Calcium and low-dose aspirin prophylaxis in women at high risk of pregnancy-induced hypertension. Effect of low-dose aspirin on vascular refractoriness in angiotensin-sensitive primigravid women. Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications. Low-dose aspirin and hypertension in pregnancy. A prospective randomized placebo-controlled trial of low-dose aspirin for prevention of intra-uterine growth retardation. A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia. A randomised trial of low dose aspirin for primiparae in pregnancy. The Jamaica Low Dose Aspirin Study Group. ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. ECPPA (Estudo Colaborativo para Prevenção da Pré-eclampsia com Aspirina) Collaborative Group. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow. Low-dose aspirin improves fetal weight in umbilical placental insufficiency. Do low-risk pregnant women with antiphospholipid antibodies need to be treated? Organizing Group of the Antiphospholipid Antibody Treatment Trial. Low-dose aspirin therapy to prevent preeclampsia. Low dose aspirin in prevention of pregnancy-induced hypertension in primigravidae at the Muhimbili Medical Center, Dar es Salaam. 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. Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial. 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. Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches. A randomized placebo-controlled study of the effect of low dose aspirin on platelet reactivity and serum thromboxane B2 production in non-pregnant women, in normal pregnancy, and in gestational hypertension. Low dose aspirin in hypertensive pregnant women: effect on pregnancy outcome and prostacyclin-thromboxane balance in mother and newborn. Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial. Trial of prophylactic administration of TXA2 synthetase inhibitor, ozagrel hydrochloride, for preeclampsia. Administration time-dependent effects of aspirin in women at differing risk for preeclampsia. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women. Effects of low-dose aspirin on uterine and fetal blood flow during pregnancy: results of a randomized, placebo-controlled, double-blind trial. Low-dose aspirin in primigravidae with positive roll-over test. Low dose aspirin for the treatment of fetal growth restriction: a randomized controlled trial. Prevention of pregnancy-induced hypertension in twins by early administration of low-dose aspirin: a preliminary report. A study of use of low dose aspirin in prevention of pregnancy induced hypertension. Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: the Essai Régional Aspirine Mère-Enfant study (Part 1). A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia. Prevention of pre-eclampsia by early antiplatelet therapy.
The objectives of the study were to confirm the validity of using oscillometric measurement of MAP in the left lateral position to identify those at high risk for developing pregnancy-induced hypertension (PIH), and to assess and compare the efficacy of prophylaxis with low-dose aspirin or calcium supplementation in high-risk patients.
                A prospective study in pregnancy; 500 normotensive, primigravid Chinese women were recruited in the second trimester of pregnancy on the basis of 80 mm Hg > or = MAP < 106 mm Hg in the antenatal clinic. They were then screened by Dinamap in a research setting, measuring MAP in the left lateral position after rest and using a cutoff value of 60 mm Hg for inclusion in the randomized study. Randomization was divided into three groups: control, low-dose aspirin, and calcium supplementation. After delivery, patients were classified as either having remained normotensive or having developed PIH, with or without proteinuria.
                The incidence of both proteinuric and nonproteinuric PIH was significantly lower in patients screened out as low risk than in those selected as high risk using a critical value of 60 mm Hg for left lateral MAP (p < 0.05). The incidence of proteinuric PIH was significantly lower in patients given low-dose aspirin than in the control group (p < 0.05). However, the confidence intervals for the effect were wide, comparable with aspirin having no effect or leading to a 16-fold reduction in the risk of preeclampsia. For those given calcium supplementation, the reduction was not significant. There was no significant difference in the incidence of nonproteinuric PIH between the control group and the two groups receiving prophylaxis.
                Oscillometric measurement of second-trimester left lateral MAP is a valid predictor of proteinuric PIH. Low-dose aspirin may offer a degree of protection from proteinuric PIH in these high-risk women. Calcium supplementation was not shown to significantly reduce the incidence of PIH. The hypothesis that an enhanced vasopressor response to angiotensin II in pregnancy may be corrected by suppressing production of platelet thromboxane A2 with low-dose aspirin was tested in a randomized, placebo-controlled, double-blind trial. We studied 36 normotensive primigravid women with an elevated blood pressure response to intravenously infused angiotensin II at 28 weeks' gestation; 18 women received 60 mg of aspirin daily and the same number received matched placebo until 34 weeks' gestation, when angiotensin-sensitivity was again determined. In women taking aspirin, values of thrombin-induced platelet malondialdehyde production were approximately 10% of those determined in the placebo group, indicating marked suppression of thromboxane A2 synthesis. In the aspirin group vascular refractoriness to angiotensin II was restored in 14 of 17 treated women, by comparison with 5 of 15 women in the placebo group who had remained normotensive. These results support the hypothesis that prostacyclin/thromboxane imbalance is an important pathophysiologic factor in the development of the enhanced angiotensin-sensitivity associated with pregnancy-induced hypertensive disorders. To determine whether prophylactic, low dose controlled-release aspirin improves outcome for pregnant women and their babies in Barbados.
                Randomised placebo-controlled trial.
                The Queen Elizabeth Hospital, Barbados.
                All women attending antenatal clinics between 12 and 32 weeks of gestation were eligible, if without specific contraindications to aspirin and unlikely to deliver immediately.
                Randomisation was computer-generated in the antenatal clinic; 1822 women were allocated to receive 75 mg controlled-release aspirin and 1825 matching placebo.
                Proteinuric pre-eclampsia, other pregnancy-induced hypertension, pregnancy duration, birthweight, stillbirths and neonatal deaths, major neonatal events.
