Preeclampsia remains a significant contributor to maternal and fetal morbidity and mortality. Several meta-analyses have helped clarify that low-dose aspirin prophylaxis should be initiated by 16 weeks of gestation in high-risk women to reduce the rate of subsequent preeclampsia by 50%.1–3 Despite this significant reduction, aspirin does not completely normalize the residual risk of preeclampsia to the rate found in low-risk women.1–3 Aspirin is thought to exert its effect by facilitating trophoblast invasion through reduced platelet thromboxane production, diminished local vasoconstriction, and improved angiogenesis.4,5 Thus, although aspirin may address thrombotic mechanisms affecting placental development, it may not fully address generalized cardiovascular and metabolic risk factors and this failure could help explain the imperfect performance of aspirin prophylaxis for preeclampsia prevention.6
Integrated first-trimester screening tools for the development of preeclampsia have been developed and validated. These tools include combinations of maternal history, biophysical parameters, uterine artery Doppler studies, and pregnancy-associated plasma protein-A concentration, highlighting the complex nature of preeclampsia. It may be unreasonable to expect aspirin to address all of these identified preeclampsia risk factors. A recent study by our group showed that first-trimester hypertension in patients with prior preeclampsia is an independent risk factor for recurrence.7 Accordingly, we tested the hypothesis that high-risk women who develop preeclampsia while on aspirin prophylaxis have more cardiovascular and metabolic risk factors, including higher first-trimester blood pressures and increased body mass index (BMI, calculated as weight [kg]/[height (m)]2), compared with women in whom aspirin prophylaxis is successful. We performed a prospective study of high-risk women who initiated aspirin prophylaxis by 16 weeks of gestation to test this hypothesis.
MATERIALS AND METHODS
Pregnant women presenting at 9–14 weeks of gestation to any of four centers in the Baltimore, Maryland, metropolitan area for first-trimester screening from 2007 to 2010 were offered enrollment in a prospective, observational study with the primary aim of developing a first-trimester multimarker predictive model for preeclampsia. The study was approved by the institutional review boards of the University of Maryland, Mercy Medical Center, and the MedStar Research Institute. A standardized ultrasound examination was performed to confirm pregnancy dating and included crown–rump length measurements and transabdominal uterine artery Doppler studies as described by the Fetal Medicine Foundation.8 The specific ultrasound techniques used in this study protocol have been previously described.9 Uterine artery notching was defined as an early diastolic blood flow acceleration after the end-systolic nadir, producing a notched appearance of the waveform. Women with confirmed first-trimester pregnancies who agreed to participate in the study provided signed informed consent. Standardized written questionnaires comprised of a complete medical history, current and prior pregnancy histories, and social and demographic information were obtained.
After completion of the questionnaire, maternal height, weight, and blood pressure were measured. After 5 minutes of rest, qualified staff performed a single blood pressure measurement with the woman in a seated position and the arm at the level of the heart. The Dinamap Pro 1000 V3 automated sphygmomanometer was used with a cuff size appropriate for maternal arm circumference. The sphygmomanometer was calibrated every 6 months in accordance with the Association for the Advancement of Medical Instrumentation guidelines. For completion of first-trimester screening, blood samples were obtained by trained nursing staff and submitted on standardized forms to NTD Laboratories for analysis. NTD Laboratories reported the results as multiples of the median after absolute measurements of pregnancy-associated plasma protein-A and free β human chorionic gonadotropin were compared with reference ranges of a normal population.10
Women were followed through pregnancy by the respective study enrollment center. Pregnancy outcomes, including the development of preeclampsia in the current pregnancy, were recorded at delivery. Preeclampsia was defined as new-onset or worsening proteinuria and maternal systolic blood pressure 140 mm Hg or greater or diastolic blood pressure 90 mm Hg or greater on two separate occasions, 6 or more hours apart, after 20 weeks of gestation. Preeclampsia superimposed on chronic hypertension was defined as worsening blood pressure and increasing proteinuria after 20 weeks of gestation.11
All information from the collaborating clinical sites was reported directly to the primary investigator at the University of Maryland School of Medicine. Study data were collected, validated, and entered into a dedicated study database by trained personnel.
In this secondary analysis of our prospectively collected data, we included women with singleton gestations who were on aspirin prophylaxis before 16 weeks of gestation with complete clinical follow-up. Aspirin prophylaxis (81 mg/d) was recommended at the time of first-trimester screening for women at high risk of developing preeclampsia, including those with prior preeclampsia, prior stillbirth, prior fetal growth restriction, thrombophilia, autoimmune disease, recurrent pregnancy loss (defined as two or more consecutive pregnancy losses), bilateral uterine artery notching, or a combination of these on first-trimester ultrasonography. Some women were prescribed disease-indicated aspirin therapy by their managing physicians before first-trimester ultrasonography, whereas others were started on risk- or ultrasound-indicated aspirin prophylaxis at the time of first-trimester screening. Verification of patient adherence to aspirin prophylaxis was performed by review of pregnancy records for each individual.
