Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Compatible (Low-Dose) Human Data Suggest Risk in 1st and 3rd Trimesters (Full-Dose)
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
The use of aspirin during pregnancy, especially of chronic or intermittent high doses, should be avoided. The drug may affect maternal and newborn hemostasis mechanisms, leading to an increased risk of hemorrhage. High doses may be related to increased perinatal mortality, intrauterine growth restriction (IUGR), and teratogenic effects. Low doses, such as 80 mg/day, appear to have beneficial effects in pregnancies complicated by systemic lupus erythematosus with antiphospholipid antibodies. In pregnancies at risk for the development of gestational hypertension and preeclampsia, and in fetuses with IUGR, low-dose aspirin (40–150 mg/day) may be beneficial, but more studies are required to assess accurately the risk:benefit ratio of such therapy. Near term, aspirin may prolong gestation and labor. Although aspirin has been used as a tocolytic agent, serious bleeding complications may occur in the newborn. Premature closure of the ductus arteriosus may occur in the latter part of pregnancy as a result of maternal consumption of full-dose aspirin. Persistent pulmonary hypertension of the newborn (PPHN) is a potential complication of the closure. If an analgesic or antipyretic is needed, acetaminophen should be considered.
FETAL RISK SUMMARY
Aspirin, a nonsteroidal anti-inflammatory drug (NSAID), is the most frequently ingested drug in pregnancy either as a single agent or in combination with other drugs (1). The terms “aspirin” and “salicylate” are used interchangeably in this monograph unless specifically separated. In eight surveys totaling more than 54,000 patients, aspirin was consumed sometime during gestation by slightly more than 33,000 (61%) (2–9). The true incidence is probably much higher than this because many patients either do not remember taking aspirin or consume drug products without realizing that they contain large amounts of salicylates (2,4,8). Evaluation of the effects of aspirin on the fetus is thus difficult because of this common, and often hidden, exposure. However, some toxic effects on the mother and the fetus from large doses of salicylates have been known since 1893 (10).
Aspirin consumption during pregnancy may produce adverse effects in the mother: anemia, antepartum or postpartum hemorrhage, prolonged gestation, and prolonged labor (5,11–14). The increased length of labor and frequency of postmaturity result from the inhibition of prostaglandin synthesis by aspirin. Aspirin has been shown to significantly delay the induced abortion time in nulliparous (but not multiparous) patients by this same mechanism (15). In an Australian study, regular aspirin ingestion was also found to increase the number of complicated deliveries (cesarean sections, breech, and forceps) (5). Small doses of aspirin may decrease urinary estriol excretion (16).
Aspirin, either alone or in combination with β-mimetics, has been used to treat premature labor (17–19). Although adverse effects in the newborn were infrequent, maternal complications in one study included non–dose-related prolonged bleeding times and dose-related vertigo, tinnitus, headache, and hyperventilation (19).
Failure of intrauterine devices (IUDs) to prevent conception has been described in two patients who consumed frequent doses of aspirin (20). The anti-inflammatory action of aspirin was proposed as the mechanism of the failure.
Low-dose aspirin (about 85 mg/day) was used to treat maternal thrombocytopenia (platelet counts <60,000/mm3) in 19 patients with either IUGR or toxemia (21). In five women who had a definite response to the aspirin, no improvement in plasma volume or fetal welfare was demonstrated.
In women with systemic lupus erythematosus complicated with either lupus anticoagulant or anticardiolipin antibody (i.e., antiphospholipid antibodies), low-dose aspirin (e.g., 80 mg/day) has been used in combination with prednisone to reduce the incidence of pregnancy loss (22–25) (see reference 22 for a review of this topic). This therapy has not been associated with drug-induced fetal or neonatal complications.
