70.  Aspirin Prophylaxis in Pregnancy



RECOMMENDATION



There is insufficient evidence to recommend for or against the routine use of aspirin to prevent

preeclampsia or intrauterine growth retardation in pregnant women, including those at high risk

(see Clinical Intervention).



Burden of Suffering



Pregnancy-associated hypertension/preeclampsia/eclampsia syndrome (see Chapter 37 for

definitions) is the second leading cause of maternal death in the U.S.1,2 In 1992, over 112,000

pregnant women (28.5/1,000 live births) developed pregnancy-associated hypertension, of

whom approximately 13% were classified as severe.3 Maternal complications associated with

preeclampsia include abruptio placentae, acute renal failure, cerebral hemorrhage, disseminated

intravascular coagulation, pulmonary edema, circulatory collapse, eclampsia, and death.4

Preeclampsia also increases the rate of cesarean delivery and prolongs the duration of

hospitalization.3,5 Neonatal complications include low birth weight (due to preterm delivery

and/or intrauterine growth retardation), preterm delivery, hypoxia, and perinatal death.6 Risk

factors for preeclampsia include age (<20 or 40 years), Native American race, family history,

nulliparity, twin gestation, chronic hypertension, diabetes, collagen vascular disease, and a

previous history of pregnancy-associated hypertension or preeclampsia.3,7,8



Efficacy of Chemoprophylaxis



Preeclampsia may be due to endothelial dysfunction caused by the systemic effects of decreased

placental blood flow.8 Compared to women with normal pregnancies, women with preeclampsia

have a relative excess of thromboxane A2 (a platelet-derived vasoconstrictor and platelet

aggregation promoter) compared to prostacyclin (an endothelial cell-derived vasodilator and

platelet aggregation inhibitor).9-11 The correction of the thromboxane A2 to prostacyclin ratio

caused by aspirin may help prevent the development of preeclampsia and its complications.12



A number of randomized controlled trials have evaluated the potential benefit of prophylactic

aspirin in preventing preeclampsia. Two studies13,14 were performed in routine obstetric

patients. Hauth13 et al. randomized 604 nulliparous women under the age of 28 years to 60 mg

aspirin or placebo daily from 24 weeks' gestation until delivery. Compared with the placebo

group, the group receiving aspirin experienced a statistically significant reduction in total and

severe preeclampsia and in levels of thromboxane B2, a metabolite of thromboxane A2. No

statistically significant differences emerged in the rates of neonatal complications (including low

birth weight, prematurity, and fetal death), maternal complications, or cesarean deliveries.

Sibai14 et al. studied 3,135 nulliparous women. These women received either 60 mg aspirin (n =

1,485) or placebo (n = 1,500) daily from <26 weeks' gestation to delivery. The treated group

had a 26% reduction in the incidence of preeclampsia compared with the placebo group (4.6% vs.

6.3%, p = 0.05). Women who received aspirin had a significant increase in the risk of abruptio

placentae: 0.7% vs. 0.1% (p = 0.01). This outcome was not defined before the trial, however; its

definition was not standardized nor was the diagnosis confirmed by external review. There were no

other significant differences in maternal or fetal outcomes.



In the largest trial to date, the CLASP Collaborative Group15 randomized 9,364 women to either

60 mg aspirin or placebo daily. Women were eligible for entry into the study for prophylactic (n

= 8,021) or therapeutic (n = 1,343) treatment if they were between 12 and 32 weeks' gestation

and either had signs or symptoms of preeclampsia or intrauterine growth retardation (IUGR) or

were considered by the physician to be at high risk for preeclampsia or IUGR (based on a history

of preeclampsia or IUGR in a previous pregnancy, chronic hypertension, renal disease, maternal

age, family history, or multiple gestation). This study found a significant, small reduction in

preterm deliveries in the aspirin group (12% reduction among high-risk asymptomatic women),

but no difference in the incidence of preeclampsia or IUGR. An increase in transfusion rates was

noted in the aspirin group; it was not associated with the occurrence or severity of postpartum

hemorrhage, however, nor were there significant differences in abruptio placentae or other

antepartum bleeding. No other maternal or fetal complications were noted. This trial may have

failed to show an effect of aspirin on preeclampsia because of the variability and subjectivity of

entry criteria (which were based on the responsible clinician's rating of risk), and the use of a

more conservative statistical analysis (a = 0.01 and two-tailed test of significance).



Three smaller trials16-18 also examined the use of aspirin in women at increased risk of

preeclampsia. These studies identified women at increased risk on the basis of results of various

screening tests, including the "rollover" test,16 wave form ultrasound,17 and angiotensin

test.18 Intervention began between 24 and 32 weeks, and the dose of aspirin ranged from 60 to

100 mg/day. Each study found a statistically significant reduction in preeclampsia in the

aspirin-treated group, but no significant differences in fetal or maternal complications. The

cesarean delivery rate was significantly lower in the aspirin group in two of the studies.17,18



Three other randomized controlled trials enrolled women with risk factors for preeclampsia,

including nulliparity, multiple gestations, chronic hypertension, and previous pregnancy with

preeclampsia, IUGR, or fetal death.19-21 All three studies showed a significant reduction in

preeclampsia in the aspirin group. Two additional trials, from Finland22 and Italy,23 found no

significant reduction in pregnancy-associated hypertension in the aspirin-treated group. These

study populations included women who had pregnancy-associated hypertension or preeclampsia in

the current pregnancy as well as asymptomatic high-risk women, however, which may have

masked a benefit.