In adult medicine, hypertension is classified by the Joint National Committee on Hypertension-7 guidelines.12 The Joint National Committee on Hypertension-7 guidelines define normal blood pressure (BP) as systolic BP less than 120 mm Hg and diastolic BP less than 80 mm Hg. Prehypertension is defined as systolic BP 120–139 mm Hg or diastolic BP 80–89 mm Hg or both, stage I hypertension as systolic BP 140–159 mm Hg or diastolic BP 90–99 mm Hg or both, and stage II hypertension as systolic BP 160 mm Hg or greater or diastolic BP 100 mm Hg or greater or both.12 For simplicity and ease of comparison with cutoffs used in adult medicine, we assigned the first-trimester measured BP values in our study participants to one of three categories for further analysis, corresponding to the Joint National Committee on Hypertension-7 guidelines: normal BP, prehypertension (Joint National Committee on Hypertension-7 guidelines definition), or hypertension (a combination of Joint National Committee on Hypertension-7 guidelines stages I and II hypertension).
We compared first-trimester characteristics of those women taking aspirin prophylaxis who developed preeclampsia with those who did not develop preeclampsia. Maternal history, demographics, systolic BP, diastolic BP, mean arterial pressure, BMI, uterine artery pulsatility index z-scores, pregnancy-associated plasma protein-A multiples of the median, and β human chorionic gonadotropin multiples of the median were analyzed using χ2, Fisher’s exact, and nonparametric tests where appropriate. Testing for normality was performed using the Shapiro-Wilk test. Uterine artery pulsatility index z-scores were calculated to correct for gestational age effects using reference ranges derived from the low-risk population with documented normal pregnancy outcomes in the collected data set. Post hoc analyses were conducted based on observations from our primary analyses. These included logistic regression analyses to determine important individual variables contributing to preeclampsia development and receiver operating characteristic curves to determine BP cutoffs with the highest sensitivity and specificity for predicting preeclampsia in this high-risk population. Calculations were performed using SPSS 20.0 software, and a P value of <.05 was considered significant.
Among the 614 women on aspirin prophylaxis, 59 (9.6%) developed preeclampsia in the studied pregnancy. The women who developed preeclampsia differed primarily in historical and anthropometric first-trimester variables. They were more likely to have diabetes mellitus (DM), hypertension, prior preeclampsia, and a BMI in the obese range (50.8% compared with 36.2%; P<.005 for all). Women on aspirin prophylaxis who developed preeclampsia also had significantly higher median first-trimester BPs than those who did not develop preeclampsia: systolic BP 127 mm Hg compared with 117 mm Hg, diastolic BP 75 mm Hg compared with 68 mm Hg, and mean arterial pressure 93 mm Hg compared with 84 mm Hg (P<.001 for all), respectively. The number of women with BPs meeting Joint National Committee on Hypertension-7 prehypertension or hypertension criteria was significantly higher in the group that developed preeclampsia (74.6% compared with 40.9%, P<.001) as was the number of women with BMI 30 or greater (50.8% compared with 36.2%, P=.034). Maternal serum pregnancy-associated plasma protein-A multiples of the median levels were lower in the preeclamptic group (0.80 compared with 0.95, P=.017; Table 1).
Based on these findings, several post hoc analyses were performed. One evaluated participant characteristics stratified by the gestational age of delivery for preeclampsia (early onset less than 34 weeks of gestation, late onset 34 weeks or greater). Fifteen (25.4%) of the 59 women developed early preeclampsia; 11 (73.3%) of these 15 women had abnormal first-trimester BPs by Joint National Committee on Hypertension-7 criteria (prehypertension and hypertension included). Of the 44 women with late preeclampsia, 33 (75%) met Joint National Committee on Hypertension-7 criteria for prehypertension or hypertension in the first trimester. These differences were statistically significant (P<.001) for both analyses.
A stepwise logistic regression analysis was performed to determine the factors independently associated with the development of preeclampsia in women on aspirin prophylaxis. With preeclampsia as the dependent variable, independent variables tested included systolic BP, diastolic BP, elevated BP by Joint National Committee on Hypertension-7 criteria (combined prehypertension or hypertension), BMI, prior preeclampsia, history of hypertension, history of DM, and pregnancy-associated plasma protein-A multiples of the median. Of these variables, only diastolic BP, prior preeclampsia, and DM remained significant (Nagelkerke R 2=0.154, P<.001). The same statistical relationship was demonstrated when absolute BP measurements were substituted by categorical classification of abnormal BP by Joint National Committee on Hypertension-7 criteria (prehypertension or hypertension) or when BMI 30 or greater was tested (Nagelkerke R 2=0.128, P<.001).
Having a first-trimester BP in the Joint National Committee on Hypertension-7 guidelines prehypertension range or higher was associated with a modestly increased risk of developing preeclampsia, whereas having a normal first-trimester BP was associated with a reduced risk of developing preeclampsia of nearly 60% (Table 2). Similar results were seen when early preeclampsia (less than 34 weeks of gestation) and late preeclampsia (34 weeks of gestation or greater) were considered separately (Table 2).