Several studies have investigated the effect of low-dose aspirin (e.g., 40–150 mg/day) on the prevention of gestational hypertension, preeclampsia, and eclampsia, and the associated fetal risks of IUGR and mortality (26–38) (see reference 36 for a review of this topic). Low-dose aspirin exerts its beneficial effects in these disorders by irreversible inactivation of platelet cyclooxygenase, resulting in a greater inhibition of thromboxane A2 synthesis than that of prostacyclin production. This inhibition restores the ratio of the two substances to a more normal value. Aspirin-induced fetal and neonatal toxicity has not been observed after the chronic use of low-dose aspirin for these indications. The lack of toxicity may be partially explained by the findings of a study published in 1989 (34). In that study, 60–80 mg of aspirin/day, starting 3 weeks before delivery and continuing until birth, inhibited maternal platelet cyclooxygenase, but not that of the newborn. These results were in agreement with other studies using 60–150 mg/day (34). Other toxicities associated with the use of full-dose aspirin near term, such as hemorrhage, premature closure of the ductus arteriosus, pulmonary hypertension, prolonged gestation, and prolonged labor, were not observed with low-dose aspirin therapy (34). Although these results are reassuring, in the opinion of some, too few studies have been reported to allow a true estimate of the fetal risk (36). However, other recent reports have observed no serious neonatal adverse effects, including hemorrhagic complications, in their series (39,40). In one of these studies, 33 women judged to be at risk for gestational hypertension were randomly assigned to either an aspirin (N = 17) or a placebo (N = 16) group during the 12th week of gestation in a single-blind study (39). Patients in the aspirin group, treated with 60 mg/day from enrollment to delivery, had a longer duration of pregnancy (39 vs. 35 weeks) and delivered heavier infants (2922 vs. 2264 g). None of the aspirin-treated women developed gestational hypertension, whereas three of the placebo group did develop the complication. In a double blind study, 65 women with increased blood pressure during the rollover test administered during the 28th or 29th week of pregnancy were randomly divided into two groups: one group was treated with 100 mg/day of aspirin (N = 34) and the other with placebo (N = 31) (40). Four women (11.8%) of the aspirin-treated group developed gestational hypertension compared with 11 (35.5%) of the placebo group.
Fetal and newborn effects, other than congenital defects, from aspirin exposure in utero, may include increased perinatal mortality, IUGR, congenital salicylate intoxication, and depressed albumin-binding capacity (2,5,12,41–43). For the latter effect, no increase in the incidence of jaundice was observed (2). Perinatal mortality in the Australian study was a result of stillbirths more often than neonatal deaths (5, 41). Some of the stillbirths were associated with antepartum hemorrhage and others may have been caused by closure of the ductus arteriosus in utero (44). Closure of the ductus has been shown in animals to be a result of aspirin inhibition of prostaglandin synthetase. In some early cases, in utero premature closure of the ductus arteriosus was probably caused by aspirin but not suspected (45). However, a large prospective American study involving 41,337 patients, 64% of whom used aspirin sometime during gestation, failed to show that aspirin was a cause of stillbirths, neonatal deaths, or reduced birth weight (46). The difference between these findings probably relates to the chronic or intermittent use of higher doses by the patients in the Australian study (44). Excessive use of aspirin was blamed for the stillbirth of a fetus in whom salicylate levels in the fetal blood and liver were 25–30 and 12 mg/dL, respectively (47). Congenital salicylate intoxication was found in two newborns exposed to high aspirin doses before delivery (42,43). Although both infants survived, one infant exhibited withdrawal symptoms beginning on the second neonatal day consisting of hypertonia, agitation, a shrill piercing cry, and increased reflex irritability (41). The serum salicylate level was 31 mg/dL. Most of the symptoms gradually subsided over 6 weeks, but some mild hypertonia may have persisted.
A 1996 case–control study investigated the relationship between aspirin and other NSAIDs and PPHN (48). Case infants (N = 103) weighed at least 2500 g at birth and had no major congenital defects, whereas controls (N = 298) were full-term infants without congenital defects. Aspirin or other NSAIDs were used by mothers of 26 cases. Because 34% of the cases and all of the controls were born at one hospital (inborn), the investigators conducted two analyses, one for inborn infants and one for the total group. For the total group, the odds ratio and 95% confidence interval (CI) for the exposures and PPHN were aspirin 4.9 (1.6–15.3) and other NSAIDs 6.2 (1.8–21.8). For inborn cases, the findings were aspirin 9.6 (2.4–39.0) and other NSAIDs 17.5 (4.3–71.6). The timing of the exposures was earlier than expected, a median 3 months for aspirin and 1 month for NSAIDs. This result led to three potential conclusions: (a) the drugs caused early structural remodeling or functional alterations of the pulmonary vasculature, (b) the agents were also used in the 3rd trimester, or (c) there was another, unidentified primary cause of PPHN. Exposure in the 3rd trimester was the most likely conclusion because it would have been consistent with the presumed mechanism of in utero premature closure of the ductus arteriosus and resulting increased risk of PPHN. However, the investigators could not determine which of the choices was correct (48). A 2001 report also found the association between aspirin and PPHN (49).
