Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen, during the 1st trimester appears to be a risk for structural anomalies and spontaneous abortions (SABs). The structural defects usually involve the heart, especially septal defects, but associations with oral clefts also have been reported. The absolute risk for these defects, however, appears to be low. When used in the 3rd trimester, NSAIDs have the potential to cause premature closure of the ductus arteriosus, which, in some cases, may result in primary pulmonary hypertension of the newborn (PPHN). In addition, the use of NSAIDs as tocolytics has been associated with an increased risk of neonatal complications, such as necrotizing enterocolitis, patent ductus arteriosus, and intraventricular hemorrhage (1), but further studies are required to confirm the magnitude of these toxicities. Because of the potential newborn toxicity, naproxen should not be used late in the 3rd trimester (1–3). Moreover, women attempting to conceive should not use any prostaglandin synthesis inhibitor, including naproxen, because of the findings in various animal models, indicating that these agents block blastocyst implantation (4,5).
Women who are pregnant or are at risk of pregnancy should be counseled on these risks. Such counseling is especially important because the use of NSAIDs during pregnancy, either prescribed or over the counter (OTC), is very common. One report stated that the use of ibuprofen in pregnancy occurred in 14.9% of the patients studied, 52% (45 of 86) of whom were exposed in the first trimester (6). NSAIDs available as OTC products in the United States include ibuprofen and naproxen, either as single-ingredient products or in decongestant/analgesic combinations. Thus, women might be exposed to NSAIDs at any time in gestation without realizing they are taking a drug with the potential for developmental toxicity.
FETAL RISK SUMMARY
Naproxen is an NSAID used in the management of the signs and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and juvenile arthritis. It is in the same subclass (propionic acids) as five other NSAIDs (fenoprofen, flurbiprofen, ibuprofen, ketoprofen, and oxaprozin). Drugs in this class have been shown to inhibit labor and to prolong the length of pregnancy (1,7).
Animal reproduction studies have been conducted in mice, rats, and rabbits. At 0.23–0.28 times, the human systemic exposure at the recommended dose, no evidence of impaired fertility or fetal harm was seen in these species (1). It was not stated if maternal toxicity prevented higher doses. A 1990 report described an investigation on the effects of several NSAIDs on mouse palatal fusion both in vivo and in vitro (8). The compounds, including naproxen, were found to induce cleft palate.
Consistent with the relatively low molecular weight (about 230), naproxen readily crosses the placenta to the fetal circulation. Twenty-eight women received two 500-mg naproxen doses, the first within 10.5–15 hours and the second within 4 hours of an elective 1st trimester pregnancy termination (9). Mean naproxen levels in maternal serum, fetal tissue, coelomic fluid, and amniotic fluid were 69.5, 6.4, 1.85, and 0.14 mcg/mL, respectively. The mean fetal:maternal drug ratio was 0.092 (9). In a woman at 30 weeks’ gestation treated with 250 mg of naproxen every 8 hours for four doses, plasma levels in twins 5 hours after the last dose were 59.5 and 68 mcg/mL (10).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1448 newborns had been exposed to naproxen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 70 (4.8%) major birth defects were observed (62 expected). Specific data were available for six defect categories, including (observed/expected) 14/14 cardiovascular defects, 2/2 oral clefts, 0/1 spina bifida, 3/4 polydactyly, 2/2 limb reduction defects, and 3/3 hypospadias. These data do not support an association between the drug and congenital defects.
A combined 2001 population-based, observational cohort study and a case–control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (2). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with SABs. A similar study, also published in 2001, failed to find a relationship, in general, between NSAIDs and congenital malformations but did find a significant association with cardiac defects and orofacial clefts (11). In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (12). (See Ibuprofen for details on these three studies.)
A brief 2003 editorial on the potential for NSAID-induced developmental toxicity concluded that NSAIDs, and specifically those with greater cyclooxygenase 2 (COX-2) affinity, had a lower risk of this toxicity in humans than aspirin (13).
