Risk Factor: C*
Class: Central nervous system drugs/ Nonsteroidal anti-inflammatory drugs
Fetal Risk Summary
Aspirin 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%) (2,3,4,5,6,7,8 and 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 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 (5,11,12,13 and 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 b-mimetics, has been used to treat premature labor (17,18 and 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 antiinflammatory 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
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 (22,23,24 and 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., 40150 mg/day) on the prevention of pregnancy-induced hypertension (PIH), preeclampsia, and eclampsia, and the associated fetal risks of intrauterine growth retardation and mortality (26,27,28,29,30,31,32,33,34,35,36,37 and 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 cyclo-oxygenase, resulting in a greater inhibition of thromboxane A2 synthesis than 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, 6080 mg of aspirin/day, starting 3 weeks before delivery and continuing until birth, inhibited maternal platelet cyclo-oxygenase, but not that of the newborn. These results were in agreement with other studies using 60150 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 pregnancy-induced hypertension were randomly assigned to either an aspirin (N=17) or 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 weeks vs. 35 weeks, p
Fetal and newborn effects, other than congenital defects, from aspirin exposure in utero, may include increased perinatal mortality, intrauterine growth retardation, congenital salicylate intoxication, and depressed albumin-binding capacity (2,5,12,41,42 and 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 2530 mg/dL 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 2nd 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.
Aspirin given in doses of 325650 mg during the week before delivery may affect the clotting ability of the newborn (48,49,50,51,52,53 and 54). In the initial study by Bleyer and Breckenridge (48), 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 (54). The use of salicylates other than aspirin may not be a problem because the acetyl moiety is apparently required to depress platelet function (55,56 and 57). 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 610 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 (58). Computed tomographic screening for ICH was conducted on 108 infants 37 days after delivery. All of the infants were either 34 weeks or less in gestation or 1500 g or less 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 (p
Aspirin readily crosses the placenta (10). When given near term, higher concentrations are found in the neonate than in the mother (61). The kinetics of salicylate elimination in the newborn have been studied (61,62 and 63).
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 1,291 malformed infants were found to have consumed aspirin during pregnancy more frequently than mothers of normal infants (64,65). 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 (66). 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 (67,68 and 69). 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 (70). The risk for defects in septation of the truncus arteriosus was increased about 2-fold 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 1,254 mothers of control infants (71). 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 (71). A brief review of this and other investigations that have examined the relationship between aspirin and congenital heart disease was published in 1985 (72). 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 (73). 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) (73). The data, from the Slone Epidemiology Unit Birth Defects Study, involved 1,381 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 6,966 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 (73). After adjustment for potentially confounding factors, the relative risks for the defects among aspirin users in comparison to controls were: 0.9 (95% confidence interval [CI] 0.8 1.1) for any cardiac defect, 1.2 (95% CI 0.62.3) for aortic stenosis, 1.0 (95% CI 0.61.4) for coarctation of the aorta, 0.9 (95% CI 0.61.4) for hypoplastic left ventricle, 0.9 (95% CI 0.61.2) for transposition of the great arteries, and 1.0 (95% CI 0.81.2) for conotruncal defects. No dose-effect relationship was observed.
In an FDA surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1,709 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.
Full-dose aspirin has been reported to affect adversely the intelligence quotient (IQ) of children exposed in utero during the first half of pregnancy (74). 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 1,529 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 (74). The physical growth parameters, height, weight, and head circumference at 4 years of age, were not significantly related to maternal use of aspirin.
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%) (75). 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 (p
In 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 retardation, 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 pregnancy-induced hypertension and preeclampsia, and in fetuses with intrauterine growth retardation, low-dose aspirin (40150 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. If an analgesic or antipyretic is needed, acetaminophen should be considered.
[*Risk Factor D if full-dose aspirin used in 3rd trimester.]
