review of literature describe different administration procedures that determine the target women for the use of aspirin to prevent preeclampsia. Determining the most effective approach to determine the target patients for the current treatment would improve the health outcomes of pregnant women globally. One of the interventions is the administration of aspirin to all pregnant women to lower the incidents of preeclampsia. Health systems using this approach would recommend that all pregnant women receive a low dosage of aspirin from the second trimester. An alternative intervention is to administer low-dose aspirin among women at a high risk of preeclampsia. Through this intervention, the risk factors for preeclampsia are identified to determine the women who are at a high risk. They include chronic hypertension, women with a history of preeclampsia, type 1 and 2 diabetes, and low pregnancy-associated plasma protein A (PAPP-A), and kidney disease. While targeting high-risk pregnant women would provide intervention to those likely to develop preeclampsia, the intervention leaves out the low-risk pregnant women. In addition to limiting the administration of low-dose aspirin to high risk pregnant women, the literature search identified interventions targeting women with hypertension. This intervention provides care to women with hypertension and leaves out high risk women with normotension. High blood pressure is a critical factor influencing the prevalence of preeclampsia and this intervention approach excludes other women from low-dose aspirin administration. Alternatively, the literature search revealed the administration of calcium doses alongside low-dose aspirin as an intervention for preeclampsia. Pregnant women, regardless of their risk levels of preeclampsia, are provided with low-dose aspirin alongside a calcium dosage beginning in the second trimester. Racial and ethnic prevalence of illnesses is a critical consideration for healthcare organizations particularly in diverse societies. It is critical that healthcare organizations develop interventions that are effective among individuals of all races and ethnic groups. The last intervention approach is based on the administration of low-dose aspirin while considering the race and ethnicity of pregnant women. Providing care based on the effectiveness among women from different racial groups would ensure equality in treatment among diverse communities. Synthesis of Results Administering Aspirin to All Women Studies conducted involving pregnant women from different countries as revealed by the literature such (12). The study targeting all women involved participants from the Democratic Republic of Congo, India, Kenya, Zambia, Pakistan, and Guatemala reveled that low-dose aspirin initiated between 6 and 13 weeks and 6 days reduces preterm deliveries (12). The provision of low-dose aspirin among all pregnant women is a critical intervention for preeclampsia. According to the findings of the study, preterm deliveries before 37 weeks were lower for the treatment group compared to the placebo group. The research demonstrated that perinatal mortality reduced among the group where aspirin was administered to the pregnant women. A system review and meta-analysis on the same population showed that while low-dose aspirin lowered the risk of preterm preeclampsia, there was no impact on term preeclampsia (13). While the studies differed in methodology, the resulted to similar outcomes on the effectiveness of low-dose aspirin on pregnant women. Administering Aspirin to All High-Risk Women Determining the risk factors for preeclampsia plays a critical role in research on the effectiveness of low-dose aspirin as an intervention approach. Studies have revealed different results on how the administration of aspirin affects the health outcomes of the mother and child. In a study in the United States involving 186 women with chronic hypertension, 191 with diabetes, and 146 women with prior preeclampsia, the administration of low-dose aspirin at 60 mg/day of low dose aspirin reduced late-onset preeclampsia by 26 % (2). The participants in the study were initiated with the treatment at <17w0d and the findings showed that the intervention was effective in reducing the incidence of preeclampsia. While this study conducted in the United States showed low-dose aspirin to be effective, a randomized control study in care facilities in China reveled no benefits of low-dose aspirin on high risk women (3). 