                All but three women from each group were followed up successfully. Forty-four percent were primigravid, and 8% had previous obstetric complications. There were no significant differences between the allocated treatment groups in the incidence of proteinuric pre-eclampsia (40 [2.2%] of those allocated aspirin, compared with 46 [2.5%] allocated placebo), of preterm delivery (255 [14.0%] vs 270 [14.8%]), of birthweight < 1500 g (32 [1.7%] vs 33 [1.8%]) or of stillbirth and neonatal death (44 [2.4%] vs 38 [2.1%]). Aspirin was not associated with excess risk of maternal or fetal bleeding.
                The results of this study in Barbados do not support the routine use of low dose aspirin for prevention of pre-eclampsia or its complications, confirming results of previous large trials in other settings. nan To evaluate the effects of low-dose aspirin on placental circulation and on the prevention of intrauterine growth retardation (IUGR).
                We conducted a prospective randomized, double blind, controlled clinical trial in 84 pregnant women (mainly nulliparous women) at high risk of IUGR. From the 28th-30th week of gestation onward, low dose aspirin (75 mg daily, study group, n = 40) or placebo (control group, n = 44) was given consecutively for 6 to 8 weeks. Pulse-wave umbilical artery Doppler velocimetry was measured before and after drug use.
                The mean value of systolic/diastolic ratio of umbilical artery flow velocity waveforms in the study group was significantly lower than that in the control group after drug use, but there was no difference between the two groups before drug use. The incidences of IRGR and preeclampsia in the study group (7.5% and 10.0% respectively) were significantly lower than those in the control group (27.3% of both). No adverse effects of low dose aspirin on both mother and fetus were observed.
                Low dose aspirin administration (75 mg daily) beginning at the early stage of third trimester may improve the fetoplacental circulation, and thus prevent IUGR and/or preeclampsia effectively. To determine whether low-dose aspirin reduces the incidence of pre-eclampsia, reduces perinatal mortality and improves birth weights in pregnant women considered at high risk of developing pre-eclampsia.
                Two-hundred fifty subjects were recruited from the antenatal clinics at Harare Central Hospital with either a previous history of pregnancy-induced hypertension or pre-existing chronic hypertension and were randomized to receive either 75 mg of aspirin (ASA) or placebo (PLA).
                Two-hundred thirty subjects (ASA, n = 113; PLA, n = 117) completed the trial. The odds of developing pre-eclampsia for those on aspirin was 0.72 times those on placebo (95% CI, 0.34-1.52). The mean birth weight was 2774 g for those on aspirin and 2694 g for those on placebo (P = 0.80). No difference was noted in the perinatal deaths (OR = 0.38; 95% CI, 0.10-1.20).
                Prophylactic use of aspirin was not associated with a significant effect on the major pregnancy outcomes assessed in this study. To investigate whether low dose aspirin medication given to primiparous women provides benefit in preventing pre-eclampsia or intrauterine growth retardation.
                Randomised double-blind controlled trial of low dose aspirin and placebo in pregnancy.
                Residents of the parishes of Kingston and St Andrew, Jamaica; 6275 primiparae enrolled between 12 and 32 weeks of gestation.
                Hypertensive disorders of pregnancy (including pre-eclampsia and eclampsia), preterm delivery, and low birthweight. In addition, to assess whether enrollment early, rather than late had more beneficial effect. Possible adverse effects on the woman and her infant were monitored.
                Of enrolled primiparae, 97% were followed throughout pregnancy. There were no differences between those on aspirin and those on placebo in the development of hypertensive disorders (e.g. for a rise in diastolic pressure of 25 mmHg the odds ratio [OR] was 1.02 [95% CI 0.86-1.21]; for proteinuric pre-eclampsia OR 1.15 [95% CI 0.92-1.44]; eclampsia OR 0.82 [95% CI 0.44-1.53]); except for oedema which was significantly less prevalent in those on aspirin (OR 0.85 [95% CI 0.75-0.96]). Women on aspirin were no significantly less likely to deliver preterm (OR 0.93 [95% CI 0.79-1.09]) or have a larger fetus (mean birthweight difference 18 g [95% CI -9 to 45]). They were, however, significantly more likely to suffer from bleeding disorders antenatally, intrapartum and postpartum; for postpartum haemorrhage OR 1.40 (95% CI 1.13-1.73).
                This trial shows that low dose aspirin has no consistent beneficial effect in primiparae. To determine the effectiveness of low dose aspirin in women at high risk of adverse outcomes associated with pre-eclampsia.
                A collaborative randomised trial comparing the effects of low dose aspirin (60 mg) with placebo on pre-eclampsia and other materno-fetal complications associated with hypertension.
                Twelve teaching maternity hospitals and 182 obstetricians' offices in Brazil.
                One thousand and nine women considered to be at high risk for the development of pre-eclampsia, or its complications, entered the study between 12 and 32 weeks of gestation. They were randomly allocated to receive aspirin (498 women) or placebo (511 women) until delivery, and follow up was obtained for 96%.
                There were no significant differences between the treatment groups in the incidence of proteinuric pre-eclampsia (6.7% aspirin-allocated compared with 6.0% placebo-allocated women), of preterm delivery (22.3% compared with 26.1%), of intrauterine growth retardation (8.5% compared with 10.1%), or of stillbirth and neonatal death (7.3% compared with 6.0%), nor were there significant differences in the incidence of proteinuric pre-eclampsia in any subgroup of women studied, including those who had systolic blood pressures of 120 mmHg or above at entry (8.5% compared with 7.3%) or those who were chronically hypertensive (10.0% compared with 7.1%). Aspirin was not associated with a significant excess of maternal or fetal bleeding.