Aspirin given in doses of 325–650 mg during the week before delivery may affect the clotting ability of the newborn (50–56). In the initial study by Bleyer and Breckenridge (50), 3 of 14 newborns exposed to aspirin within 1 week of delivery had minor hemorrhagic phenomena vs. only 1 of 17 nonexposed controls. Collagen-induced platelet aggregation was absent in the aspirin group and, although of less clinical significance, factor XII activity was markedly depressed. A direct correlation was found between factor XII activity and the interval between the last dose of aspirin and birth. Neonatal purpuric rash with depressed platelet function has also been observed after maternal use of aspirin close to term (56). The use of salicylates other than aspirin may not be a problem because the acetyl moiety is apparently required to depress platelet function (57–59). In a 1982 study, 10 mothers consuming less than 1 g of aspirin within 5 days of delivery had excessive intrapartum or postpartum blood loss, resulting in hemoglobulin levels that were markedly lower than those of controls (13,14). One mother required a transfusion. Bleeding complications seen in 9 of the 10 infants included numerous petechiae over the presenting part, hematuria, a cephalohematoma, subconjunctival hemorrhage, and bleeding from a circumcision. No life-threatening hemorrhage, effect on Apgar scores, or increased hospital stay was found, nor was bleeding observed in seven mother–infant pairs when aspirin consumption occurred 6–10 days before delivery (13,14).
An increased incidence of intracranial hemorrhage (ICH) in premature or low-birth-weight infants may occur after maternal aspirin use near birth (60). Computed tomographic screening for ICH was conducted on 108 infants 3–7 days after delivery. All of the infants were either ≤34 weeks in gestation or ≤1500 g in birth weight. A total of 53 infants (49%) developed ICH, including 12 (71%) of the 17 aspirin-exposed newborns. This incidence was statistically significant when compared with the 41 (45%) non–aspirin-exposed infants who developed ICH. The conclusions of this study have been challenged and defended (61,62). In view of the potentially serious outcome, however, full doses of aspirin should be used with extreme caution by patients in danger of premature delivery.
Aspirin readily crosses the placenta (10). When given near term, higher concentrations are found in the neonate than in the mother (63). The kinetics of salicylate elimination in the newborn have been studied (63–65).
A 2003 population-based cohort study involving 1055 pregnant women investigated the prenatal use of aspirin, other NSAIDs, and acetaminophen (66). Fifty-three women (5%) reported used of NSAIDs around the time of conception or during pregnancy, 13 of whom had a spontaneous abortion (SAB). After adjustment, an 80% increased risk of SAB was found for other NSAIDs (adjusted hazard ratio 1.8, 95% CI 1.0–3.2). Moreover, the association was stronger if the initial use of drugs was around conception or if they were used longer than 1 week. A similar association was found with aspirin, but it was weaker because there were only 22 exposures (5 SABs). No association was observed with acetaminophen (66).
The relationship between aspirin and congenital defects is controversial. Several studies have examined this question with findings either supporting or denying a relationship. In two large retrospective studies, mothers of 1291 malformed infants were found to have consumed aspirin during pregnancy more frequently than mothers of normal infants (67,68). In a retrospective survey of 599 children with oral clefts, use of salicylates in the 1st trimester was almost three times more frequent in the mothers of children with this defect (69). A reviewer of these studies noted several biases, including the fact that they were retrospective, that could account for the results (46). Three other reports of aspirin teratogenicity involving a total of 10 infants have been located (70–72). In each of these cases, other drugs and factors were present.
