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Contents: Hypertensive Diseases of Pregnancy: Original Research

Strategies for Prescribing Aspirin to Prevent Preeclampsia

A Cost-Effectiveness Analysis

Mallampati, Divya MD, MPH; Grobman, William MD, MBA; Rouse, Dwight J. MD, MSPH; Werner, Erika F. MD, MS

Author Information
doi: 10.1097/AOG.0000000000003413

Preeclampsia is a major cause of maternal morbidity and mortality. Consistent with demographic changes reflecting a population with greater risk, the prevalence of preeclampsia has been steadily rising over the past three decades.1,2 Given the growing burden of preeclampsia, various studies have sought to understand preventive interventions.3–6 Aspirin, in particular, has long been thought to decrease an individual's risk of preeclampsia owing to its antiplatelet effects.7 Data gathered from meta-analyses estimate that the use of aspirin decreases the risk of preeclampsia by approximately 10%.8–12 Other studies have suggested that aspirin has its greatest effect on reducing preterm preeclampsia, with one study suggesting a decrease in risk as high as 91%.9

To provide guidance as to who is most likely to benefit from aspirin use, the American College of Obstetricians and Gynecologists (ACOG) as well as the U.S. Preventive Services Task Force have independently released guidelines identifying populations at high-risk of preeclampsia.13,14 Both guidelines are history-based risk assessments designed to identify risk factors for preeclampsia, such as a history of preeclampsia, multifetal gestation, obesity, or chronic diseases such as hypertension or diabetes. In contrast to history-based risk assessments, the use of biomarkers and ultrasound parameters as determinants of preeclampsia risk, particularly in resource-rich settings, is a growing area of investigation as these approaches use patient-specific characteristics. Although history-based risk factors alone identified 41% of women who developed preterm preeclampsia and 37% of women who developed term preeclampsia,15 combinations of uterine artery pulsatility indices and serum measures (eg, pregnancy-associated plasma protein A and placental growth factor) have been shown in some studies to identify as many 75% of women who developed preterm preeclampsia (less than 37 weeks of gestation) and 47% of women who developed term preeclampsia (at a false positive rate of 10%).15

Although prior studies have compared the cost effectiveness of history-based risk assessment and universal aspirin use,16 a cost-effectiveness analysis of ultrasound and biomarker screening within the United States is needed. The purpose of this article is, thus, to analyze the cost effectiveness of various strategies for aspirin administration, including risk-based screening strategies, universal aspirin, and no aspirin use, in the prevention of preeclampsia in the United States.

METHODS

We created a decision analysis model that compared four strategies of preeclampsia screening and aspirin prophylaxis among the population of pregnant women in the United States (Appendix 1, available online at http://links.lww.com/AOG/B498). In the first strategy, no women received aspirin prophylaxis. In the second strategy, women received aspirin prophylaxis based on risk status conferred by biomarker and ultrasound measures. In the third strategy, aspirin prophylaxis was given according to maternal history-based risk factors as recommended by the U.S. Preventive Services Task Force (Box 1). The final strategy was universal aspirin administration. Although the latter is not standard of care and averts considerations regarding screening test characteristics, we felt it important to understand whether such a strategy would incur negative externalities due to aspirin use in comparison with the benefit it offers to case reduction of preeclampsia. We did not analyze the ACOG guidelines specifically as this was done in a previous analysis.16 Moreover, given that both ACOG and the Society for Maternal-Fetal Medicine have recently amended their recommendations to be congruent with U.S. Preventive Services Task Force recommendations, we assumed that the U.S. Preventive Services Task Force strategy would be an adequate representation of history-based risk stratification.13

Box 1.