                The results of this study do not support the routine prophylactic administration of low dose aspirin in pregnancy to any category of high risk women (even those who have chronic hypertension or who are considered to be especially liable to early onset pre-eclampsia). We carried out a prospective, randomized, double-blind, placebo-controlled study to investigate the capacity of aspirin to prevent pregnancy-induced hypertension and to alter prostaglandin metabolism. A total of 791 pregnant women with various risk factors for pre-eclamptic toxemia were screened with use of the rollover test (a comparison of blood pressure before and after the woman rolls from her left side to her back) during week 28 or 29 of gestation. Of 69 women with abnormal results (an increase in blood pressure during the rollover test), 65 entered the study and were treated with a daily dose of either aspirin (100 mg; 34 women) or placebo (31 women) during the third trimester of pregnancy. The number of women in whom pregnancy-induced hypertension developed was significantly lower among the aspirin-treated than among the placebo-treated women (4 [11.8 percent] vs. 11 [35.5 percent]; P = 0.024); the same was true for the incidence of preeclamptic toxemia (1 [2.9 percent] vs 7 [22.6 percent]; P = 0.019). The mean ratio of serum levels of thromboxane A2 to serum levels of prostacyclin metabolites after three weeks of treatment decreased by 34.7 percent in the aspirin-treated group but increased by 51.2 percent in the placebo-treated group. No serious maternal or neonatal side effects of treatment occurred in either group. We conclude that low daily doses of aspirin taken during the third trimester of pregnancy significantly reduce the incidence of pregnancy-induced hypertension and pre-eclamptic toxemia in women at high risk for these disorders, possibly through the correction of an imbalance between levels of thromboxane and prostacyclin. Early pregnancies in women with a history of recurrent spontaneous abortion (RSA) are accompanied by a deficiency in vasodilatory and anti-aggregatory prostacyclin (PGI2) and/or overproduction of its endogenous antagonist thromboxane A2 (TXA2). We evaluated the effect of a low-dose aspirin (LDA) on PGI2 and TXA2 production and on pregnancy outcome in RSA women with and without detectable anticardiolipin antibodies (ACA). Of 82 RSA women studied, 66 became pregnant, and of them, 33 (six with elevated and 27 with normal ACA concentrations) were randomized to receive LDA (50 mg/day) and 33 (six with elevated and 27 with normal ACA concentrations) to receive placebo (PLA) from a mean of 6.6 days after the missed period to delivery. Treatment with LDA inhibited platelet TXA2 production similarly in RSA women with and without detectable ACA and with continuing pregnancies (7.0 +/- 0.7 ng/ml, LDA group versus 254.5 +/- 37.8 ng/ml, PLA group, mean +/- SEM, P < 0.0001) or miscarrying pregnancies (13.8 +/- 3.8 ng/ml compared with 233.6 +/- 59.8 ng/ml, P < 0.0001 respectively). Furthermore, LDA decreased urinary excretion of the TXA2 metabolite (2,3-dinor-TXB2) both in pregnancies which went to term (6.1 +/- 0.6 ng/mmol creatinine, LDA group versus 19.3 +/- 3.0 ng/mmol creatinine, PLA group, P < 0.0001) or again ended in miscarriage (4.7 +/- 0.8 ng/mmol creatinine versus 17.3 +/- 4.4 ng/mmol creatinine, P < 0.0001 respectively), but did not affect the excretion of the prostacyclin metabolite (2,3-dinor-6-keto-PGF1alpha). Early pregnancy ultrasound examination revealed a living fetus in 58 women. Of these, seven in the LDA group (23.3%, four with elevated and three with normal ACA concentrations) and five in the PLA group (17.9%, two with elevated and three with normal ACA concentrations; not significant) experienced a miscarriage. All infants were healthy, and the frequency of growth retardation was similar in both groups (13.0%). One woman in the LDA group (4.3%) and three women receiving PLA (13.0%) developed pre-eclampsia (not significant). Therefore, although treatment with LDA caused a desirable biochemical effect, it did not improve pregnancy outcome in RSA women with or without detectable ACA. To evaluate color Doppler imaging of the uterine arteries as a screening test in nulliparous women, and to examine the role of low-dose aspirin therapy in pregnancies with abnormal uteroplacental resistance.
                At the routine 18-week fetal morphology ultrasound scan, 955 nulliparous women underwent color Doppler imaging of the uterine arteries. Abnormal uteroplacental vascular resistance was defined with respect to both the systolic-diastolic ratio of the flow velocity waveform and the presence of an ipsilateral early diastolic notch. Those with abnormal uterine artery waveforms were asked to participate in a randomized controlled trial of aspirin therapy. Pregnancy outcomes were compared in women with normal or abnormal flow velocity waveforms, as well as in the two arms of the intervention study.
                Of 186 women with abnormal uteroplacental resistance according to criteria defined previously, 102 agreed to randomization to either low-dose aspirin (100 mg/day) or placebo for the remainder of the pregnancy. Abnormal uterine artery flow velocity waveforms were associated with statistically significant increases in preeclampsia (11 versus 4%), birth weight below the tenth percentile (28 versus 11%), and adverse pregnancy outcome (45 versus 28%). Prophylactic aspirin therapy did not result in a significant reduction in pregnancy complications.
                Abnormal uteroplacental resistance at 18 weeks' gestation was associated with a significant increase in adverse pregnancy outcome. Low-dose aspirin did not reduce pregnancy complications in women with uteroplacental insufficiency. nan We identified 19 women who had persistently positive test results for antiphospholipid antibodies who were considered to be at low risk because they had none of the associated signs or symptoms of the antiphospholipid antibody syndrome. They had had no (10/19, 53%) or just one prior spontaneous abortion and did not have a history of thrombosis or thrombocytopenia. Many (8/19, 42%) had had a prior uncomplicated pregnancy ending in a live birth. These women were randomly assigned to receive low-dose aspirin (81 mg daily) or usual care. There were few obstetric complications recorded in either treatment group. One woman in the aspirin group had a fetal death, and one in the usual care group had a low-birth-weight infant. The frequency of complications was so low that > 600 such women would need to be entered into a randomized trial to evaluate whether low-dose aspirin would be beneficial treatment during a pregnancy. We concluded that treatment of pregnant women with antiphospholipid antibodies who are otherwise at low risk cannot be justified on the basis of the available evidence. Our aim was to test the hypothesis that acetylsalicylate (aspirin) treatment reduces the incidence or severity of pregnancy-associated hypertension.
