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Abstract
Abstract This study investigated the effects of low-dose acetylsalicylic acid (aspirin) on blood pressure in pregnant women who were at risk of developing gestational hypertension or preeclampsia and who received aspirin at different times of the day according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 100 pregnant women. Blood pressure for each subject was automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery. Women were randomly assigned to one of six groups according to treatment (placebo, 50 subjects or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Results indicated that there was (1) no effect on blood pressure from placebo at any time (P>.212) and (2) a highly statistically significant (P<.001) time-dependent effect on blood pressure from aspirin. There was no effect of aspirin on blood pressure at time 1 (compared with placebo), but the blood pressure reduction was highly statistically significant after time 2 and, to a greater extent, after time 3 (mean reduction of 12 and 8 mm Hg in 24 hours for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). These time-dependent effects of aspirin on blood pressure should be taken into account for the optimization of long-term aspirin administration at low doses for prevention of preeclampsia. In any meta-analysis of aspirin effects, inquiries about the time when the subjects took the drug are indicated and may account for discrepancies in the literature.
Pregnancies complicated by elevated blood pressure (BP) or preeclampsia contribute markedly to perinatal morbidity and mortality.1 Gestational hypertension and preeclampsia ordinarily occur during the second half of pregnancy. Many of the physiological changes of preeclampsia are essentially a reversal of those that accompany a healthy pregnancy (lack of an increase in plasma volume, elevation of BP, increases in peripheral vascular resistance, and reduced production of aldosterone compared with a healthy pregnancy).2 Although the exact cause of preeclampsia is unknown, several mechanisms have been suggested, including enhanced sensitivity to vasopressors, an abnormal maternal immunological reaction, and an imbalance in the production of vasoactive prostaglandins (thromboxane A2 and prostacyclin), resulting in vasoconstriction of small arteries, platelet activation, and uteroplacental insufficiency.2 3 4 Since thromboxane A2 and prostacyclin are derived from arachidonic acid through the action of cyclooxygenase, acetylsalicylic acid (ASA, aspirin) at low dose (81 mg/d; by acetylation of this enzyme) selectively inhibits the synthesis of platelet thromboxane A2 without affecting the production of endothelium-derived prostacyclin.4 A higher dose (325 mg/d), however, significantly reduces prostacyclin levels.4 5 This selective inhibition may be the pharmacological basis for an effect of ASA in gestational hypertension and preeclampsia.6
Several studies aimed to test the effects of low-dose ASA in the prevention of preeclampsia have concluded that the beneficial effects of such treatment outweigh adverse ones.7 These controlled trials were usually conducted in small groups of pregnant women selected according to several criteria for establishing a high risk of preeclampsia. The benefits shown by these small trials in the prevention of preeclampsia have not been corroborated by larger, randomized, controlled trials, usually carried out in the general obstetric population (see the revision in Reference 88 ). These studies concluded that the use of low-dose ASA during pregnancy was safe for the fetus, the newborn, and the mother, but the results did not support the routine prophylactic use of ASA for the prevention of preeclampsia.
Although some of these reports showed average values of casual BP measurements for pregnant women before and after long-term administration of ASA, the study of any possible effect from ASA on BP was never a primary objective. On the other hand, little if any attention has been paid so far in clinical trials to the timing of ASA administration. Recent results, however, suggest that the effects of ASA on lipid peroxides and β-adrenergic receptors in clinically healthy women are dependent on the time of ASA administration.9 Rhythms of clotting and fibrinolytic inhibitors have also been described.10 Moreover, the inhibition of collagen-induced platelet aggregation produced by ASA is circadian-time dependent.11 Finally, a time-dependent effect of low-dose ASA on BP has been recently documented in clinically healthy volunteers as well as in patients with mild hypertension12 : in both cases results indicated a small but statistically significant BP reduction when ASA (100 mg/d for 1 week) was administered in the evening and, to a larger extent, at bedtime; such effects could not be demonstrated when the same dose of ASA was administered on awakening. Accordingly, we have examined in pregnant women with a high risk of developing preeclampsia the possibility that low-dose ASA could have an effect on BP during gestation and that this effect could be dependent on the time of ASA administration.