U.S. Preventive Services Task Force Guidelines for Aspirin Use for the Prevention of Preeclampsia*

Moderate risk factors (consider aspirin if there are several moderate risk factors)

  • Family history of preeclampsia
  • Nulliparous
  • Obesity
  • Race
  • Socioeconomic status
  • Age older than 35 years
  • Prior low birth weight or small-for-gestational age neonate

High risk factors (recommend aspirin if there is one or more high risk factors)

  • Personal history of preeclampsia
  • Multifetal gestation
  • Chronic hypertension
  • Diabetes (type 1 or 2)
  • Kidney or autoimmune disease

* Based on risk factors that can be obtained from the patient's medical history.

Adapted with permission of the U.S. Preventive Services Task Force. From: Table. Clinical Risk Assessment for Preeclampsia. Final Recommendation Statement: Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality From Preeclampsia: Preventive Medication. U.S. Preventive Services Task Force. September 2014. https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication.

In the ultrasound and biomarker measure strategy, we derived the probability that a woman will develop preeclampsia depending on whether she is considered low or high risk based on her screening assessment. Women who screen as high risk were assumed to have base-case risks of 4.3% (range 3.5–6.5%) and 7.5% (range 7.0–12.5%) of developing preterm and term preeclampsia, respectively; women who screened as low risk had a base-case risk of 0.8% (range 0.69–4.3%) and 2.2% (range 1.8–4.3%).1,2,15,17–21 Estimations and ranges of preeclampsia risk among high-risk women were derived from studies that analyzed both the performance of ultrasound and biomarker measures within various populations of patients as well studies looking at the role of aspirin in women who screen as high risk.17,18 In contrast, estimations regarding low-risk women were derived by identifying population-level risk for preterm and term preeclampsia and adjusting them for cases that occurred in high-risk women.1,2,22

In our base-case analysis, we estimated that, if a patient screens positive per U.S. Preventive Services Task Force guidelines, she has a 54% chance of screening positive with ultrasound and biomarker screening.18,23 This probability was varied between 43% and 86% in sensitivity analyses. In patients who screened negative by U.S. Preventive Services Task Force guidelines, we assumed a 5% risk of screening positive by ultrasound and biomarker measures17,18 and varied this risk from 2% to 21%. Estimates regarding a woman's risk of screening positive by ultrasound and biomarker measures were taken from studies that explicitly evaluated the positive predictive value of the screen among women screened by history-based factors or that studied women who had other risk factors for developing preeclampsia.18,24

To preserve consistency of probability inputs in the model, each strategy arm divides patients, first, by whether they are high or low risk by U.S. Preventive Services Task Force guidelines and then, second by ultrasound and biomarker screen. The subsequent management of each of those groups and outcomes, however, depends on the specific strategy of the model arm.

In the U.S. Preventive Services Task Force approach, women eligible to receive aspirin must have one or more high-risk factors (history of preeclampsia, chronic hypertension, multifetal gestation, autoimmune disease) or at least two moderate risk factors (nulliparity, obesity, or a family history of preeclampsia).14 We assumed that in a population of women from the United States, approximately 8% would have at least one high-risk factor and that 20% would have at least two moderate risk factors (Table 1).14,16 Thus in the base-case analysis, we assumed 28% of women would screen positive using U.S. Preventive Services Task Force guidelines. In sensitivity analyses, we varied this estimate widely from 13% to 70% based on ranges reported in prior literature.16

Table 1.
Table 1.:
Model Estimates

In the base-case analysis, regardless of the reason for aspirin administration (ultrasound and biomarker screening, history-based screening, or universal aspirin), we assumed that women initiated aspirin before 16 weeks of gestation and did not assume a particular dosage of aspirin. We assumed that there was 100% compliance or perfect use and that all women who needed aspirin, either because they were screened as high risk or because universal aspirin was the strategy, initiated aspirin. The latter assumption was tested in sensitivity analyses by varying the proportion of women who initiated aspirin from 0% to 100%. We assumed that the use of aspirin reduced the risk of preterm preeclampsia by 61% (RR=0.39) while exerting no effect on term preeclampsia (RR=1.0).9,10 Initially, we assumed no benefit of aspirin administration on term preeclampsia rates to be conservative because in many individual studies the CI for risk reduction of term preeclampsia with aspirin crosses one.9,10 In sensitivity analysis, we varied the relative risk of preterm preeclampsia with aspirin from 0.09 to 0.93 and term preeclampsia from 0.59 to 1.8–12,25