Breast Feeding Summary
Aspirin and other salicylates are excreted into breast milk in low concentrations. Sodium salicylate was first demonstrated in human milk in 1935 (76). 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 g/mL (77). 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 1.110 g/mL (78,79). 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 (79). Peak levels have also been reported to occur at 9 hours (80). Only one report has attributed infant toxicity to salicylates obtained in mothers milk (81). A 16-day-old female infant developed severe salicylate intoxication with a serum salicylate level of 24 mg/dL on the 3rd hospital day. Milk and maternal serum levels were not obtained. 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.
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 (82).
- Corby DG. Aspirin in pregnancy: maternal and fetal effects. Pediatrics 1978;62(Suppl):9307.
- Palmisano PA, Cassady G. Salicylate exposure in the perinate. JAMA 1969;209:5568.
- Forfar JO, Nelson MM. Epidemiology of drugs taken by pregnant women: drugs that may affect the fetus adversely. Clin Pharmacol Ther 1973;14:63242.
- Finnigan D, Burry AF, Smith IDB. Analgesic consumption in an antenatal clinic survey. Med J Aust 1974;1:7612.
- Collins E, Turner G. Maternal effects of regular salicylate ingestion in pregnancy. Lancet 1975;2:3357.
- Slone D, Heinonen OP, Kaufman DW, Siskind V, Monson RR, Shapiro S. Aspirin and congenital malformations. Lancet 1976;1:13735.
- Hill RM, Craig JP, Chaney MD, Tennyson LM, McCulley LB. Utilization of over-the-counter drugs during pregnancy. Clin Obstet Gynecol 1977;20:38194.
- Harrison K, Thomas I, Smith I. Analgesic use during pregnancy. Med J Aust 1978;2:161.
- Bodendorfer TW, Briggs GG, Gunning JE. Obtaining drug exposure histories during pregnancy. Am J Obstet Gynecol 1979;135:4904.
- Jackson AV. Toxic effects of salicylate on the foetus and mother. J Pathol Bacteriol 1948;60:58793.
- Lewis RN, Schulman JD. Influence of acetylsalicylic acid, an inhibitor of prostaglandin synthesis, on the duration of human gestation and labour. Lancet 1973;2:115961.
- Rudolph AM. Effects of aspirin and acetaminophen in pregnancy and in the newborn. Arch Intern Med 1981;141:358-63.
- Stuart MJ, Gross SJ, Elrad H, Graeber JE. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis. N Engl J Med 1982;307:90912.
- Stuart MJ. Aspirin and maternal or neonatal hemostasis. N Engl J Med 1983;308:281.
- Niebyl JR, Blake DA, Burnett LS, King TM. The influence of aspirin on the course of induced midtrimester abortion. Am J Obstet Gynecol 1976;124:60710.
- Castellanos JM, Aranda M, Cararach J, Cararach V. Effect of aspirin on oestriol excretion in pregnancy. Lancet 1975;1:859.
- Babenerd VJ, Kyriakidis K. Acetylsalicylic acid in the prevention of premature delivery. Fortschr Med 1979;97:4636.
- Wolff F, Bolte A, Berg R. Does an additional administration of acetylsalicylic acid reduce the requirement of betamimetics in tocolytic treatment? Geburtshilfe Frauenheilkd 1981;41:2936.
- Wolff F, Berg R, Bolte A. Clinical study of the labour inhibiting effects and side effects of acetylsalicylic acid (ASA). Geburtshilfe Frauenheilkd 1981;41:96100.
- Buhler M, Papiernik E. Successive pregnancies in women fitted with intrauterine devices who take antiinflammatory drugs. Lancet 1983;1:483.
- Goodlin RC. Correction of pregnancy-related thrombocytopenia with aspirin without improvement in fetal outcome. Am J Obstet Gynecol 1983;146:8624.
- Gant NF. Lupus erythematosus, the lupus anticoagulant, and the anticardiolipid antibody. Supplement No. 6, May/June 1986, to Pritchard JA, MacDonald PC, Gant NF. Williams Obstetrics. 17th ed. Norwalk, CT:Appleton-Century-Crofts, 1985.
- Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med 1985;313:13226.
- Elder MG, DeSwiet M, Robertson A, Elder MA, Flloyd E, Hawkins DF. Low-dose aspirin in pregnancy. Lancet 1988;1:410.
- Lockshin MD, Druzin ML, Qamar T. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gynecol 1989;160:43943.
- Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet 1985;1:8402.
- Beaufils M, Uzan S, Donsimoni R, Colau JC. Prospective controlled study of early antiplatelet therapy in prevention of preeclampsia. Adv Nephrol 1986;15:8794.
- Ylikorkala O, Makila U-M, Kaapa P, Viinikka L. Maternal ingestion of acetylsalicylic acid inhibits fetal and neonatal prostacyclin and thromboxane in humans. Am J Obstet Gynecol 1986;155:3459.
- Spitz B, Magness RR, Cox SM, Brown CEL, Rosenfeld CR, Gant NF. Low-dose aspirin. I. Effect on angiotensin II pressor responses and blood prostaglandin concentrations in pregnant women sensitive to angiotensin II. Am J Obstet Gynecol 1988;159:103543.
- Wallenburg HCS, Rotmans N. Prevention of recurrent idiopathic fetal growth retardation by low-dose aspirin and dipyridamole. Am J Obstet Gynecol 1987;157:12305.
- Wallenburg HCS, Rotmans N. Prophylactic low-dose aspirin and dipyridamole in pregnancy. Lancet 1988;1:939.
- Uzan S, Beaufils M, Bazin B, Danays T. Idiopathic recurrent fetal growth retardation and aspirin-dipyridamole therapy. Am J Obstet Gynecol 1989;160:763.
- Wallenburg HCS, Rotmans N. Idiopathic recurrent fetal growth retardation and aspirin-dipyridamole therapy. Reply. Am J Obstet Gynecol 1989;160:7634.
- Sibai BM, Mirro R, Chesney CM, Leffler C. Low-dose aspirin in pregnancy. Obstet Gynecol 1989;74:5517.
- Trudinger B, Cook CM, Thompson R, Giles W, Connelly A. Low-dose aspirin improves fetal weight in umbilical placental insufficiency. Lancet 1988;2:2145.
- Romero R, Lockwood C, Oyarzun E, Hobbins JC. Toxemia: new concepts in an old disease. Semin Perinatol 1988;12:30223.
- Lubbe WF. Low-dose aspirin in prevention of toxaemia of pregnancy. Does it have a place? Drugs 1987;34:5158.
- Wallenburg HCS, Dekker GA, Makovitz JW, Rotmans P. Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotensin-sensitive primigravidae. Lancet 1986;1:13.
- Benigni A, Gregorini G, Frusca T, Chiabrando C, Ballerini S, Valcamonico A, Orisio S, Piccinelli A, Pinciroli V, Fanelli R, Gastaldi A, Remuzzi G. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med 1989;321:35762.
- Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E, Tamarkin M, Barkai G, Ben-Baruch G, Yahal I, Blankstein J, Goldman B, Mashiach S. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. N Engl J Med 1989;321:3516.
- Turner G, Collins E. Fetal effects of regular salicylate ingestion in pregnancy. Lancet 1975;2:3389.
- Earle R Jr. Congenital salicylate intoxication-report of a case. N Engl J Med 1961;265:10034.
- Lynd PA, Andreasen AC, Wyatt RJ. Intrauterine salicylate intoxication in a newborn. A case report. Clin Pediatr (Phila) 1976;15:9123.
- Shapiro S, Monson RR, Kaufman DW, Siskind V, Heinonen OP, Slone D. Perinatal mortality and birth-weight in relation to aspirin taken during pregnancy. Lancet 1976;1:13756.
- Arcilla RA, Thilenius OG, Ranniger K. Congestive heart failure from suspected ductal closure in utero. J Pediatr 1969;75:748.