1000 pregnant women were treated with 100mg low-dose aspirin or a placebo and the findings showed no significant difference between the groups in the health of the mother and the baby. A key similarity between the studies is that they both involved high-risk women and randomized control designs were adopted. Additionally, the studies involved large samples but yielded contrary results on the efficacy of low-dose aspirin (2,3). Demographic and social factors were likely to be caused of the variation in the findings in the studies since one was conducted in China while the other research was undertaken in the United States. Moreover, different dosages were used for the studies indicating a cause for variation in the health outcomes of the participants. More importantly, however, the studies took different approaches in determining the initiation of the administration of intervention. The study conducted in the United States administered the treatment prior to 17w0d pregnancy (2). On the other hand, the methodology for the study conducted among women in hospitals in China initiated treatment to women between 12 and 20 weeks of their pregnancy (3). This difference in methodology was potentially influential in the variation in the findings from the two studies. A study taking a different approach by including women from different countries; Spain United Kingdom, Israel, Greece, Belgium, and Italy found similar results as the United states study (2,14). The findings showed that there was a significant difference be high risk women treated with low-dose aspirin and placebo (14). The multinational study, however, included considerations of the effect of participants who withdrew or women lost during follow up showing the variables had no effect on the findings. A study conducted among 30 women in the United States revealed that there was no difference in the risk of preeclampsia among women administered with low-dose aspirin and placebo. Unlike other studies among high-risk women, this study relied on a small sample as a result of difficulties in the recruitment process that relied on 6 risk factors of preeclampsia (15). The sample size and sampling procedure proved to be critical in determining the outcomes of the study on the efficacy of low-dose aspirin on preventing preeclampsia. Aspirin Effect in High-Risk Women with Stage 1 Hypertension One of the risk factors for preeclampsia is the history of hypertension among pregnant women. One of the studies identified in the current review investigated the role of stage I hypertension in the benefits of low-dose aspirin as an intervention for preeclampsia (9). Like other studies, the current research identified other risk factors to include the history of preeclampsia and diabetes mellitus (2,3). However, this study investigated specifically the role of hypertension on the efficacy of low-dose aspirin administered to prevent preeclampsia among pregnant women. The findings showed that women with hypertension had a higher reduction in the rate of preeclampsia compared to other high risk normotension women. Hypertension was revealed to be a significant risk factor for preeclampsia that should be considered when determining the recipients of low-dose aspirin. A study targeting high-risk women in China showed that the rate of preeclampsia was much lower among normotensive women than those with stage 1 hypertension (11). The study models were similar apart from the target population resulting to differences in social and health factors. Aspirin and Calcium Supplementation Determining the effect of low-dose aspirin and calcium supplementation would expand the current knowledge on the interventions for preeclampsia. A study on 49 Brazilian women were recruited to participate in a study to determine the efficacy of 100 mg aspirin supplemented with 2 g calcium would affect the health outcomes of pregnant women (10). Among the high-risk women recruited in the study, there was no difference in the rates of pre-term births between the placebo and the treatment groups. Effect of Race and Ethnicity and Risk Level on Aspirin Efficacy Racial inequality in healthcare is a critical issue of concern for interventions including the prevention of preeclampsia and its effects on pregnant women. The literature review included a study comparing how non-Hispanic women responded to the treatment compared to pregnant women from other ethnicities in the United States. Women were enrolled into a study to determine the efficacy of low-dose aspirin administered to low and high-risk women from different ethnic and racial groups (16). The findings showed that while the risk of preeclampsia was reduced among low-risk white women, the same was not observed among other groups. Conclusion Preeclampsia is a health condition affecting pregnant women that is associated with high blood pressure and an increased risk of pre-term births. Low-dose aspirin is the clinically accepted prevention of this health condition but policies on how it should be administered are unclear. Literature review shows mixed findings on the effectiveness of the treatment with studies including a large number of participants indicating significant reduction in the risk of pre-term births. Additionally, the benefits of low-dose aspirin in reducing the risk of preeclampsia were observed in studies involving low-risk participants. The findings demonstrate the need to facilitate the provision of low-dose aspirin as a preventive measure for the complications associated with preeclampsia. References 1. Who is at risk of preeclampsia? [Internet]. https://www.nichd.nih.gov/. [cited 2022 Mar 7]. Available from: https://www.nichd.nih.gov/health/topics/preeclampsia/conditioninfo/risk 2. Moore G, Allshouse A, Post A, Galan H, Heyborne K. Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study. J Perinatol Off J Calif Perinat Assoc. 2015 May;35(5):328–31. 3. Lin L, Huai J, Li B, Zhu Y, Juan J, Zhang M, et al. A randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in women at high risk in China. Am J Obstet Gynecol. 2022 Feb 1;226(2):251.e1-251.e12. 4. CDC. High Blood Pressure During Pregnancy [Internet]. Centers for Disease Control and Prevention. 2021 [cited 2022 Apr 18]. Available from: https://www.cdc.gov/bloodpressure/pregnancy.htm 5. Website. Preeclampsia - What Is Preeclampsia [Internet]. Preeclampsia Foundation - Saving mothers and babies from preeclampsia. [cited 2022 Mar 7]. Available from: https://www.preeclampsia.org/what-is-preeclampsia 6. How do health care providers diagnose preeclampsia, eclampsia, and HELLP syndrome? [Internet]. https://www.nichd.nih.gov/. [cited 2022 Apr 18]. Available from: https://www.nichd.nih.gov/health/topics/preeclampsia/conditioninfo/diagnosed 7. Sutton ALM, Harper LM, Tita ATN. Hypertensive Disorders in Pregnancy. Obstet Gynecol Clin North Am. 2018 Jun 1;45(2):333–47. 8. Preeclampsia: Pathophysiology and Clinical Presentations [Internet]. American College of Cardiology. [cited 2022 Mar 7]. Available from: https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2020/09/30/19/20/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2ften-points-to-remember%2f2020%2f09%2f30%2f19%2f20%2fPreeclampsia-Pathophysiology-and 9. Hauspurg A, Sutton EF, Catov JM, Caritis SN. Aspirin Effect on Adverse Pregnancy Outcomes Associated With Stage 1 Hypertension in a High-Risk Cohort. Hypertens Dallas Tex 1979. 2018 Jul;72(1):202–7. 10. Souza EV, Torloni MR, Atallah AN, dos Santos GMS, Kulay L, Sass N. Aspirin plus calcium supplementation to prevent superimposed preeclampsia: a randomized trial. Braz J Med Biol Res. 2014 Apr 11;47(5):419–25. 11. Huai J, Lin L, Juan J, Chen J, Li B, Zhu Y, et al. Preventive effect of aspirin on preeclampsia in high-risk pregnant women with stage 1 hypertension. J Clin Hypertens. 2021;23(5):1060–7. 12. Hoffman MK, Goudar SS, Kodkany BS, Metgud M, Somannavar M, Okitawutshu J, et al. Low-Dose Aspirin for the Prevention of Preterm Delivery in Nulliparous Women with a Singleton Pregnancy: A Randomised Multi-country Placebo Controlled Trial. Lancet Lond Engl. 2020 Jan 25;395(10220):285–93. 13. Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018 Mar;218(3):287-293.e1. 14. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613–22. 15. Odibo AO, Goetzinger KR, Odibo L, Tuuli MG. Early prediction and aspirin for prevention of pre-eclampsia (EPAPP) study: a randomized controlled trial. Ultrasound Obstet Gynecol. 2015;46(4):414–8. 16. Tolcher MC, Sangi-Haghpeykar H, Mendez-Figueroa H, Aagaard KM. Low-dose aspirin for preeclampsia prevention: efficacy by ethnicity and race. Am J Obstet Gynecol MFM. 2020 Nov 1;2(4):100184. Appendix I: Literature Grid Source (Full Citation) Study Purpose Study Design Population Key Finding Conclusion – this should also include study limitations/critiques Huai J, Lin L, Juan J, Chen J, Li B, Zhu Y, et al. Preventive effect of aspirin on preeclampsia in high-risk pregnant women with stage 1 hypertension. J Clin Hypertens. 2021;23(5):1060–7. To investigate if low-dose aspirin reduces the occurrence of preeclampsia among women with stage 1 hypertension. Randomized Controlled Trial 898 participants with high risk of preeclampsia recruited in China Stage 1 hypertension was lower in the control group Stage 1 hypertension is a key risk factor for preeclampsia among pregnant women. Tolcher MC, Sangi-Haghpeykar H, Mendez-Figueroa H, Aagaard KM. Low-dose aspirin for preeclampsia prevention: efficacy by ethnicity and race. Am J Obstet Gynecol MFM. 2020 Nov 1;2(4):100184. To determine if there are ethnicity and race differences in the efficacy of aspirin in preeclampsia prevention Secondary analysis of data from 2 controlled trials 3134 pregnant women participating in two MFMU network trials in the United States Low-dose aspirin was effective among low-risk non-Hispanic women but not in other groups. The efficacy of aspirin differs by ethnicity and race and between high or low risk women. Hauspurg A, Sutton EF, Catov JM, Caritis SN. Aspirin Effect on Adverse Pregnancy Outcomes Associated With Stage 1 Hypertension in a High-Risk Cohort. Hypertens Dallas Tex 1979. 