The perspective of this study was societal. To estimate the costs to the U.S. health care system of term and preterm preeclampsia, we accessed data from the Healthcare Cost and Utilization Project from the Agency for Healthcare Research and Quality and adjusted for inflation using the Consumer Price Index such that all costs were normalized to May 2018 U.S. dollars (Table 1).16,26 In sensitivity analyses, we varied costs anywhere from half to three times the estimated mean to account for variations in antenatal care depending on the gestational age at which a woman presented to care as well as for the wide geographic and facility-dependent variations in health care costs in the United States. The base-case additional maternal cost of preterm preeclampsia in the model was estimated at $4,410, and the cost of term preeclampsia was estimated at $2,044. The costs of term and preterm preeclampsia did not account for the neonatal costs of preterm delivery but rather solely for maternal hospitalization. In the base-case analysis, the neonatal costs of a preterm delivery were estimated to be $20,604 based on hospital costs, lengths of stay, and related complications.27 Although there are no studies explicitly detailing the costs of the ultrasound and biomarker screen in the United States, we estimated these costs based on an analysis performed in Israel that used uterine artery pulsatility index, placental protein-13 and pregnancy-associated plasma protein.28 We also gathered data on the cost of ultrasound screening using Doppler and first trimester aneuploidy screening to ensure these estimates were consistent with U.S. costs and other costs reported in the literature.29,30 For our model, we used a base-case of $124 for the cost of ultrasound and biomarker screening, but varied the cost widely in the sensitivity analysis.

In our model, aspirin was associated with two possible side effects: gastrointestinal bleeding and aspirin-exacerbated respiratory disease. Because there is a lack of large-scale studies on the effects of aspirin in pregnant women and because randomized controlled trials have not reported consistently on these side effects, we derived our estimates from the general medicine literature.31–33 Moreover, we estimated that the probability of gastrointestinal bleeding while on aspirin is 0.022%, with an associated cost of $12,142, whereas the probability of aspirin-exacerbated respiratory disease is 0.48%, with an associated cost of $1,029.16,34,35

Outcomes from our model included preeclampsia-related costs and number of cases of preeclampsia per 100,000 pregnant women based on prevention strategy. We assumed that the willingness-to-pay, or the threshold at which a strategy is considered cost effective, was $90,843 per case of preeclampsia, as this value reflects twice the current estimated short-term (12 months) infant and maternal costs of one case of preeclampsia to the health care system.36 We performed one- and two-way sensitivity analyses varying the probabilities at which women screen low and high risk for preeclampsia, as well as for the relative risk reduction of preeclampsia due to aspirin use, the side effects of aspirin, the proportion of women who receive aspirin, and various costs. Finally, we performed a Monte Carlo simulation to vary all model inputs simultaneously. With the exception of our cost ranges which were modeled as gamma or beta distributions, other inputs were modeled as normal distributions. This analysis was performed using TreeAge Pro 2018.

RESULTS

With no aspirin, there were 4,234 cases of preeclampsia for every 100,000 pregnant women (4.23%) and preeclampsia-associated costs were $38,967,706. The universal aspirin strategy was associated with a lower rate of preeclampsia (3.47%), and, compared with no aspirin, $18,750,381 less is spent for every 100,000 women. Similarly, compared with universal aspirin administration, the use of U.S. Preventive Services Task Force guidelines was associated with an increase in cost to the health care system of $8,011,725 and 346 additional cases of preeclampsia per 100,000 pregnant women; biomarker and ultrasound screening was associated with an additional $19,216,551 spent and 308 additional cases of preeclampsia (Table 2). Thus, universal aspirin strategy dominated all three other aspirin strategies, resulting in fewer cases of preeclampsia and costing less.