                Patients were nulliparous, healthy, and with a singleton gestation at between 20 and 22 weeks' gestation. A sample size of 600 patients was calculated on the basis of p < or = 0.05 and 90% power of observation. A 2-week placebo-controlled "run-in" was used to select compliant patients. Randomization occurred at 24 weeks, with 60 mg of aspirin or placebo treatment from randomization to delivery.
                Follow-up was maintained on 99% of the patients. The randomized patients had a 94% pill compliance index. At randomization, serum thromboxane medians were similar in both groups. Thromboxane B2 levels in the aspirin group decreased significantly from baseline at 29 to 31 weeks, 34 to 36 weeks, and at delivery as compared with an overall increase in the placebo group. Preeclampsia developed in five of 302 women (1.7%) who received aspirin versus 17 of 302 (5.6%) who received the placebo (p = 0.009). Preeclampsia was severe in one aspirin and in six placebo recipients (p = 0.06).
                Daily ingestion of 60 mg of aspirin beginning at 24 weeks' gestation significantly reduced the occurrence of preeclampsia. There is evidence that aspirin in low doses favourably influences the course and outcome of pregnancy in women at risk of developing pregnancy-induced hypertension. We conducted a double blind prospective randomized study to investigate the effect of low dose aspirin in preventing pregnancy-induced hypertension. Two hundred and one primigravidae from twenty weeks of pregnancy and above were screened using the roll-over test. Of the 127 women with an increase in blood pressure during the roll-over test, 126 women entered the study and were treated with a daily dose of either aspirin (80 mg) or placebo up to 10 days before the expected date of delivery. Samples of urine were collected for detection of aspirin. The incidence of pregnancy-induced hypertension in the aspirin treated group was significantly lower than in the placebo treated group; 3.17% versus 15.9% with a p value of 0.02. It is concluded that low daily doses of aspirin taken from twenty weeks of pregnancy significantly reduce the incidence of pregnancy-induced hypertension, possibly through the correction of an imbalance in levels of thromboxane and prostacyclin. Whether low-dose aspirin prevents preeclampsia is unclear. It is not recommended as prophylaxis in women at low risk for preeclampsia but may reduce the incidence of the disease in women at high risk.
                We conducted a double-blind, randomized, placebo-controlled trial in four groups of pregnant women at high risk for preeclampsia, including 471 women with pregestational insulin-treated diabetes mellitus, 774 women with chronic hypertension, 688 women with multifetal gestations, and 606 women who had had preeclampsia during a previous pregnancy. The women were enrolled between gestational weeks 13 and 26 and received either 60 mg of aspirin or placebo daily.
                Outcome data were obtained on all but 36 of the 2539 women who entered the study. The incidence of preeclampsia was similar in the 1254 women in the aspirin group and the 1249 women in the placebo group (aspirin, 18 percent; placebo, 20 percent; P=0.23). The incidences in the aspirin and placebo groups for each of the four high-risk categories were also similar: for women with pregestational diabetes mellitus, the incidence was 18 percent in the aspirin group and 22 percent in the placebo group (P=0.38); for women with chronic hypertension, 26 percent and 25 percent (P= 0.66); for those with multifetal gestations, 12 percent and 16 percent (P=0.10); and for those with preeclampsia during a previous pregnancy, 17 percent and 19 percent (P=0.47). In addition, the incidences of perinatal death, preterm birth, and infants small for gestational age were similar in the aspirin and placebo groups.
                In our study, low-dose aspirin did not reduce the incidence of preeclampsia significantly or improve perinatal outcomes in pregnant women at high risk for preeclampsia. To assess the effectiveness of low-dose aspirin in the prevention of preeclampsia and intrauterine growth restriction (IUGR) in high-risk pregnant women with abnormal findings at uterine artery Doppler velocimetry performed at 14-16 weeks.
                Randomized controlled clinical trial.
                Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Egypt.
                The trial enrolled 139 women at risk of preeclampsia or IUGR, with abnormal uterine artery Doppler findings that included the presence of unilateral or bilateral diastolic notch, high resistance index (RI), or high pulsatility index (PI) at 14-16 weeks of gestation. The women were randomly allocated into two groups, one receiving aspirin since admission to hospital (n=74) and the other serving as control (n=65). All women were followed up until delivery to assess maternal and perinatal outcomes. T-test was used for comparison of quantitative variables, and categorical variables were compared by chi2 test. OUTCOME CRITERIA: Development of mild or severe preeclampsia, time of onset of preeclampsia, preterm delivery, and the development of IUGR.
                Preeclampsia developed in 35% of women receiving aspirin and 62% of women in the control group (P=0.003), with severe preeclampsia developing in 8% and 23% of women (P=0.215), respectively. Preeclampsia before 37 weeks of gestation was recorded in only 4% of women receiving aspirin as opposed to 83% of controls (P<0.001). In the group of women receiving aspirin, 19% of newborns suffered from IUGR as opposed to 32%of newborns in the control group (P=0.106). There was no significant difference between the two groups in the rate of preterm delivery (P=0.080), mode of delivery (P=0.971), Apgar score <5 after one minute (P=0.273) and after 5 minutes (P=0.941), maternal or neonatal bleeding (P=0.948), and neonatal birth weight (P=0.399).
