Secondary Logo

Journal Logo

Contents: Original Research

A Cost–Benefit Analysis of Low-Dose Aspirin Prophylaxis for the Prevention of Preeclampsia in the United States

Werner, Erika F. MD; Hauspurg, Alisse K. MD; Rouse, Dwight J. MD

Author Information
doi: 10.1097/AOG.0000000000001115

Preeclampsia is responsible for a tremendous burden of maternal and perinatal morbidity and mortality.1,21,2 At present, preeclampsia complicates between 3.1% and 7.2% of the births in the United States,2,32,3 and one in seven preterm births and one in 10 maternal deaths in the United States can be directly attributed to preeclampsia and eclampsia.4 Although there are well-established risk factors for preeclampsia (obesity, multiple gestation, advanced maternal age) and mitigating these risk factors would probably reduce the rate of preeclampsia and its subsequent morbidities, the only intervention that has been shown to reduce the risk of preeclampsia is low-dose aspirin. Multiple randomized controlled trials and meta-analyses have demonstrated that when pregnant women with various risk factors for preeclampsia take 60–150 mg of aspirin daily (or similar drugs such as dipyridamole), their overall risk of preeclampsia is reduced.5–175–175–175–175–175–175–175–175–175–175–175–175–17 This benefit obtains for women with a wide variety of risk factors for preeclampsia.5 Moreover, aspirin reduces the rate of preterm birth.5–7,9,105–7,9,105–7,9,105–7,9,105–7,9,10

Currently, the American College of Obstetricians and Gynecologists (the College) recommends low-dose aspirin only for a narrow segment of pregnant women: those with a history of preeclampsia necessitating delivery before 34 weeks of gestation and those with preeclampsia in more than one prior pregnancy.18 The U.S. Preventive Services Task Force, after performing their own systematic review,5 released much broader recommendations, encouraging all women at high risk for preeclampsia (eg, those with diabetes or chronic hypertension) and any woman with two or more moderate risk factors (eg, nulliparity, obesity) to take low-dose aspirin.19 Given these divergent recommendations, we developed a decision model to evaluate the risks, benefits, and costs of different approaches to aspirin prophylaxis for pregnant women in the United States.


We created a decision model to compare four approaches to aspirin prophylaxis and applied it to a hypothetical cohort of 4 million women giving birth annually in the United States (Appendix 1, available online at In the first approach, no women received aspirin. In the other three, varying proportions of women received 81 mg aspirin by mouth per day. In the College approach, only women with a history of preeclampsia necessitating delivery before 34 weeks of gestation or with preeclampsia in more than one prior pregnancy received aspirin.18 In the U.S. Preventive Services Task Force approach, women with a history of preeclampsia and those with multiple gestation, chronic hypertension, diabetes mellitus, renal disease, or autoimmune disease received aspirin.19 Additionally, women with two or more moderate risk factors such as nulliparity, obesity, African American race, age 35 years or older, a family history of preeclampsia, or a personal history of pregnancy complications (eg, a history of delivering a small-for-gestational-age neonate or an interpregnancy interval of more than 10 years) also received aspirin. In the fourth approach, all women received aspirin. We assumed women initiated aspirin after their first prenatal visit and continued it until delivery.

We assumed that aspirin reduced the rate of preeclampsia in women at moderate and high risk for preeclampsia.5–175–175–175–175–175–175–175–175–175–175–175–175–17 In the baseline analysis, we assumed that moderate-risk women benefited only half as much as high-risk women to account for the uncertainty surrounding the magnitude of benefit for the less well-studied moderate risk factors, and to avoid biasing our model toward treatment. We assumed no benefit from aspirin for low-risk women.8,108,10 Regardless of risk category, compliance with aspirin was assumed to be 77% (the same rate that was reported in a large population representative cohort of pregnant women in the United States for vitamin supplementation) but was varied from 0% to 100% in sensitivity analysis.20 Model outputs included cases of preeclampsia, preterm birth, perinatal and maternal deaths, placental abruption, maternal gastrointestinal bleeding, exacerbated respiratory disease, incremental direct medical expenditures, and quality-adjusted life-years (QALYs) gained by the avoidance of perinatal death and prematurity.