2018 Jul;72(1):202–7. To determine the effect of aspirin on adverse pregnancy outcomes among high-risk cohort with stage 1 hypertension Secondary analysis of data collected in a double-blinded, randomized trial with placebo control There were 1072 participants. The population was pregnant women with high risk of preeclampsia in the United States The administration of aspirin had a higher reduction rate of preeclampsia on women with stage 1 hypertension that normotensive women It is critical to recognize hypertension when determining the need to administer aspirin among pregnant women Souza EV, Torloni MR, Atallah AN, dos Santos GMS, Kulay L, Sass N. Aspirin plus calcium supplementation to prevent superimposed preeclampsia: a randomized trial. Braz J Med Biol Res. 2014 Apr 11;47(5):419–25. To evaluate the efficacy of calcium and aspirin administrated together would prevent preeclampsia Randomized Controlled Trail 49 participants were women with chronic hypertension and abnormal uterine artery in Sao Paulo, Brazil. There was no significant difference in the growth restriction between placebo and aspirin groups. Administration of aspirin did not affect growth restriction as a result of preeclampsia. Odibo AO, Goetzinger KR, Odibo L, Tuuli MG. Early prediction and aspirin for prevention of pre-eclampsia (EPAPP) study: a randomized controlled trial. Ultrasound Obstet Gynecol. 2015;46(4):414–8. To determine the effectiveness of early administration of aspirin in preventing pre-eclampsia among high-risk women A randomized double-blind, placebo-controlled study design 30 women with high risk of preeclampsia at their first trimester in health facilities near Washington University No difference in the risk of preeclampsia between the control and treatment group. The study was underpowered by methodology. Researchers concluded that changes should be made in future studies to improve results Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018 Mar;218(3):287-293.e1 To determine the effectiveness of low-dose aspirin in the prevention of preterm and term preeclampsia Systematic review and metanalysis of primary data. 18,907 participants of 16 trials conducted globally. Aspirin reduces risk of preterm but not term preeclampsia Focus should be made on the prevention of preterm preeclampsia using low-dose aspirin Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613–22. To evaluate if intake of low-dose aspirin during pregnancy lowers the chances or preeclampsia Placebo controlled randomized trial. 1776 women with singleton pregnancies participated in the study. Participants were from the United Kingdom, Italy, Spain, Belgium, Greece, and Israel There were lower incidents of preterm preeclampsia among participants receiving aspirin than the placebo group. Administering aspirin reduces the risk of preterm preeclampsia Hoffman MK, Goudar SS, Kodkany BS, Metgud M, Somannavar M, Okitawutshu J, et al. Low-Dose Aspirin for the Prevention of Preterm Delivery in Nulliparous Women with a Singleton Pregnancy: A Randomised Multi-country Placebo Controlled Trial. Lancet Lond Engl. 2020 Jan 25;395(10220):285–93. To determine if low-dose aspirin led to the prevention of preterm delivery among pregnant women. Multinational randomized controlled study 11,976 pregnant women from Guatemala, Kenya, Democratic Republic of Congo, Pakistan, and Zambia. Participants were 6 to 13w6d pregnant. Perinatal mortality and preterm birthrates lower for women in the aspirin group than the placebo group The rate of preterm delivery is reduced by early intervention through low dose aspirin Moore G, Allshouse A, Post A, Galan H, Heyborne K. Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study. J Perinatol Off J Calif Perinat Assoc. 2015 May;35(5):328–31. To assess if women of high-risk hypertension start early prevention method such as aspirin lower chances of preeclampsia Randomized Controlled Trail 523 women visiting 12 medical centers in the United States. Women who were 20 weeks’ gestation Risk of preeclampsia reduction rate of 41% of the women with early treatment of low-dose aspirin. Initiating aspirin before week 17 of pregnancy should be recommended to high risk pregnant women. Lin L, Huai J, Li B, Zhu Y, Juan J, Zhang M, et al. A randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in women at high risk in China. Am J Obstet Gynecol. 2022 Feb 1;226(2):251.e1-251.e12. To determine the efficacy of low-dose aspirin in the prevention of preeclampsia among high risk pregnant women in China. Randomized controlled trial in 11 Chinese provinces. 1000 participants were pregnant women visiting 13 tertiary hospitals in China. The rate preeclampsia among participants of aspirin and placebo treatment was the same. The treatment of pregnant women in China with low-dose aspirin did not reduce the risk of preeclampsia Appendix II: Abstracts Preventive effect of aspirin on preeclampsia in high-risk pregnant women with stage 1 hypertension Abstract Studies reported that women in a...