                Low-dose aspirin administered as early as 14-16 weeks of gestation to pregnant women at high risk of preeclampsia with abnormal uterine Doppler findings may reduce or modify the course of severe preeclampsia. Its effects on the prevention of IUGR need further evaluation. Although low-dose aspirin has been reported to reduce the incidence of preeclampsia among women at high risk for this complication, its efficacy and safety in healthy, nulliparous pregnant women are not known.
                We studied 3135 normotensive nulliparous women who were 13 to 26 weeks pregnant to determine whether treatment with aspirin reduced the incidence of preeclampsia. Of this group, 1570 women received 60 mg of aspirin per day and 1565 received placebo for the remainder of their pregnancies. We also evaluated the effect of aspirin on maternal and neonatal morbidity.
                Of the original group of 3135 women, 2985 (95 percent) were followed throughout pregnancy and the immediate puerperium. The incidence of preeclampsia was lower in the aspirin group (69 of 1485 women [4.6 percent]) than in the placebo group (94 of 1500 women [6.3 percent]) (relative risk, 0.7; 95 percent confidence interval, 0.6 to 1.0; P = 0.05), whereas the incidence of gestational hypertension was 6.7 and 5.9 percent, respectively. There were no significant differences in the infants' birth weight or in the incidence of fetal growth retardation, postpartum hemorrhage, or neonatal bleeding problems between the two groups. Subgroup analysis showed that preeclampsia occurred primarily in women whose initial systolic blood pressure was 120 to 134 mm Hg (incidence among such women, 5.6 percent in the aspirin group vs. 11.9 percent in the placebo group; P = 0.01). The incidence of abruptio placentae was greater among the women who received aspirin (11 women, vs. 2 in the placebo group; P = 0.01).
                Low-dose aspirin decreases the incidence of preeclampsia among nulliparous women, primarily through its effect in those who have elevated systolic blood pressure initially. This treatment does not decrease perinatal morbidity but increases the risk of abruptio placentae. To evaluate the efficacy of low-dose acetylsalicylic acid in the prevention of pregnancy-induced hypertension and intrauterine growth retardation in high-risk pregnancies as determined by transvaginal Doppler ultrasound study of the uterine arteries at 12 to 14 weeks of gestation.
                Randomised, double blind and placebo-controlled trial.
                The Department of Obstetrics and Gynaecology, Tampere University Hospital, Finland.
                One hundred and twenty pregnant women considered to be at high risk of pre-eclampsia or intrauterine growth retardation were screened by transvaginal Doppler ultrasound at 12 to 14 weeks of gestation.
                Ninety pregnant women with bilateral notches in the uterine arteries were randomised to receive acetylsalicyclic acid 0.5mg/kg/day (n = 45) or placebo (n = 45) from 12 to 14 weeks of gestation.
                Hypertensive disorders of pregnancy and intrauterine growth retardation.
                Forty-three women on acetylsalicyclic acid and 43 on placebo were successfully followed up. The use of acetylsalicyclic acid was associated with a statistically significant reduction in the incidence of pregnancy-induced hypertension (11.6% vs 37.2%, RR = 0.31, 95% CI 0.13-0.78) and pre-eclampsia (4.7% vs 23.3%, RR = 0.2, 95% Cl 0.05-0.86). The incidence of hypertension before 37 weeks of pregnancy was also significantly reduced (2.3% vs 20.9%, RR = 0.22, 95% CI 0.05-0.97). The reduction in the incidence of intrauterine growth retardation (2.3% vs 7%) was not statistically significant. Acetylsalicyclic acid was not associated with excess risk of maternal or fetal bleeding.
                In women rated in Doppler velocimetry waveform analysis to be at high risk of pre-eclampsia, low-dose acetylsalicyclic acid reduces the incidence of pregnancy-induced hypertension and especially proteinuric pre-eclampsia. To investigate the effect of 60 mg aspirin daily on platelet reactivity and prostaglandin production in various groups of patients. Similar regimens, which are thought to act through inhibition of platelet thromboxane production, are currently undergoing clinical assessment for the prevention of pre-eclampsia and intrauterine growth retardation.
                A prospective randomized placebo controlled study.
                University Hospital, Nottingham.
                12 non-pregnant female volunteers, 18 normal primigravidae before 16 weeks gestation and 16 pregnant women admitted with gestational hypertension (GH) at a mean gestation of 38 weeks.
                In the non-pregnant women blood samples were taken before and after a 10-day course of 60 mg aspirin daily. The primigravidae had blood samples taken at 16 weeks and then they were randomized to receive either 60 mg aspirin daily or a matched placebo. Further blood samples were obtained at 28, 32 and 36 weeks.
                Changes in platelet reactivity and release reaction, and serum thromboxane production, were estimated in whole blood.
                60 mg aspirin daily significantly inhibited cyclo-oxygenase dependent platelet aggregation, release reaction and serum thromboxane production in non-pregnant and pregnant women, and in women with GH (P less than 0.01). When adrenaline was used as the aggregating agent, the cyclo-oxygenase pathway was recruited in the increased reactivity seen in the third trimester of normal pregnancy, and was sensitive to inhibition by low dose aspirin.
                Low dose aspirin would appear to be an appropriate agent for the inhibition of platelet reactivity associated with hypertensive pregnancy. To study the effect of daily treatment with 50 mg of aspirin (ASA) on the hypertensive pregnancy complications and on the production prostacyclin (PGI2) and thromboxane A2 (TxA2) in high risk pregnant women and their infants.
                Placebo controlled prospective study.
                Departments of Obstetrics and Gynaecology, University of Helsinki, University of Oulu and Central Hospital of Middle Finland, Finland.
                Two hundred and eight pregnant women with pre-existing hypertension or a history of severe preeclampsia in their previous pregnancy. Prostanoids were studied in a subgroup of 18 women.