We generated estimates for the model by performing a bibliographic search in PubMed using the MeSH terms preeclampsia and aspirin and limiting the study type to meta-analysis or systematic review (Table 1). Using these studies and their bibliographies, we identified the requisite risk factor prevalence and outcome data. When population-based estimates were not available from this original query, we searched the National Vital Statistics. For still missing point estimates, we performed individual PubMed searches to estimate the prevalence of particular risk factors, prioritizing recent U.S. prospective studies. Cost data were obtained from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization project21 and from several large economic analyses of hospital costs for preterm birth, gastrointestinal bleeding, obstetric bleeding, and respiratory disease22–2522–2522–2522–25 (Table 2).

Table 1-a
Table 1-a:
Meta-analysis Outcome Data
Table 1-b
Table 1-b:
Meta-analysis Outcome Data

A woman's risk for preeclampsia and preterm birth depended on her risk category (Tables 2 and 3). Based on the best population prevalence rates available, we assumed 0.35% of pregnant women would receive aspirin under the College approach (Appendix 2, available online at The U.S. Preventive Services Task Force guidelines recommend that women with one or more high risk factors receive aspirin. Although the high risk factors independently sum to a prevalence of 7.9%, the factors overlap. Thus, conditional probabilities were used to calculate the percentage of women with one or more of the high risk factors (7.2%; Appendix 2, Because there are no population data on this composite variable, in sensitivity analysis we allowed the percentage of high-risk women in the population to range from 3% to 20%. Women defined as at risk by the College or high risk by the U.S. Preventive Services Task Force were assumed to have a 19.4% risk of developing preeclampsia6,9,116,9,116,9,11; in sensitivity analysis, this risk was varied from 12%, consistent with the risk for multiple gestations, to 26%, the risk for women with chronic hypertension.11 Women deemed at risk by the College or high risk by the U.S. Preventive Services Task Force were also assumed to have a 40% (range 18–43%) risk of delivering preterm (before 37 weeks of gestation).5,6,9,11,265,6,9,11,265,6,9,11,265,6,9,11,265,6,9,11,26

Table 2
Table 2:
Probability Estimates
Table 3
Table 3:
Risk Factors for Preeclampsia Among Pregnant Women in the United States*

The U.S. Preventive Services Task Force approach also recommends low-dose aspirin for women with two or more moderate risk factors (Table 3). If these factors were independent of one another, an additional 27.6% of women would be eligible for prophylaxis with aspirin (Appendix 3, available online at However, it is unlikely that these factors are completely independent, nor are they likely entirely independent of high risk factors. Thus, we assumed all high-risk women also had two or more moderate risk factors, leaving 20.4% of the population with two or more moderate risk factors but no high risk factors. In sensitivity analyses we allowed this estimate to vary widely (10–50%). Women in this group had a 6.2% (range 4.1–8.3%) risk of developing preeclampsia9,279,27 and a 16.1% (range 8–24.2%) risk of preterm delivery for any reason.9,11,279,11,279,11,27 We further assumed in the baseline analysis that only 80% of women with moderate risk factors would be ascertained and receive aspirin, but in a sensitivity analysis we allowed this estimate to vary to as low as 50%, consistent with the failure-to-screen rate seen when risk-based gestational diabetes mellitus screening is used.28

Low-risk women were assumed to have a 2.1% risk of preeclampsia.27 In our sensitivity analysis, this number was allowed to range from 1.5% to 6.7%.3,63,6 Because we could not find a population-based estimate for the risk of preterm birth in women at low risk for preeclampsia, we set the preterm birth rate to 7.5% to ensure that our modeled cohort had an overall preterm birth rate consistent with the U.S. population.29 In the sensitivity analysis, we allowed this estimate to range from 3.3% to 10.7%.30,3130,31

Perinatal death (fetal plus neonatal) rates were estimated based on the underlying maternal risk factors. The principal data on fetal and neonatal death rates were obtained from the National Vital Statistics32 and adjusted using data that evaluated the risk of perinatal death in women with known risk factors for preeclampsia.3,93,9 We assumed low-, moderate-, and high-risk pregnancies had an associated 0.54% (0.1–1.2%), 2.49% (0.54–5.3%), and 5.67% (1.08–7.2%) risk of perinatal death.

