Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production

Abstract

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.

Management of the obstetric antiphospholipid syndrome

“…The fetal period begins at 10 menstrual weeks (i.e., 70 days from conception) and extends until the time of delivery. In unselected obstetric patients, 10-15% of recognized pregnancies end in loss, with Ͼ85% of losses occurring during the (pre)embryonic periods (11,12). The rate of fetal loss after 14 weeks of gestation is 2% (11).…”

“…Chromosomal abnormalities of the conceptus account for more than half of sporadic (pre)embryonic losses, and, in many cases, a visible embryo never forms. In contrast, genetic abnormalities of the conceptus are less common in women with at least 3 consecutive pregnancy losses (12). In women with Ն3 spontaneous abortions, a normal embryonic ultrasound beyond 6-8 weeks of gestation provides a favorable prognosis with a Ն80% chance for a live birth (13).…”

“…In those women whose pregnancy and clinical histories put them in the second category (those with recurrent early fetal loss or at least 1 fetal loss, without SLE or previous thrombosis), 3 observational studies evaluated the outcome in women treated with aspirin alone (44), those who received a combination of heparin and aspirin (45), and those who declined pharmacologic treatment and received standard care (46). In 9 prospective studies (12,(29)(30)(31)(32)(47)(48)(49)(50), 2 treatment strategies were compared. All but 2 of these studies (47,50) were randomized studies.…”

“…All but 2 of these studies (47,50) were randomized studies. The treatments included placebo (12,29,32), aspirin alone (12,(30)(31)(32)47,49), aspirin plus prednisone (29,48,49), and heparin plus aspirin (30,31,47,48,50) (Table 3). Evaluation of pregnancies started with a positive pregnancy test (12,29,32,44,47,48,50) or the presence of fetal heart activity (30,31,45,46,49).…”

“…Most women in these studies met the criteria for obstetric APS (14), because they had at least 3 consecutive miscarriages (12,(30)(31)(32)(45)(46)(47)50), at least 2 unexplained pregnancy losses before 12 weeks of gestation or at least 1 pregnancy loss after 12 weeks (44,48,49), or at (47,50). Three studies (47,48,50) emphasized exclusion of women with low aCL levels, and another (49) emphasized inclusion of women with low aCL levels.…”