- Collins E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstet Gynecol 1981;58(Suppl):57S62S.
- Aterman K, Holzbecker M, Ellenberger HA. Salicylate levels in a stillborn infant born to a drug-addicted mother, with comments on pathology and analytical methodology. Clin Toxicol 1980;16: 2638.
- Bleyer WA, Breckenridge RJ. Studies on the detection of adverse drug reactions in the newborn. II. The effects of prenatal aspirin on newborn hemostasis. JAMA 1970;213:204953.
- Corby DG, Schulman I. The effects of antenatal drug administration on aggregation of platelets of newborn infants. J Pediatr 1971;79:30713.
- Casteels-Van Daele M, Eggermont E, de Gaetano G, Vermijlen J. More on the effects of antenatally administered aspirin on aggregation of platelets of neonates. J Pediatr 1972;80:6856.
- Haslam RR, Ekert H, Gillam GL. Hemorrhage in a neonate possible due to maternal ingestion of salicylate. J Pediatr 1974;84:5567.
- Ekert H, Haslam RR. Maternal ingested salicylate as a cause of neonatal hemorrhage. Reply. J Pediatr 1974;85:738.
- Pearson H. Comparative effects of aspirin and acetaminophen on hemostasis. Pediatrics 1978;62(Suppl):9269.
- Haslam RR. Neonatal purpura secondary to maternal salicylism. J Pediatr 1975;86:653.
- O’Brien JR. Effects of salicylates on human platelets. Lancet 1968;1:77983.
- Weiss HJ, Aledort ML, Shaul I. The effect of salicylates on the haemostatic properties of platelets in man. J Clin Invest 1968;47:216980.
- Bleyer WA. Maternal ingested salicylates as a cause of neonatal hemorrhage. J Pediatr 1974;85:7367.
- Rumack CM, Guggenheim MA, Rumack BH, Peterson RG, Johnson ML, Braithwaite WR. Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet Gynecol 1981;58(Suppl):52S-6S.
- Soller RW, Stander H. Maternal drug exposure and perinatal intracranial hemorrhage. Obstet Gynecol 1981;58:7357.
- Corby DG. Editorial comment. Obstet Gynecol 1981;58:73740.
- Levy G, Procknal JA, Garrettson LK. Distribution of salicylate between neonatal and maternal serum at diffusion equilibrium. Clin Pharmacol Ther 1975;18:2104.
- Levy G, Garrettson LK. Kinetics of salicylate elimination by newborn infants of mothers who ingested aspirin before delivery. Pediatrics 1974;53:20110.
- Garrettson LK, Procknal JA, Levy G. Fetal acquisition and neonatal elimination of a large amount of salicylate. Study of a neonate whose mother regularly took therapeutic doses of aspirin during pregnancy. Clin Pharmacol Ther 1975;17:98103.
- Richards ID. Congenital malformations and environmental influences in pregnancy. Br J Prev Soc Med 1969;23:21825.
- Nelson MM, Forfar JO. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. Br Med J 1971;1:5237.
- Saxen I. Associations between oral clefts and drugs during pregnancy. Int J Epidemiol 1975;4:37 44.
- Benawra R, Mangurten HH, Duffell DR. Cyclopia and other anomalies following maternal ingestion of salicylates. J Pediatr 1980;96:106971.
- McNiel JR. The possible effect of salicylates on the developing fetus. Brief summaries of eight suggestive cases. Clin Pediatr (Phila) 1973;12:34750.
- Sayli BS, Asmaz A, Yemisci B. Consanguinity, aspirin, and phocomelia. Lancet 1966;1:876.
- Zierler S, Rothman KJ. Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy. N Engl J Med 1985;313:34752.
- Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109:4339.
- Zierler S. Maternal drugs and congenital heart disease. Obstet Gynecol 1985;65:15565.
- Werler MM, Mitchell AA, Shapiro S. The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects. N Engl J Med