None of the individual trials or meta-analyses was sufficiently large to adequately assess maternal death. In the United States, the maternal death rate is 16 per 100,000.33 In absence of directly informative data, we assumed that to the degree aspirin reduced preeclampsia, it would reduce the rate of preeclampsia-associated maternal death (1.5/100,000).4

We used data from five meta-analyses to estimate the risk reduction that aspirin would confer. In our baseline analysis, we used the point estimates from the most recent published meta-analysis.5 In sensitivity analyses, we allowed the relative risks to vary to the most extreme 95% confidence bounds from the five meta-analyses (Table 1).5–7,9,105–7,9,105–7,9,105–7,9,105–7,9,10 Although none of the meta-analyses found statistically significant detrimental effects from aspirin, to account for the possibility of rare adverse effects from aspirin, we assumed aspirin increased the risk of gastrointestinal bleeding and aspirin-exacerbated respiratory disease. This latter condition occurs in approximately 7.2% (range 5.3–9%) of the 6.7% (range 5.5–8.7%) of women who have underlying asthma or asthma-like symptoms.34,3534,35

The cost of aspirin was based on the current consumer price in the United States for the course of the pregnancy (base case $5, range $1–20).36 To estimate the direct excess medical costs associated with preeclampsia, we used primary Agency for Healthcare Research & Quality data, subtracting the mean costs associated with a delivery complicated by preeclampsia ($7,428) from the mean costs associated with a delivery not complicated by preeclampsia ($4,020) to arrive at our baseline estimate of $3,408.21 The direct excess medical cost of a preterm birth ($19,285) was based on a large study that was part of the Healthcare Cost and Utilization Project that included all births at less than 37 weeks of gestation.22 In sensitivity analysis we allowed both of these cost estimates to vary by 50%. We also included cost estimates for placental abruption, gastrointestinal bleeding, and aspirin-exacerbated respiratory disease (Table 2).23–25,3723–25,3723–25,3723–25,37 All costs were converted to 2015 U.S. dollars using the Consumer Price Index. Only costs that occurred in the year of the delivery were considered. Thus, we did not discount costs and assumed they had a gamma distribution.

To calculate neonatal QALYs, we assumed an average life expectancy of 78.7 years for infants who survive the neonatal period, a utility of 1 for healthy term neonates, 0.96 for preterm neonates, and 0 for perinatal demise.33,3833,38 All QALYs were discounted by 3% per year in the baseline analysis (range 0–5% in sensitivity analysis). In the baseline analysis, we assumed aspirin lowered the rate of preterm birth but had no effect on perinatal death. In sensitivity analysis, we allowed the relative risk of perinatal death with aspirin to range from 0.65 to 1.1.5–7,9,105–7,9,105–7,9,105–7,9,105–7,9,10

We performed one-way sensitivity analyses allowing all probability, cost, and life-year estimates to vary to their extremes. We also performed a probabilistic (Monte Carlo) sensitivity analysis in which all variables were allowed to vary simultaneously to their individual extremes. We deemed an approach to be cost-beneficial when it resulted in direct medical cost savings. We defined the incremental cost-effectiveness ratio for this study as the additional cost required to gain one neonatal QALY and judged an incremental cost-effectiveness ratio of less than $100,000 U.S. to be cost-effective.39 We built the decision model using TreeAge Pro 2011. The study did not involve human participants and was exempt from institutional review board approval.


In the baseline analysis, without aspirin prophylaxis, 167,200 (4.18%) women would develop preeclampsia compared with 166,720 (4.17%) with the College approach, 153,160 (3.83%) with the U.S. Preventive Services Task Force approach, and 152,240 (3.81%) with universal aspirin administration (Table 4). Broader aspirin use would be associated with a parallel reduction in preterm births and maternal deaths but an increase in significant maternal gastrointestinal bleeding events, placental abruption, and aspirin-exacerbated respiratory disease (Table 4). In the baseline analysis, the U.S. Preventive Services Task Force approach was the most cost-beneficial approach, resulting in direct annual medical cost savings of $364,495,520, compared with the College approach, and cost savings of $12,424,360 annually compared with universal prophylaxis (Table 4). Of note, although universal prophylaxis is less cost-beneficial than the U.S. Preventive Services Task Force approach, it is nevertheless highly cost-effective with an incremental cost-effectiveness ratio of $8,174 for each neonatal QALY gained.