Table 2.
Table 2.:
Outcomes and Preeclampsia-Associated Costs of Each Strategy (Per 100,000 Women)

We explored conditions under which universal aspirin might not be the optimal strategy. It ceased to be the dominant strategy when fewer than 58% of women in the universal strategy actually received aspirin (eg, owing to provider oversight or nonuse by the patient) at which point the U.S. Preventive Task Force strategy became cheaper. If aspirin were taken by fewer than 55.2% of pregnant women, a strategy of universal aspirin prophylaxis exceeded the willingness-to-pay threshold and was, therefore, not cost effective. At that point, the U.S. Preventive Task Force Strategy was the most cost-effective strategy (Fig. 1).

Fig. 1.
Fig. 1.:
Cost effectiveness based on the probability that aspirin is administered in a universal aspirin strategy vs the use of a screening strategy (willingness to pay=$90,843). Green indicates the probabilities of aspirin use in which universal aspirin is below the willingness-to-pay threshold and, therefore, cost effective. Orange indicates when the U.S. Preventive Services Task Force screen is below the willingness-to-pay threshold and cost effective.Mallampati. Cost Effectiveness of Aspirin to Prevent Preeclampsia. Obstet Gynecol 2019.

As expected, universal aspirin prophylaxis was associated with the highest rate of gastrointestinal bleeding and aspirin-exacerbated respiratory illness, resulting in 20 cases and 480 cases respectively per 100,000 pregnant women (Table 2). Given the uncertainty of our estimates for these side effects, we investigated the probability of side effects that would result in universal aspirin administration no longer being the preferred strategy (ie, either because it wasn't dominant or above the willingness-to-pay threshold) and found that only at improbably high rates would universal aspirin not be preferred. For example, when the rate of gastrointestinal bleeding was more than 0.94%, universal aspirin ceased to be the dominant strategy and at a rate of 4.8%, it was no longer cost effective—the U.S. Preventive Services Task Force strategy was then cost effective. When the prevalence of aspirin-exacerbated respiratory disease was more than 11.8%, the strategy of universal aspirin ceased to be dominant and, at a rate of 57%, it was no longer a cost-effective strategy—the U.S. Preventive Services Task Force strategy was cost effective.

In a Monte Carlo simulation with 10,000 trials, universal aspirin prophylaxis was the preferred strategy in 91% of the simulations, and the U.S. Preventive Services Task Force Screen was preferred in 8.5% of simulations. A strategy of no aspirin prophylaxis was preferred in only 0.5% of simulations, and the use of ultrasound and biomarker measures was never preferred.

DISCUSSION

In our analysis of the cost effectiveness of four different preeclampsia prevention strategies using our base-case estimates, universal aspirin administration was the dominant strategy—it was associated with the prevention of the most cases of preeclampsia and the least costs. Universal aspirin administration remained the dominant strategy across many one- and two-way sensitivity analyses, with the exception of sensitivity analyses related to the probability of universal aspirin being initiated. In no sensitivity analyses were the use of ultrasound and biomarker parameters the most preferred strategy—although this strategy produced the second fewest cases of preeclampsia, the costs associated with this strategy far exceeded those of the U.S. Preventive Services Task Force guidelines and universal aspirin, thus offering little benefit with regards to cost effectiveness. In a Monte Carlo simulation that varied all inputs simultaneously, universal aspirin administration is the preferred strategy in 91% of situations. The risk of preeclampsia within the model is 4.23% which is consistent with the probability of preeclampsia on a population level—we believe this finding demonstrates a strength of the accuracy of our model.1,2,17