A 1985 study found a possible association between the use of aspirin in early pregnancy and congenital heart disease (73). The risk for defects in septation of the truncus arteriosus was increased about twofold over nonexposed controls. In an earlier retrospective case–control comparison of the relationship between maternal drug intake and congenital heart disease, aspirin was used by 80 of 390 mothers of infants with defects vs. 203 of 1254 mothers of control infants (74). Twelve of the exposed infants had transposition of the great arteries and six had tetralogy of Fallot, but the association between the drug and these defects was weak. The study could not distinguish between the effects of the drug and the underlying condition for which the drug was used (74). A brief review of this and other investigations that have examined the relationship between aspirin and congenital heart disease was published in 1985 (75). The review concluded that too few data existed to associate aspirin with cardiac defects.
A study published in 1989, however, concluded that 1st trimester use of aspirin did not increase the risk of congenital heart defects in relation to other structural anomalies (76). The interval examined encompassed the time of major cardiac development (i.e., from the 5th week after the onset of the last menstrual period to the 9th week of gestation). The data, from the Slone Epidemiology Unit Birth Defects Study, involved 1381 infants with any structural cardiac defect and five subgroups with selected cardiac defects (subgroups were not mutually exclusive): aortic stenosis (N = 43), coarctation of the aorta (N = 123), hypoplastic left ventricle (N = 98), transposition of the great arteries (N = 210), and conotruncal defects (N = 791). A control group of 6966 infants with other malformations was used for comparison. Infants with syndromes that included cardiac defects, such as Down’s syndrome or Holt-Oram syndrome, were excluded from the data, as were mothers who were uncertain about 1st trimester aspirin use or its frequency. After adjustment for potentially confounding factors, the relative risks for the defects among aspirin users in comparison to controls were as follows: 0.9 (95% CI 0.8–1.1) for any cardiac defect, 1.2 (95% CI 0.6–2.3) for aortic stenosis, 1.0 (95% CI 0.6–1.4) for coarctation of the aorta, 0.9 (95% CI 0.6–1.4) for hypoplastic left ventricle, 0.9 (95% CI 0.6–1.2) for transposition of the great arteries, and 1.0 (95% CI 0.8–1.2) for conotruncal defects. No dose–effect relationship was observed (76).
A 2003 case–control study was conducted to identify drug use in early pregnancy that was associated with cardiac defects (77). Cases (cardiovascular defects without known chromosome anomalies) were drawn from three Swedish health registers (N = 5015). Controls were all infants born in Sweden in 1995–2001 (N = 577,730). Associations were identified for several drugs, some of which were probably due to confounding from the underlying disease or complaint or multiple testing, but some were thought to be true drug effects. The total exposed, number of cases, and odds ratio (OR, 95% CI) for NSAIDs and aspirin were 7698, 80 cases, 1.24 (0.99–1.55) and 5920, 52 cases, 1.01 (0.76–1.33), respectively. These results demonstrated no association with cardiac defects (77).
In an FDA surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1709 newborns had been exposed to aspirin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 83 (4.9%) major birth defects were observed (73 expected). Specific data were available for six defect categories, including (observed/expected) 19/17 cardiovascular defects, 2/3 oral clefts, 0/1 spina bifida, 3/5 polydactyly, 1/3 limb reduction defects, and 6/4 hypospadias. These data do not support an association between the drug and the defects.
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 14,864 of whom used aspirin during the 1st trimester (6). For use anytime during pregnancy, 32,164 (64%) aspirin exposures were recorded. This prospective study did not find evidence of a teratogenic effect with aspirin. However, the data did not exclude the possibility that grossly excessive doses of aspirin may be teratogenic. An Australian study of 144 infants of mothers who took aspirin regularly in pregnancy also failed to find an association between salicylates and malformations (41). Based on these studies and the fact that aspirin usage in pregnancy is so common, it is not possible to determine the teratogenic risk of salicylates, if indeed it exists.
A 1996 case–control study of gastroschisis found a significantly elevated risk with ibuprofen (see Ibuprofen) and other medications and exposures (78). A significant association also was found for aspirin (N =7, OR 4.67, 95% CI 1.21–18.05). The data supported a vascular hypothesis for the pathogenesis of gastroschisis (78).