Table 4
Table 4:
Summary of Pregnancy Outcomes in the Baseline Analysis*

In one-way sensitivity analysis, as long as compliance with aspirin was at least 1%, the U.S. Preventive Services Task Force approach was more cost-effective than the no aspirin or College approach. Universal aspirin prophylaxis was both more cost-beneficial and more cost-effective than the U.S. Preventive Services Task Force approach when aspirin conferred more than a 16% relative reduction in preterm birth among high-risk women or when aspirin was at least 71% as effective at preventing preeclampsia and preterm birth in moderate-risk women as it was in high-risk women.

In probabilistic sensitivity analyses (10,000 simulations), compared with no aspirin administration, the College approach and the U.S. Preventive Services Task Force approach were cost-beneficial in greater than 99% of simulations and universal aspirin administration in 97.9% of simulations. The U.S. Preventive Services Task Force approach was more cost-beneficial than the College approach in greater than 99% of simulations and more cost-beneficial than universal aspirin administration in 79.4%. Assuming a willingness-to-pay threshold of $100,000 per neonatal QALY gained, universal aspirin was the most cost-effective approach in 99.3% of simulations. Even at a willingness-to-pay threshold of $20,000 per QALY, universal aspirin was the most cost-effective approach in greater than 95% of simulations.


Prior randomized studies, which cumulatively have included more than 37,000 women at risk for preeclampsia, clearly establish that low-dose aspirin prophylaxis lowers the risk of preeclampsia and preterm birth and confers these benefits without apparent harm. Thus, the remaining question over low-dose aspirin use in pregnancy is not a scientific one, but rather a question of health policy: who should be treated and what are the expected risks, benefits, and costs of one policy compared with another? Our analysis suggests that the U.S. Preventive Services Task Force approach is the most cost-beneficial, achieving 94% of the possible preeclampsia rate reduction that can be obtained with aspirin while exposing only one fourth of pregnant women to the theoretical risks of aspirin. Compared with the U.S. Preventive Services Task Force approach, universal aspirin administration would require more than 3 million women to take aspirin to prevent 920 cases of preeclampsia, an incremental number needed to treat of 3,325. Even so, universal administration is highly cost-effective and maximizes the reduction in preeclampsia and preterm birth. However, under some plausible estimates for harm, universal aspirin administration would increase the number of placental abruptions, cases of perinatal death, episodes of maternal gastrointestinal bleeding, and respiratory disease relative to the U.S. Preventive Services Task Force approach. Unequivocally, limiting aspirin administration to the narrow segment of women recommended by the College18 would be associated with little reduction in the burden of preeclampsia, preterm birth, and therefore costs.

Although the U.S. Preventive Services Task Force approach is the most cost-beneficial policy, risk-based approaches have well-recognized and substantial limitations, largely related to their implementation. To the degree that they require a detailed history and consistent risk factor assessment, they are often misapplied and thus fail to reach some proportion of patients who stand to benefit. For this reason, other targeted screening approaches in obstetrics have been abandoned (eg, gestational diabetes and group B streptococcal screening) because of substantially diminished disease detection or prevention compared with universal screening approaches.28,40,4128,40,4128,40,41