                The women were randomised to receive ASA (50 mg/day, n = 103) or placebo (n = 105) from the mean of 15 weeks gestational age to delivery. The exacerbation of pre-existing hypertension or the appearance of hypertension in previously normotensive women, the appearance of proteinuria and fetal growth were the main end points, but some other clinical characteristics were also recorded. Urinary excretion of PGI2 and TxA2 metabolites by mothers and infants and their production in umbilical arteries in vitro were also studied.
                Two women (one in both groups) had miscarriages, and one pregnancy was terminated for fetal anencephaly (ASA group). In addition, seven women discontinued the treatment due to urticaria (two women in ASA group), increased activity of aspartate amino transferase in serum (one woman in both groups), or increased bleeding time (one woman in ASA group, two women in placebo group), and one woman in the placebo group was lost from follow-up. Thus the end points could be assessed in 97 women taking ASA and 100 women taking placebo. ASA did not diminish the rate of the rise of blood pressure without (12 vs 14, respectively) or with proteinuria (9 vs 11), but fetal haemodynamic disturbances as assessed by Doppler equipment (1/44 vs 6/45 women studied, P = 0.05) and need for treatment in neonatal intensive care unit (10 vs 21, P = 0.04) were more rare in ASA group. ASA tended to increase the birthweight of the newborn (3348 +/- 707 g vs 3170 +/- 665 g, mean +/- SD, P = 0.07), but two perinatal deaths occurred in ASA group. ASA prolonged the bleeding time of the mother (435 s, 210-998 s (geometric mean, range) vs 349 s, 210-690 s, P = 0.02), but caused no extra blood loss during delivery, nor affected neonatal hemostasis. In a subgroup of mothers (ASA, n = 10; placebo, n = 8), ASA inhibited more than 90% of platelet TxA2-production, and caused a 65 to 80% decrease in the urinary excretion of TxA2 metabolites, but no decrease in the urinary excretion of PGI2 metabolites.
                ASA did not prevent the rise of maternal hypertension, but improved fetal haemodynamic performance and reduced the need of intensive neonatal care. It inhibited strongly maternal thromboxane A2 but not PGI2 production and thus shifted the balance between PGI2/TxA2 to the dominance of the vasodilatory, anti-aggregatory side. The efficacy of low-dose aspirin in preventing fetal growth retardation was tested in a randomised, placebo-controlled, double-blind trial. A secondary aim was to find out whether dipyridamole improves the efficacy of aspirin. 323 women at 15-18 weeks' amenorrhoea were selected at twenty-five participating centres on the basis of fetal growth retardation and/or fetal death or abruptio placentae in at least one previous pregnancy. They were randomly allocated to groups receiving placebo, 150 mg/day aspirin, or 150 mg/day aspirin plus 225 mg/day dipyridamole, for the remainder of the pregnancy. In the first phase of the trial all actively treated patients (n = 156) were compared with the placebo group (n = 73). Mean birthweight was significantly higher in the treated than in the placebo group (2751 [SD 670] vs 2526 [848] g; difference 225 g [95% CI 129-321 g], p = 0.029) and the frequency of fetal growth retardation in the placebo group was twice that in the treated group (19 [26%] vs 20 [13%]; p less than 0.02). The frequencies of stillbirth (4 [5%] vs 2 [1%]) and abruptio placentae (6 [8%] vs 7 [5%]) were also higher in the placebo than in the treated group. The benefits of aspirin treatment were greater in patients with two or more previous poor outcomes than in those with only one. In the second analysis, of aspirin only (n = 127) vs aspirin plus dipyridamole (n = 119), no significant differences were found. There was no excess of maternal or neonatal side-effects in the aspirin-treated patients. In an attempt to investigate the prophylactic effect of a thromboxane A2 (TXA2) synthetase inhibitor on pregnant women with a high risk of preeclampsia, the following clinical study was undertaken.
                Forty pregnant women were randomly allocated to control or treatment groups. Ozagrel Hydrochloride (400 mg/day, orally) and placebo were started at 20 weeks of gestation and continued until delivery.
                Seventeen of 20 (85%) women in the control group developed preeclampsia, whereas 9 of 20 (45%) in the treatment group developed preeclampsia. Ozagrel Hydrochloride significantly (p < 0.01) reduced the occurrence of preeclampsia, and the incidence of both hypertension (p < 0.05) and proteinuria (p < 0.01) was significantly less in the treatment group compared with the control group. One month after administration, the mean plasma concentration of TXB2, a metabolite of TXA2, was significantly decreased (p < 0.01) to 62.4 +/- 13.6%, whereas that of 6-keto prostaglandin F1 alpha, a metabolite of PGI2, was significantly increased (p < 0.01) to 206.7 +/- 52.8%. There were no maternal or fetal side effects observed.