Receiver operating characteristic curves were created to determine systolic BP and diastolic BP cutoff values with the highest sensitivity and specificity for the development of preeclampsia. The systolic BP criterion was greater than 122 mm Hg, corresponding to the Joint National Committee on Hypertension-7 guidelines prehypertension range, and the diastolic BP cutoff was greater than 72 mm Hg. For systolic BP, the sensitivity was 66% and the specificity was 70% (likelihood ratio 2.2, 95% confidence interval [CI] 1.80–2.70). For diastolic BP, the sensitivity was 64% and the specificity was 71% (likelihood ratio 2.23, 95% CI 1.80–2.80; Fig. 1).
A significant risk reduction for the development of preeclampsia is achieved when low-dose aspirin prophylaxis is initiated before 16 weeks of gestation in high-risk women.1–3 We previously demonstrated that elevated first-trimester BP in women with prior preeclampsia independently increases their recurrence risk.7 The present study identified cardiovascular and metabolic risk factors, including first-trimester BP elevation and higher BMI, to be associated with the development of preeclampsia in women initiating first-trimester aspirin. First-trimester normotension, a potential therapeutic target, was associated with a 56% reduction in the risk of preeclampsia.
Aspirin reduces platelet aggregation, diminishes microvascular vasoconstriction, and enhances microangiogenesis.4,5 During early placentation, these actions are presumed to facilitate trophoblast invasion and thereby potentially ameliorate the placental pathology that precedes the development of preeclampsia. We adopted the policy to prescribe first-trimester aspirin for women with abnormal uterine artery Doppler and risk factors for preeclampsia.13 This explains the high rate of abnormal uterine artery Doppler in our nested cohort. Notably, first-trimester BP elevation emerges as a significant risk factor in these women. Moreover, BP-related risks are apparent below the overt hypertension threshold. These observations are consistent with risk profiles observed in women with prior preeclampsia and corroborate the important contribution of BP to adult cardiovascular disease risk.6,7,14
Women who develop preeclampsia have cardiovascular, metabolic, or thrombotic risk profiles.6 We demonstrate an independent contribution of Joint National Committee on Hypertension-7 guidelines prehypertension or hypertension, history of DM, and prior preeclampsia to the development of preeclampsia. We do not demonstrate differences in uterine artery Dopplers in the women on aspirin prophylaxis who develop preeclampsia, suggesting that uterine artery blood flow resistance and trophoblast dysfunction do not contribute to the differences in preeclampsia rate. The effect of BP is already apparent in the prehypertension range; this is very consistent with the concept that cardiovascular vulnerability predisposes to end-organ disease at lower BP in patients at risk.14
In the Framingham Heart Study, combinations of risk factors with suboptimal BPs (including BP in the prehypertension range) confer a much greater hazard for the development of cardiovascular disease.14 A longitudinal study using data from the first National Health and Nutrition Examination Survey confirmed the potentiation of effects when Joint National Committee on Hypertension-7 guidelines defined prehypertension and cardiovascular risk factors coexist.15 Translated into the context of pregnancy, pre-existing risks and suboptimal maternal BP adaptation may potentiate each other to increase the risk for subsequent preeclampsia at lower BPs than in healthy women.7,16 All patients in our study were enrolled by 14 weeks of gestation and some were already taking aspirin prophylaxis at enrollment. Accordingly, we would expect these women to have already reached their gestational BP nadir.17–19 Therefore, BP elevations in this cohort likely represent pre-existing hypertension and suboptimal maternal cardiovascular adaptation. Regardless of the underlying mechanism, a first-trimester BP in the Joint National Committee on Hypertension-7 guidelines prehypertension range or greater was associated with a more than doubling of preeclampsia risk, whereas normotension was associated with a reduced risk of early- and late-onset disease.
Primary investigators in the Framingham Heart Study advocate the use of global risk assessment tools to help guide management for patients with elevated BP.20,21 In pregnancy, integrating several risk factors improves the predictive performance of first-trimester algorithms, mirroring the Framingham Risk Score.22,23 Initiation of BP management in pregnancy is typically reserved for women meeting overt criteria for hypertension.24 The fact that normal first-trimester BP (less than 120/80 mm Hg) was associated with a decreased preeclampsia risk in women on aspirin prophylaxis highlights the importance of BP in preeclampsia development. Extrapolating from the internal medicine literature, and supported by our study findings, further research is warranted to clarify the role of first-trimester antihypertensive therapy at lower BP thresholds.
Study strengths include prospective acquisition of standardized information on a large population of women with source-verified aspirin intake. Adherence to aspirin therapy was not, however, objectively verified. Another limitation is that the timing of aspirin intake was not standardized, which may affect BP.18 Our interpretation is based on single first-trimester BP measurements at enrollment, which has been validated for prediction but does not account for subsequent BP control. We elected to use measured first-trimester BPs rather than the history of chronic hypertension, because this provides an objective measure of BP control at the time of enrollment. Furthermore, measured BPs determine the magnitude of risk for end-organ damage in adult medicine. Our study was performed in an urban population comprised mostly of African American patients (55%) and may not be applicable to all populations.
In summary, this study suggests that in high-risk women initiating low-dose aspirin by 16 weeks of gestation, increased first-trimester BP contributes to the failure of aspirin prophylaxis.
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