Our analysis has several limitations. Some of our estimates lack precision, for example, the utilities used to calculate QALYs and the extent to which moderate risk factors are independent of one another. Nevertheless, even fairly substantial variations from our point estimates have modest effects on the magnitude of potential benefits and harms. Furthermore, whenever possible we attempted to account for the best recognized risks of aspirin, such as gastrointestinal bleeding, even if there were no data that these risks would apply to a relatively young, healthy population.42 In the baseline analysis we assumed that aspirin did not lower the rate of perinatal death, although in all of the meta-analyses, the point estimate with aspirin was below 1.0.5–7,9,105–7,9,105–7,9,105–7,9,105–7,9,10 We may have underestimated the benefits of universal prophylaxis in that it is likely that the risk for preeclampsia operates along a biological continuum, and there is some evidence that women with only one risk factor (eg, nulliparity) would benefit from aspirin prophylaxis.43,4443,44 As with many decision analyses, our model is unable to account for all important costs. Almost certainly, women who experience complications will be less economically productive in the short term, and we did not account for this diminished productivity nor did we account for the costs associated with prematurity beyond hospital discharge.22 Although we considered it, we did not account for potential aspirin-associated medicolegal costs, if for no other reason that the magnitude and direction of these costs are unpredictable.

We conclude that to not use low-dose aspirin on a more widespread basis than is recommended by the College is a missed opportunity to prevent preeclampsia, preterm birth, and decrease health care costs. Ideally, aspirin should be initiated before 16 weeks of gestation.7 From the standpoint of parsimony, and minimization of potential aspirin risks, the U.S. Preventive Services Task Force approach is a better approach than universal administration. However, universal administration, with its ease of implementation and potential to maximize the health benefits of aspirin, may in fact be the more rational and clinically pragmatic approach. In either case, broad low-dose aspirin administration to pregnant women would almost certainly reduce maternal and perinatal disease, save lives, and lower health care costs in the United States by millions of dollars annually.