Methods
Subjects
We studied 100 pregnant white women (70 primipara) who were at a higher risk for gestational hypertension or preeclampsia than the general obstetric population and who were thus receiving medical care at the Obstetric Physiopathology (high-risk) Unit of the Hospital General Clínico Universitario de Galicia, Santiago de Compostela, Spain. Reasons for receiving medical care at this unit include, among others, family or personal history of either gestational hypertension, preeclampsia, or chronic hypertension; cardiovascular, endocrine, bleeding, or metabolic disease; and a personal history of previous spontaneous abortion, multiple pregnancy, obesity, and adolescent or middle-aged nulliparous pregnancy (<18 or >35 years). The relative risk of gestational hypertension and preeclampsia in this unit is about three times that of the general obstetric population in our setting. Inclusion criteria for this trial were absence of any condition requiring the use of antihypertensive medication, maternal age (18 to 40 years), and gestational age (<16 weeks). Exclusion criteria were, among others, multiple pregnancy, chronic hypertension, chronic liver disease, any disease requiring the use of anti-inflammatory medication, diabetes or any other endocrine disease such as hyperthyroidism, as well as intolerance to the use of an ambulatory BP monitor. The minimum sample size for this trial (96 subjects) was set a priori with the objective to show as statistically significant at the 95% level a BP reduction of ≥6 mm Hg in the 24-hour mean of BP at the time of delivery after administration of ASA compared with placebo, after assuming 4 mm Hg as an estimate of the joint standard deviation.13 Apart from the 100 subjects providing information, a total of 7 subjects who did not comply with all requirements set a priori for this clinical trial were eliminated from the study. Reasons for elimination included the use of additional medication during the trial, noncompliance with the assigned medication (missing more than six tablets during any given month), and the impossibility of providing all required BP profiles (see below). Subjects providing fewer than five profiles of ambulatory BP monitoring (ABPM) were eliminated from the study.
BP Assessment
The systolic and diastolic BPs of each subject were automatically monitored every 30 minutes during the day (9 am to 10 pm) and hourly during the night for 48 hours with an ABPM-630 Colin device at the time of recruitment and then every 4 weeks until delivery. BP series were eliminated from analysis when they showed an irregular schedule during the days of sampling, an odd sampling with spans of >3 hours without BP measurement, or a night resting span <6 hours or >12 hours. The total number of BP series provided by the women under investigation fulfilling all mentioned requirements set a priori was 701. During BP sampling, all women were following their usual diurnal waking (≈7:30 am to approximately midnight) and nocturnal resting routine and following their normal daily activity routine with minimal restrictions: they were told to follow a similar schedule during the days of sampling and to avoid the use of medication (including ASA) for the duration of the trial. Clinical evaluation of the BP monitoring device according to the standards published by the Association for Advancement of Medical Instrumentation14 has been previously established.15 ABPM was performed in addition to the woman’s routine antenatal care, and no person was hospitalized during monitoring. The BP cuff was worn on the nondominant arm. Cuff size was determined by upper-arm circumference at the time of each visit. ABPM always started between 10 am and 1 pm. During monitoring, each subject maintained a diary regarding information about their activity cycle, dietary consumption, physical activity, emotional state, and other external or internal stimuli possibly affecting BP.