                It seems likely that Ozagrel Hydrochloride could be used for the prevention of preeclampsia in high-risk pregnant women. This study extends previous results on the effects of low-dose aspirin on blood pressure in pregnant women at differing risk of developing hypertension in pregnancy and who received aspirin at different times according to their rest-activity cycle. A double-blind, randomized, placebo-controlled trial was conducted in 240 pregnant women randomly assigned to 1 of 6 groups according to treatment (placebo 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). Blood pressure and heart rate for each subject were automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery, as well as at puerperium (6 to 8 weeks after delivery). Subjects were further divided for comparative purposes according to the results of the tolerance-hyperbaric test for early identification of those with a higher risk for developing hypertensive complications in pregnancy. Results indicated that there was no effect of aspirin on blood pressure at time 1 (compared with placebo). A blood pressure reduction was, however, highly statistically significant at time 2 and, to a greater extent, at time 3 (mean reductions of 14.2 and 9.6 mm Hg in 24-hour means for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). Effects of aspirin on blood pressure were significantly larger for women with a positive test at the time of recruitment (P<0.001). Differences in blood pressure among pregnant women receiving aspirin at different times in the circadian cycle disappeared at puerperium (P>0.212). There was no effect of aspirin or placebo on heart rate. This study corroborates the statistically significant, time-dependent effect of low-dose aspirin on blood pressure in pregnant women with differing risk of developing hypertensive complications in pregnancy. Although the mechanism involved in the administration-time-dependent responsiveness of blood pressure to aspirin still remains uncertain, the use of doses of aspirin <80 mg/d that do not affect placental thromboxane, initiation of the use of aspirin after 16 weeks' gestation, and the lack of circadian timing for aspirin administration could all explain the lack of positive results in previous clinical trials. There is evidence that aspirin in low doses favorably influences the course of pregnancy-induced hypertension, but the mechanism, although assumed to involve suppression of the production of thromboxane by platelets, has not been established. We performed a randomized study of the effect of the long-term daily administration of 60 mg of aspirin (n = 17) or placebo (n = 16) on platelet thromboxane A2 and vascular prostacyclin in women at risk for pregnancy-induced hypertension. Low doses of aspirin were associated with a longer pregnancy and increased weight of newborns. Serum levels of thromboxane B2, a stable product of thromboxane A2, were almost completely (greater than 90 percent) inhibited by low doses of aspirin. The urinary excretion of immunoreactive thromboxane B2 was significantly reduced without changes in the level of 6-keto-prostaglandin F1 alpha, a product of prostacyclin. Mass spectrometric analysis showed that aspirin reduced the excretion of the 2,3-dinor-thromboxane B2 metabolite--mainly of platelet origin--by 81 percent and of thromboxane B2, probably chiefly of renal origin, by 59 percent. The urinary excretion of 6-keto-prostaglandin F1 alpha and of its metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha was not affected. Low doses of aspirin only partially (63 percent) reduced neonatal serum thromboxane B2. No hemorrhagic complications were observed in the newborns. Thus, in women at risk for pregnancy-induced hypertension, low doses of aspirin selectively suppressed maternal platelet thromboxane B2 while sparing vascular prostacyclin, but only partially suppressed neonatal platelet thromboxane B2, allowing hemostatic competence in the fetus and newborn. 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. This study was conducted to evaluate uteroplacental and fetal hemodynamics in fetuses exposed to low-dose aspirin (100 mg/d).
                Randomized, placebo-controlled, double-blind trial.
                The study protocol included singleton pregnancies of less than 20 gestational weeks at risk for pre-eclampsia or fetal growth restriction. Exclusion criteria were diabetes mellitus, pre-existing proteinuric hypertension or fetal malformations. Forty-three pregnant women were randomly allocated to daily treatment with 100 mg aspirin (n = 22) or placebo (n = 21).
                Pulsed Doppler measurements of the uterine artery, fetal middle cerebral artery, fetal aorta, ductus arteriosus and atrioventricular valves were performed longitudinally at 14 day intervals starting from 18 gestational weeks until delivery. Results were expressed as group medians (aspirin vs. placebo) and were analyzed by Mann-Whitney U-test.
                There was no difference in uterine, umbilical, aortic, middle cerebral and ductus arteriosus blood flow between the aspirin group and controls. Median ductal peak flow velocities increased with gestational age in both groups, but differences between groups did not reach significance. In the third trimester of pregnancy, ductal peak velocities > 140 cm/s were occasionally observed in both groups. However, end diastolic velocities > 35 cm/s or atrioventricular valve regurgitation never occurred.
                Daily administration of low-dose aspirin during the second and third trimesters of pregnancy does not alter uteroplacental or fetoplacental hemodynamics and does not cause moderate or severe constriction of the ductus arteriosus. In a prospective, randomized, double-blind study for the prevention of pregnancy-induced hypertension and preeclampsia, 41 primigravidae with positive roll-over test (28th-32nd week of pregnancy) received 80 mg aspirin/day or placebo until the end of the 37th week. In the patients treated with acetylsalicylic acid (n = 22), 3 cases of proteinuria occurred, but no hypertensive pregnancy complication. In the placebo group (n = 19), 10 patients developed pregnancy-induced hypertension (6 of them preeclampsia). Group-specific differences concerning the occurrence of hypertension were statistically highly significant (p = 0.0004). No relevant differences were observed with regard to pregnancy duration, birth weight and umbilical artery pH value. The placebo group included 1 intrauterine death. No increased tendency to maternal or fetal bleeding was noticed. The purpose of this study was to investigate the hypothesis that maternal administration of 100mg aspirin each day will improve birth-weight and other measures of neonatal size when given as a treatment to pregnancies complicated by fetal growth restriction and umbilical-placental insufficiency. A randomized, double-blind, placebo controlled study design was employed; 51 pregnant women were enrolled. The entry criteria were a fetal abdominal circumference < 10th per centile together with an umbilical artery Doppler systolic/diastolic ratio > 95th per centile between 28 and 36 weeks' gestation. Compliance was assessed by serial measurement of maternal serum thromboxane B2 levels. The mean gestational age at enrolment was 32 weeks and at delivery was 36 weeks. There were no differences between the 2 groups in gestational age at birth; birth-weight or birth-weight ratio; circumferences of the head, chest or abdomen; skin fold thicknesses; or neonatal morbidity. Low dose aspirin therapy did not alter Doppler systolic/diastolic ratios. After 14 days therapy, mean thromboxane B2 levels fell more than 80% from baseline values; 10.5% of women did not demonstrate biochemical confirmation of aspirin ingestion, despite verbal confirmation of compliance. We conclude that low dose aspirin therapy is not of benefit in the treatment of pregnancies complicated by fetal growth restriction and umbilical-placental insufficiency between 28 and 36 weeks' gestation. Effectiveness of early administered low-dose aspirin in prevention of pregnancy-induced hypertension (PIH) and fetal growth retardation in twin pregnancies was investigated in a randomized placebo controlled, double-blind trial in 47 twin pregnancies.