There are several studies in the literature that assesses the cost effectiveness of ultrasound and biomarker measures although there are limitations to the analyses.16,28,30,37 The first and second study, performed in Israel and Canada, compared ultrasound and biomarker measures with history-based screening and concluded that the use of ultrasound and biomarker measures is cost effective.28,30 Neither of these analyses, however, evaluated universal aspirin use. A third analysis performed with data from the Irish and English health care systems demonstrated that routine aspirin use among low-risk nulliparous women was a dominant strategy to ultrasound and biomarker screening as well as to no aspirin use.37

Finally, a cost-effectiveness analysis of preeclampsia screening strategies in the United States, demonstrated that both universal aspirin use and the U.S. Preventive Task Force screen are cost effective, although the latter is more cost beneficial.16 This article, however, differs from our cost-effectiveness analysis as it outlines neonatal quality-adjusted life-years as the primary outcome and identifies both placental abruption and perinatal death as a potential harm of universal aspirin administration. When designing our current analysis, we chose to exclude perinatal death and instead focus on preeclampsia per se, and we did not consider placental abruption, because prior literature has not identified a significantly increased risk of abruption with aspirin use.13 Moreover, the prior publication does not evaluate the role of ultrasound and biomarker measures. Our analysis evaluated a variety of screening strategies that have clinical applicability or potential applicability in the United States.

It is possible that adherence to aspirin in pregnancy is a function of whether it is universally recommended or whether it is specifically recommended to women who screen as high risk. Studies have suggested widely ranging adherence rates for any medication in pregnancy, and also that rates for aspirin use among pregnant women are similar to those of nonpregnant individuals.38 A recent randomized controlled trial assessing aspirin use for preeclampsia prevention among low-risk nulliparous women demonstrated that both women who were given aspirin owing to ultrasound and biomarker screening and women who routinely took aspirin had an average adherence of 95%.39 An opt-out approach to aspirin administration has recently been advocated as a way to achieve high rates of aspirin use irrespective of patient risk status.40

Our analysis has several limitations. Our estimates of women who screen as high risk through ultrasound and biomarker screening are derived from studies that are primarily from European populations. Because those populations potentially differ by composition, it is possible that the ultimate detection rate as a result of those screens would be different in a U.S.-based population. Second, our model is built to reflect women who initiate aspirin before 16 weeks and does not specifically address variations in aspirin dosing. Third, in contrast to traditional cost-effectiveness analyses, we chose not to make quality-adjusted life-years our outcome of interest. This was done intentionally given concerns regarding their precision and ability to effectively guide health care policy decisions41; we, therefore, elected to assess the cost with regards to preventing one case of preeclampsia. Given that prior cost-effectiveness analyses regarding this topic also report on costs related to cases of preeclampsia, we believe that this particular study is comparable with others, not only in the topic, but also in methodology.28,30 Lastly, our model does not address serum screening alone to predict preeclampsia (which has been a topic of investigation in the United States) but rather the combination of ultrasound and serum measures.42,43

Ultimately, universal aspirin is a relatively low-cost intervention for a condition that has considerable morbidity, reportedly few risks, and demonstrates potential in improving both health care costs and health outcomes. In contrast, other screening strategies, such as ultrasound and biomarker measures, would be costlier and potentially only accessible in places with the appropriate resources. The use of universal aspirin, moreover, might also lower rates of fetal growth restriction and preterm birth.8,10,44 Although not explicitly recommended to influence growth restriction, stillbirth, and preterm birth, and although data are mixed, the influence of aspirin on the pathophysiology of abnormal placentation, placental dysfunction, and preterm contractions demonstrates a potential benefit.13 A determination of particularly relevant estimates, such as the adherence rates of aspirin use under different risk-profiles, interventions that can enhance adherence, and improved model certainty regarding the most cost-effective strategy can further help elucidate the best approach for preeclampsia prophylaxis. Our model demonstrates that under a wide range of conditions, universal aspirin administration in pregnancy is the preferred strategy for preeclampsia prevention.

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