Medications
The volunteers were randomly assigned (double-blind, randomized, controlled trial) to one of six groups, defined according to treatment (placebo, 50 subjects; or ASA, 100 mg/d, 50 subjects) and to the timing of daily administration of ASA and placebo: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Baseline characteristics (given in Table 1⇓) related to age, weight, height, and 24-hour mean BP values obtained from the first profile of ABPM (before treatment started) were similar for all six groups. Oral ingestion of ASA or placebo started at 12 to 16 weeks of gestation and continued until the day of delivery. The dose of 100 mg used in this trial corresponds with the actual lower dose commercially available in Spain and is also the closest dose to the medication used in most clinical trials on the prophylactic use of ASA (60 to 80 mg/d are now currently used in protocols designed for testing any beneficial effects of ASA for prevention of preeclampsia, in keeping with the generally recommended dose of 1 mg/kg of weight).
Demographic and Baseline Blood Pressure Characteristics of Pregnant Women Under Investigation1
Assignment of volunteers to each of the six groups was done by one member of the research team, according to the order of recruitment, by following an allocation table designed to give the same probability to each of the six groups and constructed by a different member of the research team using a computerized random-number generator. Placebo (microcrystalline cellulose, corn starch, saccharin, and citric acid [to simulate the flavor of ASA]) and ASA (100 mg uncoated tablets) were prepared in an identical manner and provided monthly to the volunteers in a box containing three blister packs, each with 10 tablets. The boxes, grouped in packs of seven (to cover medication for the duration of pregnancy) and labeled with the randomization number, were assigned to each patient at the time of her recruitment. The Ethics Committee of Clinical Research from the Medical School approved the study. All volunteers signed consent forms before entering the study.
Statistical Methods
Original oscillometric data from each of the 701 BP series were edited according to commonly used criteria for the removal of outliers and measurement errors.16 The remaining data were first analyzed by the use of Chronolab,17 a software package for biologic signal processing by linear and nonlinear least-squares estimation that, among others, includes the single and population-mean cosinor methods,18 as well as the fit of multiple components.18 In particular, each BP series was analyzed by the least-squares fit of a multiple component cosine curve with periods of 24 and 12 hours to determine the rhythm-adjusted mean, or MESOR (midline estimating statistic of rhythm), and the amplitudes of both components. This model has been shown to describe sufficiently well the circadian pattern of BP variability,19 20 despite the fact that other ultradian rhythms can be demonstrated as statistically significant in some but not all individuals studied by 48-hour ABPM. Since the data were obtained at an unequidistant sampling rate covering two cycles (48 hours), the MESOR provides a better estimation of the true 24-hour mean than the average of all BP values (usually overestimating the true mean due to the denser sampling during activity).
The estimates of the 24-hour mean thus obtained for all BP series of each pregnant woman were expressed as a percentage of the MESOR computed for that subject from the BP series sampled before treatment started (in order to avoid interindividual differences in BP along gestation). The time of sampling for each BP series, originally in gestational age, was expressed in months from the pretreatment monitoring (somehow more representative of duration of treatment than gestational age). The values of 24-hour mean thus normalized were used to establish their pattern of variation along duration of treatment for each of the six groups of pregnant women by polynomial regression analysis. Any possible differing effect of ASA or placebo administration upon BP for any of the three treatment times was evaluated by comparing the average 24-hour mean of BP for each group by the use of a parametric t test. Effects of medication (placebo or ASA) and circadian time of treatment upon BP along duration of treatment were also evaluated by analysis of variance.
Results
Placebo Versus ASA on Awakening (Time 1)
Fig 1⇓ shows the variation of the 24-hour mean (expressed as percent of the value obtained for each subject before treatment started) of systolic (top) and diastolic BP (bottom) along gestation (expressed in months from the pretreatment monitoring) in pregnant women receiving either placebo or 100 mg/d of ASA on awakening, starting at the 12th to 16th week of pregnancy. This figure represents, first, the histograms with the mean values of the 24-hour mean of BP with their standard error for each month of treatment along gestation; second, the figure also shows the best model of predictable BP variability along gestation for each group of women (receiving either placebo or ASA) obtained by polynomial regression analysis.
Variation of 24-hour mean of systolic (SBP, top) and diastolic blood pressure (DBP, bottom) along gestational age in pregnant women taking either placebo or aspirin (100 mg/d) at awakening, starting at the 12-16 week of gestation.