Full-dose aspirin has been reported to affect adversely the IQ of children exposed in utero during the first half of pregnancy (79). In a longitudinal prospective study of the effects of prenatal alcohol exposure on child health and development conducted between 1974 and 1975, drug histories were obtained from 1529 women during the 5th month of pregnancy. At birth, 421 children were selected for later follow-up based on a system of prebirth criteria. Of these, 192 (45.6%) had been exposed to aspirin during the first half of pregnancy. A significant and negative association was discovered between aspirin and child IQ and the children’s attentional decrements when they were examined at 4 years of age. The association was not changed after adjustment for a wide variety of potentially confounding covariates. Of interest, the data indicated that girls were significantly more affected than boys. The physical growth parameters, height, weight, and head circumference at 4 years of age, were not significantly related to maternal use of aspirin (79).
In a similar study, data were collected in 19,226 pregnancies by the Collaborative Perinatal Project; aspirin exposure during the first half of pregnancy was reported by 10,159 (52.8%) (80). In contrast to the earlier report, the mean child IQs at 4 years of age in the exposed and nonexposed groups were 98.3 and 96.1, respectively. Adjustment for multiple confounders reduced the difference between the groups to less than one point. No relationship between the amount of aspirin consumed and child IQ was found. The investigators concluded that an adverse effect of in utero aspirin exposure on child IQ was unlikely (80).
Women attempting to conceive should not use any NSAID, including aspirin, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (81,82). Moreover, as noted above, NSAIDs have been associated with SABs in humans (see Ibuprofen for additional studies).
A 2012 report from the National Birth Defects Prevention Study found associations between exposures to NSAIDs (aspirin, ibuprofen, and naproxen) and several birth defects (83). The data for this case–control study came from approximately 20,470 women with expected due dates in 1997–2004. Among this group, 3173 women (15.5%) were exposed to NSAIDs in the 1st trimester. Although the results suggested that NSAIDs are not a major cause of birth defects, the study did find several small-to-moderate but statistically significant increases in nine defects. The drug, adjusted OR and 95% CI for each defect were: anencephaly/craniorachischisis—aspirin (2.1; 1.1–4.3); spina bifida—ibuprofen (1.6; 1.2–2.1); encephalocele—naproxen (3.5; 1.2–10); anophthalmia/microphthalmia—aspirin (3.0; 1.3–7.3), ibuprofen 1.9; 1.1–3.3, and naproxen 2.8; 1.1–7.3); cleft lip ± cleft palate—ibuprofen (1.3; 1.1–1.6) and naproxen (1.7; 1.1–2.5); cleft palate—aspirin (1.8; 1.1–2.9); transverse limb deficiency—naproxen (2.0; 1.0–3.8); amniotic bands/limb body wall—aspirin (2.5; 1.1–5.6) and ibuprofen (2.2; 1.4–3.5); and a heart defect (isolated pulmonary valve stenosis)—naproxen (2.4; 1.3–4.5). The analysis of the latter defect was limited to term births only. The authors acknowledged that further studies were needed because most of these associations had not been reported from other databases (83).
BREASTFEEDING SUMMARY
Aspirin and other salicylates are excreted into breast milk in low concentrations. Sodium salicylate was first demonstrated in human milk in 1935 (84). In one study of a mother taking 4 g daily, no detectable salicylate in her milk or in her infant’s serum was found, but the test sensitivity was only 50 mcg/mL (85). Reported milk concentrations are much lower than this level. Following single or repeated oral doses, peak milk levels occurred at around 3 hours and ranged from 1.1 to 10 mcg/mL (86,87). This represented a milk:plasma ratio of 0.03–0.08 at 3 hours. Because salicylates are eliminated more slowly from milk than from plasma, the ratio increased to 0.34 at 12 hours (86). Peak levels have also been reported to occur at 9 hours (88). Only one report has attributed infant toxicity to salicylates obtained in mother’s milk (89). A 16-day-old female infant developed severe salicylate intoxication with a serum salicylate level of 24 mg/dL on the third hospital day. Milk and maternal serum aspirin levels were not obtained, but the mother was taking 650 mg every 4 hours. Although the parents denied giving the baby aspirin or other salicylates, it is unlikely, based on the above reports, that she could have received the drug from the milk in the quantities found (89).
Adverse effects on platelet function in the nursing infant exposed to aspirin via the milk have not been reported but are a potential risk. The American Academy of Pediatrics recommends that aspirin should be used cautiously by the mother during lactation because of potential adverse effects in the nursing infant (90).
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