1. Lyndon A, Lee HC, Gilbert WM, Gould JB, Lee KA. Maternal morbidity during childbirth hospitalization in California. J Matern Fetal Neonatal Med 2012;25:2529–35.
2. Lisonkova S, Sabr Y, Mayer C, Young C, Skoll A, Joseph KS. Maternal morbidity associated with early-onset and late-onset preeclampsia. Obstet Gynecol 2014;124:771–81.
3. Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, et al.. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med 2010;362:1282–91.
4. Creanga AA, Berg CJ, Syverson C, Seed K, Bruce FC, Callaghan WM. Pregnancy-related mortality in the United States, 2006–2010. Obstet Gynecol 2015;125:5–12.
5. Henderson JT, O'Connor E, Whitlock EP. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2014;160:695–703.
6. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1791–8.
7. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al.. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010;116:402–14.
8. Subtil D, Goeusse P, Puech F, Lequien P, Biausque S, Breart G, et al.. Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: the Essai Régional Aspirine Mère-Enfant study (Part 1). BJOG 2003;110:475–84.
9. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. The Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD004659. DOI: 10.1002/14651858.CD004659.pub2.
10. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol 2013;41:491–9.
11. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al.. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701–5.
12. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-Dose Aspirin Study in Pregnancy) collaborative group. Lancet 1994;343:619–29.
13. Caspi E, Raziel A, Sherman D, Arieli S, Bukovski I, Weinraub Z. Prevention of pregnancy-induced hypertension in twins by early administration of low-dose aspirin: a preliminary report. Am J Reprod Immunol 1994;31:19–24.
14. McParland P, Pearce JM, Chamberlain GV. Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension. Lancet 1990;335:1552–5.
15. Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E, Tamarkin M, et al.. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. N Engl J Med 1989;321:351–6.
16. Vainio M, Kujansuu E, Iso-Mustajärvi M, Mäenpää J. Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches. BJOG 2002;109:161–7.
17. Villa PM, Kajantie E, Räikkönen K, Pesonen AK, Hämäläinen E, Vaino M, et al.. Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO trial and a meta-analysis of randomised trials. BJOG 2013;120:64–74.
18. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists Task Force on hypertension in pregnancy. Vol 122. Washington (DC): The American College of Obstetricians and Gynecologists; 2013. p.1122–31.
19. LeFevre ML; U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161:819–26.
20. Branum AM, Bailey R, Singer BJ. Dietary supplement use and folate status during pregnancy in the United States. J Nutr 2013;143:486–92.
21. HCUP databases. Healthcare cost and utilization project (HCUP). Rockville (MD): Agency for Healthcare Research and Quality; 2006–2009. Available at: Retrieved May 1, 2015.
22. Russell RB, Green NS, Steiner CA, Meikle S, Howse JL, Poschman K, et al.. Cost of hospitalization for preterm and low birth weight infants in the United States. Pediatrics 2007;120:e1–9.
23. Nicholson WK, Frick KD, Powe NR. Economic burden of hospitalizations for preterm labor in the United States. Obstet Gynecol 2000;96:95–101.
24. Saltzman JR, Tabak YP, Hyett BH, Sun X, Travis AC, Johannes RS. A simple risk score accurately predicts in-hospital mortality, length of stay, and cost in acute upper GI bleeding. Gastrointest Endosc 2011;74:1215–24.
25. James AH, Patel ST, Watson W, Zaidi QR, Mangione A, Goss TF. An assessment of medical resource utilization and hospitalization cost associated with a diagnosis of anemia in women with obstetrical bleeding in the United States. J Womens Health (Larchmt) 2008;17:1279–84.
26. Ankumah NA, Cantu J, Jauk V, Biggio J, Hauth J, Andrews W, et al.. Risk of adverse pregnancy outcomes in women with mild chronic hypertension before 20 weeks of gestation. Obstet Gynecol 2014;123:966–72.
27. Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, et al.. Obesity, obstetric complications and cesarean delivery rate—a population-based screening study. Am J Obstet Gynecol 2004;190:1091–7.
28. Griffin ME, Coffey M, Johnson H, Scanlon P, Foley M, Stronge J, et al.. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabet Med 2000;17:26–32.
29. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2012. Natl Vital Stat Rep 2013;62:1–20.
30. Cnattingius S, Villamor E, Johansson S, Edstedt Bonamy AK, Persson M, Wikström AK, et al.. Maternal obesity and risk of preterm delivery. JAMA 2013;309:2362–70.
31. Miranda ML, Edwards SE, Myers ER. Adverse birth outcomes among nulliparous vs. multiparous women. Public Health Rep 2011;126:797–805.
32. Mathews TJ, MacDorman MF. Infant mortality statistics from the 2009 period linked birth/infant death data set. Natl Vital Stat Rep 2013;61:1–27.
33. Hoyert DL, Xu J. Deaths: preliminary data for 2011. Natl Vital Stat Rep 2012;61:1–51.
34. Rajan JP, Wieinger NE, Stevenson DD, White AA. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. J Allergy Clin Immunol 2015;135:676–81.e1.
35. Hansen C, Joski P, Freiman H, Andrade S, Toh S, Dublin S, et al.. Medication exposure in pregnancy risk evaluation program: the prevalence of asthma medication use during pregnancy. Matern Child Health J 2013;17:1611–21.
36. Red book: Pharmacy's fundamental resource. 114th ed. Montvale (NJ): PDR Network LLC; 2010.
37. Ivanova JI, Bergman R, Birnbaum HG, Colice GL, Silverman RA, McLaurin K. Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma. J Allergy Clin Immunol 2012;129:1229–35.
38. Werner EF, Pettker CM, Zuckerwise L, Reel M, Funai EF, Henderson J, et al.. Screening for gestational diabetes mellitus: are the criteria proposed by the international association of the Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care 2012;35:529–35.