Results in Fig 1⇑ indicate that, for both groups of pregnant women, BP follows a predictable pattern of variation that can be approximated by a second-order model in time (months of treatment). Results indicate a steady decrease in systolic and diastolic BP up to the 20th week of pregnancy (about one and a half months of treatment), followed by an increase in BP up to the day of delivery (about six and a half months after treatment started). This pattern of variation is fully equivalent to that previously shown for the BP of 189 pregnant women sampled on several occasions during their gestation but receiving no treatment.21
Fig 1⇑ also indicates that the model of variation of the 24-hour mean of BP along gestation is similar for both groups of pregnant women. Moreover, there is no statistically significant difference among groups of women in the average value of 24-hour mean at any time along gestation (P>.264 in all cases). Table 2⇓ indicates that, at the time of delivery, the predictable average difference in 24-hour mean between women receiving either placebo or ASA on awakening is not statistically significant (P=.304 and P=.881 for systolic and diastolic BP, respectively).
Time-Dependent Effects of Aspirin (ASA) Administration on Blood Pressure in Pregnant Women Receiving Either Placebo or ASA (100 mg/d) at Different Times of Day, Starting at 12-16 Weeks of Gestation1
Placebo Versus ASA 8 Hours After Awakening (Time 2)
Fig 2⇓ compares the predictable variation in BP along time of treatment in pregnant women receiving either placebo or 100 mg/d of ASA at time 2. The predictable pattern of variation for both systolic and diastolic BP again follows a second-order model. In opposition to the results shown in Fig 1⇑ for pregnant women receiving placebo or ASA at time 1 (awakening), the models obtained for women receiving placebo or ASA 8 hours after awakening are not similar (P<.001 in a test for comparison of second-order coefficients from the regression models, for both systolic and diastolic BP). Results indicate that the differences in the average value of the 24-hour mean of BP between women receiving placebo or ASA at time 2 are statistically significant after the second month of treatment (P<.038). Table 2⇑ further indicates that, at the time of delivery, the statistically significant difference (P<.001) in the mean value of BP between women receiving placebo and those receiving ASA at time 2 is 7.4 mm Hg for systolic BP and 4.6 mm Hg for diastolic BP.
Variation of 24-hour mean of systolic (SBP, top) and diastolic blood pressure (DBP, bottom) along gestational age in pregnant women taking either placebo or aspirin (100 mg/d) 8 hours after awakening, starting at 12-16 weeks of gestation. *Statistically significant difference between placebo and aspirin with P<.05. **Difference with P<.005.
Placebo Versus ASA at Bedtime (Time 3)
Fig 3⇓ summarizes the effects on the 24-hour mean of systolic (top) and diastolic (bottom) BP of a daily dose of either placebo or 100 mg of ASA ingested at bedtime in pregnant women with high risk for preeclampsia. The second-order patterns of variation of the 24-hour mean of BP resemble those shown in Fig 2⇑ for women receiving medication at time 2. When the pregnant women took ASA, BP continued to decrease slightly after the second month of treatment, without reaching the mean BP level obtained before treatment started. Results indicate statistically significant differences in BP between placebo and ASA given at bedtime after the second month of treatment (P<.025). Table 2⇑ indicates that, at the time of delivery, there is a predictable BP reduction of 12 mm Hg in the 24-hour mean of systolic BP and of 7.5 mm Hg in the 24-hour mean of diastolic BP for those women receiving 100 mg/d of ASA at bedtime as compared to the women receiving placebo at the same circadian time.
Variation of 24-hour mean of systolic (SBP, top) and diastolic blood pressure (DBP, bottom) along gestational age in pregnant women taking either placebo or aspirin (100 mg/d) at bedtime, starting at 12-16 weeks of gestation. *Statistically significant difference between placebo and aspirin with P<.05. **Difference with P<.005.