Three trials, two randomized15,24 and one nonrandomized,25 tested the efficacy of low-dose

aspirin in the prevention of IUGR in asymptomatic high-risk women. The CLASP trial15 (see

above) of women at increased risk of IUGR found no difference in incidence of IUGR between those

who were randomized to receive aspirin prophylaxis compared to placebo. In the other randomized

controlled trial,24 pregnant women with a history of poor outcomes (including IUGR) in two

earlier pregnancies were randomized to receive either aspirin 150 mg/day or a placebo,

beginning at 15 to 18 weeks' gestation. Those given aspirin had significantly heavier babies (mean

225 g higher; p = 0.03), and the proportion weighing less than the 10th percentile was decreased

from 26% to 13% in the treated group (p < 0.02). The nonrandomized trial also found a

significant reduction in IUGR in the aspirin group. Two other randomized controlled trials cited

above found no difference in IUGR incidence with aspirin prophylaxis, but the inclusion of both

symptomatic and asymptomatic high-risk women may have concealed an effect.22,23



The safety of aspirin prophylaxis in pregnancy must be carefully considered. While there have

been sporadic reports of congenital heart defects associated with aspirin use in the first trimester

of pregnancy, no causal link between aspirin and birth defects has been established.26 Preterm

closure of the ductus arteriosus has also been reported. High-dose aspirin consumption close to

delivery can result in maternal and fetal clotting abnormalities such as increased maternal

bleeding and neonatal intracranial hemorrhage.12,27 Maternal effects were seen with doses of

1,500-2,500 mg/day, and neonatal effects with doses of 325-1,500 mg/day. Bleeding problems

have not generally been reported at low doses (60-150 mg/day),28-30 although most trials

were too small to detect rare adverse effects. The two largest trials each found a significantly

increased risk of bleeding: abruptio placentae in one trial14 and an increased risk of postpartum

maternal transfusion in the other.15 A meta-analysis of 11 randomized controlled trials of

low-dose aspirin prophylaxis in pregnancy did not find an association, however, between aspirin

and either abruptio placentae or perinatal mortality.31



Effectiveness of Counseling



Little information on compliance with daily aspirin prophylaxis during pregnancy is available. In

one trial, 315 of 919 women failed a 2-week run-in period due to poor compliance with either

visits or medication.13 In another trial, 35 of 39 women recruited for a placebo-controlled study

of low-dose aspirin therapy in the prevention of preeclampsia refused participation.32 Reasons

for refusal included fear that aspirin would harm the fetus or the pregnant woman, the belief that

pregnant women should not participate in experimental studies of drugs, and the belief that women

should avoid medications during pregnancy.



Recommendations of Other Groups



No organization currently recommends routine aspirin prophylaxis in pregnancy for the

prevention of preeclampsia or intrauterine growth retardation.



Discussion



Numerous randomized controlled trials among both low-risk and high-risk pregnant women

indicate that aspirin prophylaxis reduces the incidence and severity of preeclampsia.

Nevertheless, no consistent reductions in other fetal or maternal complications have been seen.

Although the CLASP trial found a significant reduction in preterm delivery, most trials to date

have had insufficient power to identify clinically important differences in rates of prematurity,

respiratory distress syndrome, and perinatal death. A meta-analysis of controlled trials reported

no significant effect of aspirin on perinatal mortality.31 In addition, the largest trial in healthy

low-risk women14 found a significant increase in the risk of abruptio placentae, a  potentially

life-threatening complication for both the fetus and the woman, while the CLASP trial15 reported

an increased risk of maternal transfusion postpartum. Hence, the net health impact of routine

aspirin prophylaxis remains uncertain. While aspirin appears to reduce the incidence of

preeclampsia, it is unknown whether it improves other, perhaps more important, fetal and

maternal outcomes. Preeclampsia may be only one manifestation of a broader underlying

pathophysiologic defect. Complications commonly attributed to preeclampsia may be due to the

underlying pathology and not to preeclampsia per se. If so, prevention of preeclampsia may not

translate into an overall clinical benefit.



One randomized trial found a beneficial effect of aspirin on birth weight among women at increased

risk for delivering an infant with IUGR. While statistically significant, this effect may have little

clinical impact due to problems with the definition of "growth retardation." This study did not

differentiate constitutionally small infants with progressive intrauterine growth from infants

with faulty growth patterns. In addition, other randomized trials in asymptomatic and

symptomatic women have not reported significant effects on IUGR. Further studies are warranted

to confirm any benefit, to determine the optimal gestational ages for administration, and to find the

lowest effective dose of aspirin.



CLINICAL INTERVENTION



There is insufficient evidence to recommend for or against routine aspirin prophylaxis in

pregnancy for the prevention of either preeclampsia ("C" recommendation) or intrauterine

growth retardation ("C" recommendation). Clinicians may wish to inform patients at high risk of

preeclampsia that aspirin prophylaxis has been shown to decrease this risk, but such patients

should also be informed that aspirin has not been proven to improve overall fetal or maternal

outcomes, that one large trial raised the possibility of an increased risk of abruptio placentae, and

that aspirin can have additional unpleasant and occasionally serious side effects.



The draft of this chapter was prepared for the U.S. Preventive Services Task Force by Peter W.

Pendergrass, MD, MPH, and Carolyn DiGuiseppi, MD, MPH.



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