39. Shiroiwa T, Sung YK, Fukuda T, Lang HC, Bae SC, Tsutani K. International survey on willingness-to-pay (WTP) for one additional QALY gained: what is the threshold of cost effectiveness? Health Econ 2010;19:422–37.
40. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59:1–36.
41. Schrag SJ, Zell ER, Lynfield R, Roome A, Arnold KE, Craig AS, et al.. A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates. N Engl J Med 2002;347:233–9.
42. van Kruijsdijk RC, Visseren FL, Ridker PM, Dorresteijn JA, Buring JE, van der Graaf Y, et al.. Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women. Heart 2015;101:369–76.
43. Hauth JC, Goldenberg RL, Parker CR Jr, Philips JB 3rd, Cooper RL, DuBard MB, et al.. Low-dose aspirin therapy to prevent preeclampsia. Am J Obstet Gynecol 1993;168:1083–91.
44. Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L, et al.. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1993;329:1213–8.
45. Hernández-Díaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study. BMJ 2009;338:b2255.
    46. Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol 2013;209:544.e1–12.
      47. Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW, et al.. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol 2012;119:1234–42.
        48. Block-Abraham DM, Turan OM, Doyle LE, Kopelman JN, Atlas RO, Jenkins CB, et al.. First-trimester risk factors for preeclampsia development in women initiating aspirin by 16 weeks of gestation. Obstet Gynecol 2014;123:611–7.
          49. Melchiorre K, Wormald B, Leslie K, Bhide A, Thilaganathan B. First-trimester uterine artery Doppler indices in term and preterm pre-eclampsia. Ultrasound Obstet Gynecol 2008;32:133–7.
            50. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980–2010: age-period-cohort analysis. BMJ 2013;347:f6564.
              51. Multiple gestation: complicated twin, triplet, and high-order multifetal pregnancy. ACOG Practice Bulletin No. 56. American College of Obstetricians and Gynecologists. Obstet Gynecol 2004;104:869–83.
                52. Campbell KH, Savitz D, Werner EF, Pettker CM, Goffman D, Chazotte C, et al.. Maternal morbidity and risk of death at delivery hospitalization. Obstet Gynecol 2013;122:627–33.
                  53. Flenady V, Koopmans L, Middleton P, Frøen JF, Smith GC, Gibbons K, et al.. Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet 2011;377:1331–40.
                    54. Lethbridge-Cejku M, Schiller JS, Bernadel L. Summary health statistics for U.S. adults: National Health Interview Survey, 2002. Vital Health Stat 10 2004:1–151.
                      55. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep 2003;52:1–113.
                        56. Audibert F, Boucoiran I, An N, Aleksandrov N, Delvin E, Bujold E, et al.. Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. Am J Obstet Gynecol 2010;203:383.e1–8.
                          57. Fink JC, Schwartz SM, Benedetti TJ, Stehman-Breen CO. Increased risk of adverse maternal and infant outcomes among women with renal disease. Paediatr Perinat Epidemiol 1998;12:277–87.
                            58. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al.. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008;58:15–25.
                              59. Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol 1995;86:555–9.
                                60. Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Mathews TJ. Births: final data for 2011. Natl Vital Stat Rep 2013;62:1–69, 72.
                                  61. Obesity in pregnancy. Committee Opinion No. 549. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:213–7.
                                    62. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 2012;307:491–7.
                                      63. Rotchell YE, Cruickshank JK, Gay MP, Griffiths J, Stewart A, Farrell B, et al.. Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications. Br J Obstet Gynaecol 1998;105:286–92.
                                        64. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001;153:332–7.
                                          65. Pilliod RA, Cheng YW, Snowden JM, Doss AE, Caughey AB. The risk of intrauterine fetal death in the small-for-gestational-age fetus. Am J Obstet Gynecol 2012;207:318.e1–6.
                                            66. Laopaiboon M, Lumbiganon P, Intarut N, Mori R, Ganchimeg T, Vogel JP, et al.. Advanced maternal age and pregnancy outcomes: a multicountry assessment. BJOG 2014;121(suppl 1):49–56.
                                              67. Cappell MS. Gastric and duodenal ulcers during pregnancy. Gastroenterol Clin North Am 2003;32:263–308.
                                                68. Masclee GM, Valkhoff VE, Coloma PM, de Ridder M, Romio S, Schuemie MJ, et al.. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology 2014;147:784–92.e9.
                                                  69. Feinstein LB, Holman RC, Yorita Christensen KL, Steiner CA, Swerdlow DL. Trends in hospitalizations for peptic ulcer disease, United States, 1998–2005. Emerg Infect Dis 2010;16:1410–8.
                                                    70. Barton JR, Istwan NB, Rhea D, Collins A, Stanziano GJ. Cost-savings analysis of an outpatient management program for women with pregnancy-related hypertensive conditions. Dis Manag 2006;9:236–41.
                                                      71. Clowse ME, Jamison M, Myers E, James AH. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199:127.e1–6.

                                                        Supplemental Digital Content

                                                        © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.