Placebo Administered at Different Times of the Day
The comparison of the histograms represented in Figs 1 through 3⇑⇑⇑ for women receiving placebo at different circadian times indicates no difference between the three groups with respect to BP. Moreover, the predictable variation of BP along gestation shown in these figures is similar to that previously obtained from pregnant women receiving no treatment.21 Results from analysis of variance further indicate the lack of differences between the three groups of pregnant women receiving placebo at different times (P>.212 in all cases). Table 2⇑ indicates the lack of statistically significant differences between these three groups of subjects at the time of delivery.
ASA Administered at Different Times of the Day
The comparison of the histograms from Figs 1 through 3⇑⇑⇑ indicates a highly statistically significant time-dependent effect of low-dose ASA on BP: there is no effect when ASA is administered at awakening; the BP reduction is, however, statistically significant when ASA is given 8 hours after awakening, and, to a greater extent, when ASA is administered at bedtime. Results from analysis of variance indicate that the differences in the mean value of BP are statistically significant almost as soon as the first month of treatment for systolic BP (P=.079 for the first month after treatment, P=.009 for the second month and decreasing thereafter). Table 2⇑ further indicates that, with respect to the time of delivery, the use of 100 mg/d of ASA at bedtime can decrease BP an average of 9.5 mm Hg (systolic) and 7.7 mm Hg (diastolic) as compared to the use of the same dose of ASA on awakening. The differences between ASA given at time 2 or time 3 are close to borderline statistically significant; there is an additional reduction of 3.2 mm Hg in systolic and 2.3 in diastolic BP when ASA is ingested at the most convenient time (bedtime) for practical reasons.
Discussion
The major conclusion from this study is that ASA selectively decreases BP as a function of the time of its administration in relation to the rest-activity cycle of each individual pregnant woman. Results indicate that (1) there is no statistically significant difference in BP (P>.386) between women receiving placebo and those studied previously receiving no treatment21 ; (2) there is no statistically significant difference in BP (P>.212) between women receiving placebo at different circadian times; (3) there is a highly statistically significant BP reduction consistently increased along gestation in women receiving 100 mg/d of ASA (P<.001 from a comparison of ASA versus placebo without taking into account circadian time of medication); and (4) the effect of ASA on BP is markedly time dependent: there is no effect when ASA is taken on awakening (Fig 1⇑), but the BP reduction is highly significant when ASA is ingested 8 hours after awakening (Fig 2⇑) and, to a larger extent, at bedtime (Fig 3⇑; average reduction of 12 and 8 mm Hg in 24-hour mean for systolic and diastolic BP, respectively, at the time of delivery as compared to placebo given at bedtime).
The average reduction of BP in pregnant women when ASA is taken at time 2 and, to a greater extent, at time 3, compared with placebo, deserves further discussion. The reduction in BP, consistently observed after the first month of treatment, is by far statistically significant and obtained with a sample size required to show, as significant, differences of just 6 mm Hg in the 24-hour mean of BP, a value exceeded by the results shown in Table 2⇑. Moreover, even when the differences in BP between those two treatment times (about 3 mm Hg) are not statistically significant, the additional BP reduction at time 3 is significant from the practical point of view: bedtime is more convenient and easier to remember for the patients than “8 hours after awakening.” Finally, the results seem to have biological significance. On the one hand, the BP reduction observed when ASA was taken at time 2 or time 3 is several times larger than the average difference in the 24-hour mean of BP for consecutive days of measurement (about 0.75 mm Hg). On the other hand, the time-dependent effects of ASA administration on BP during pregnancy shown in Figs 1 through 3⇑⇑⇑ are fully coincident with results previously shown in clinically healthy subjects as well as in patients with mild hypertension receiving the same dose (100 mg/d) of ASA.12