                Twenty-four women received 100 mg of aspirin daily from mean gestational age of 17.7 wk, and 23 women ingested placebo from a mean gestational age of 18 wk until delivery. The placebo and aspirin group were similar in age, weight gain, zygosity, gravidity, parity, and obstetrical antecedents. Treatment lasted for a mean period of 16.8 wk and 18.3 wk in the placebo and aspirin groups, respectively. The mean gestational age at birth was 35.0 wk and 36.4 wk in the placebo and aspirin groups, respectively.
                PIH was noted in six women (26%) in the placebo group, but in only one woman (4%) in the aspirin treated patients (P < .05). The mean combined fetal weights of both twins, and the mean weight of the second twin at delivery were significantly higher in the aspirin treated mothers than in the placebo treated gravidas (mean difference of 781 g, P < .02 and mean difference of 488 g, P < .005, respectively). Intrauterine growth retardation (< 10th percentile) concerned 11 (24%) and six (13%) fetuses in the placebo and aspirin groups, respectively. No adverse effects of treatment to either the mothers or the infants were noted.
                Low-dose aspirin reduces the incidence of PIH and has a beneficial effect on fetal growth in twin pregnancies. Additional clinical trials are needed in order to define and select subgroups of twins where aspirin treatment is recommended. Forty-six nulliparous women in third trimester of pregnancy with a raised blood pressure of 30 mm Hg (systolic) or/and 15 mm Hg (diastolic) or both, over baseline values were treated with 75 mg of aspirin per day. The results are compared with another 48 age, height, weight, and gestational period matched nulliparaous women with similar condition for trial selection, who were treated as control. There is considerable more number of cases in the control group than in aspirin treated group showing subsequent rise of BP, appearance of proteinuria, and severe pre-eclamptic toxaemia. The aspirin treated group showed increased mean gestational age at termination 39.4 +/- 2.6 weeks as against 38.2 +/- 3.4, increased foetal weight 2860 +/- 552 g as against 2540 +/- 720 g. No case of neonatal haemorrhagic manifestations or congenital malformations were seen. However not much result is obtained with aspirin therapy in cases with established pregnancy induced hypertension or with proteinuria. Hence it is concluded that aspirin therapy should be given to prevent pregnancy induced hypertension. As predictability of other screening tests are not unequivocal, criterion used in this series for screening may be used. To reduce the incidence of pre-eclampsia in nulliparous women, in accordance with the suggestion of a recent meta-analysis that low dose aspirin might decrease this incidence by more than half if used early enough in and at a sufficient dose during pregnancy (more than 75 mg).
                Multicentre randomised double-blinded placebo-controlled trial.
                Twenty eight centres in Northern of France and one in Belgium.
                Three thousand and two hundred ninety-four nulliparous women recruited between 14 and 20 weeks.
                Randomisation to either 100 mg aspirin or placebo daily from inclusion through 34 weeks.
                Preeclampsia was defined as hypertension (> or =140 and or 90 mmHg) associated with proteinuria (> or =0.5 g/L).
                The aspirin (n = 1644) and placebo (n = 1650) groups did not differ significantly in the mothers' incidence of pre-eclampsia (28 of 1632 [1.7%] vs 26 of 1637 [1.6%]; relative risk, RR, 1.08, 95% CI 0.64-1.83), hypertension, HELLP syndrome or placental abruption, or in the children's incidence of perinatal deaths or birthweight below the 10th centile. The incidence of babies with birthweight below the third centile was significantly higher in the aspirin group, with no explanation. The incidence of maternal side effects was higher in the aspirin group, principally because of a significantly higher rate of haemorrhage.
                Aspirin at a dose of 100 mg does not reduce the incidence of pre-eclampsia in nulliparous women. Aspirin (100 mg) is associated with an increase in bleeding complications. To determine if aspirin (ASA) therapy reduces the incidence of pre-eclampsia in women at high risk of this condition.
                Randomised clinical trial. We recruited pregnant women with gestational age at randomisation <14 weeks, who satisfied the following criteria: chronic hypertension, history of severe pre-eclampsia or eclampsia or intrauterine growth retardation (IUGR) or intrauterine foetal death. Nineteen women in the no-treatment group and 16 in the ASA group were successfully followed up.
                The mean birthweight was higher in the ASA group than in the no-treatment group (2790 g (S.D. 340 g) versus 2616 g (S.D. 779 g)), but the difference was not statistically significant. We found no statistically significant differences between the groups in the proportion of infants with birthweight below 2500 g (13.3% versus 29.4%) and the number of cases with pregnancy-induced hypertension (PIH)/pre-eclampsia (31.3% versus 36.8%).
                These limited data give some support to the potential favourable effect of early treatment with ASA in pregnant women at risk of PIH and IUGR. 102 patients at high risk of pre-eclampsia and/or fetal growth retardation were randomly allocated to treatment with 300 mg dipyridamole and 150 mg aspirin daily from 3 months' gestation onwards (group A) or to the control group (group B, no treatment). Group A was twice as likely as group B to have a normal pregnancy. Pre-eclampsia occurred in 6 patients in group B and none in group A. Major complications (fetal death or severe growth retardation) occurred in 9 patients in group B and none in group A. Platelet count and plasma volume were significantly higher in group A than in group B throughout pregnancy. The treatment did not produce serious adverse effects. Antiplatelet therapy given early in pregnancy to high-risk patients may thus protect against pre-eclampsia and fetal growth retardation.
Antiplatelet agents, largely low-dose aspirin, have moderate benefits when used for prevention of pre-eclampsia and its consequences. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose.
[Note: The 16 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]