The sample size of this trial, obtained a priori with the objective to test any possible differing effect of low-dose ASA on BP compared to placebo, is, however, too small to derive conclusions regarding a possible reduction in the incidence of gestational hypertension or preeclampsia by the use of low-dose ASA. With this limitation notwithstanding, Table 3⇓ provides information on pregnancy outcome for the 100 women participating in this trial. Results from this table indicate the lack of statistically significant differences between the six treatment groups in gestational age at time of delivery as well as in newborn’s weight and Apgar score. The number of documented cases of IUGR was similar for placebo (2 cases) and ASA (1 case). The number of cesarean sections (due to all possible causes, including selective cesarean section) was also similar. Preterm delivery (before 37 weeks of gestation) was higher among women receiving placebo; there was no case of preterm delivery among women receiving ASA at time 2 and time 3. The number of pregnancies complicated with gestational hypertension (conventional BP values above 140/90 mm Hg for systolic/diastolic BP without clinical record of hypertension previous to pregnancy) and preeclampsia (here defined as gestational hypertension and proteinuria, above 300 mgr/24 h, with or without edema) was higher among women receiving placebo, but the difference between placebo and ASA is just borderline statistically significant (P=.062). The differences are, however, statistically significant (P=.004) if we compare the incidence of gestational hypertension and preeclampsia for the groups of placebo and ASA taken at time 1 (when there is no effect on BP) with the incidence in women receiving ASA at time 2 and time 3 (when ASA actually reduces BP as compared to placebo). There was no other complication (maternal or neonatal bleeding, neonatal death, placental abruption, antepartum hemorrhage) documented in the women under investigation. Therefore, even though the sample size was too small to draw conclusions, the use of low-dose ASA was not associated with an increase of maternal or neonatal complications; low-dose ASA was safe for the mother, the fetus, and the newborn; and, finally, a significant decrease in the number of documented cases of gestational hypertension and preeclampsia was observed only when ASA was administered at time 2 and time 3.
Pregnancy Outcome of Women Under Investigation and Their Newborns1
With respect to the time-dependent BP lowering by ASA as compared to placebo, recent studies have also shown statistically significant circadian rhythms in thromboxane and prostacyclin production,10 22 circulating platelets,23 platelet aggregation,10 24 25 26 clotting and fibrinolytic inhibitors,10 as well as in the inhibition of platelet aggregation produced by ASA.11 Another factor to be taken into consideration is the pharmacokinetic observation that ASA exhibits a faster drug disappearance rate when administered during the morning compared to the evening.27 These results complement time-dependent changes that have been described when the pharmacokinetics of nonsteroid anti-inflammatory drugs were investigated in humans.28 29
In summary, results indicate a statistically significant time-dependent effect of low-dose ASA on BP in pregnant women with high risk of developing gestational hypertension or preeclampsia. The mechanism(s) involved in the responsiveness of BP to ASA administered at different times according to the rest-activity cycle is unknown and awaits further investigation. In any event, one may at least conclude that any prospective study on the prophylactic advantages of ASA should systematically investigate the effect of timing. These time-dependent effects of ASA on BP should be taken into account in the optimization of long-term ASA administration at low dose for prevention of preeclampsia. In any meta-analysis of ASA effects, inquiries about the time when subjects took the drug are indicated and may account for discrepancies in the literature.
Acknowledgments
This research was supported in part by grants from Dirección General de Investigación Científica y Técnica, DGICYT, Ministerio de Educación y Ciencia (PB92-1111 and PB93-0372); Consellería de Educación e Ordenación Universitaria, Xunta de Galicia (XUGA-32202-897 and XUGA-32205-B95); and Vicerrectorado de Investigación, Universidad de Vigo.
Footnotes
-
Reprint requests to Prof Ramón C. Hermida, PhD, Director, Bioengineering and Chronobiology Labs, ETSI Telecomunicación, Campus Universitario, Vigo (Pontevedra) 36200, Spain.
- Received March 15, 1997.
- Revision received May 12, 1997.
- Accepted May 27, 1997.
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- Time-Dependent Effects of Low-Dose Aspirin Administration on Blood Pressure in Pregnant Women