A 2003 study using data from three Swedish health registers (1995–2001) that included maternal drug history collected prospectively identified 1142 infants with orofacial clefts (isolated or with other malformations, excluding chromosome anomalies) (14). Compared with the expected number (2.9) of orofacial clefts, there were eight naproxen-exposed cases, a relative risk of 2.72 (95% confidence interval [CI] 1.17–5.36).
A 2003 case–control study, using data from the same Swedish registers as the above study, was conducted to identify drug use in early pregnancy that was associated with cardiac defects (15). Cases (cardiovascular defects without known chromosome anomalies) (N = 5015) were compared with controls consisting of all infants born in Sweden from 1995 to 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. For NSAIDs, the total exposed, number of cases, and odds ratios (ORs) with 95% CI were NSAIDs (all) (7698; 80 cases; 1.24, 0.99–1.55), naproxen (1679; 24 cases; 1.70, 1.14–2.54), diclofenac (1362; 15 cases; 1.30, 0.78–2.16), ibuprofen (4124; 37 cases; 1.08, 0.78–1.50), and aspirin (5920; 52 cases; 1.01, 0.76–1.33). Five of the defects observed with naproxen were two infants with transposition of the great vessels and three with endocardial cushion defects (one infant had both defects). The authors noted that further studies were needed to verify or reject the hypothesis (15).
A 2004 case report described a 24-year-old woman who took naproxen (550 mg about twice a week), bisoprolol (5 mg/day), and sumatriptan (100 mg about once a week) for migraine headaches during the first 5 weeks of pregnancy (16). An elective cesarean section was performed at 37 weeks’ for breech presentation to deliver a 3125-g male infant. The infant had a wide bilateral cleft lip/palate, marked hypertelorism, a broad nose, and bilateral but asymmetric toe abnormalities (missing and hypoplastic phalanges) (16).
A 2006 case–control study found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the 1st trimester (17). A population-based pregnancy registry (N = 36,387) was developed by linking three databases in Quebec. The combined database covered all of the pregnancies that occurred in Quebec from January 1997 through June 2003. Inclusion criteria were mothers of singleton infants, 15–45 years of age, who were prescribed an NSAID or other medications during pregnancy. The use of OTC NSAIDs was a potential confounder but the investigators provided reasonable arguments that such exposure was unlikely. The data were adjusted for chronic comorbidities, including rheumatoid arthritis and disease-modifying anti-rheumatic drugs, hypothyroidism and thyroid drugs, and chronic or gestational hypertension. Adjustment also was made for 1st trimester use of known human teratogens (17).
Case infants were those with any congenital anomaly diagnosed in the first year of life (17). Up to 10 controls (infants without a congenital anomaly) were selected for each case and matched with cases for maternal age, urban or rural residence, gestational age, and diabetes status. There were 93 infants (8.8%) with congenital defects from 1056 mothers who had filled prescriptions for NSAIDs in the 1st trimester. In controls, there were 2478 infants (7%) with anomalies from 35,331 mothers who had not filled such a prescription. The adjusted OR (aOR) was 2.21 (95% CI 1.72–2.85). The aOR for cardiac septal closure was 3.34 (95% CI 1.87–5.98). There also was a significant association for anomalies of the respiratory system 9.55 (95% CI 3.08–29.63), but this association disappeared when cases coded as “unspecified anomaly of the respiratory system” were excluded. For the cases involving septal closure, 61% were atrial septal defects and 31% were ventricular septal defects. There were no significant associations for oral clefts or defects involving other major organ systems. The five most common NSAIDs were naproxen (35%), ibuprofen (26%), rofecoxib (15%), diclofenac (9%), and celecoxib (9%). Among these agents, the only significant association was for ibuprofen prescriptions in the 1st trimester and congenital defects (p <0.01) (17).
Prostaglandin synthesis inhibitors may cause constriction of the ductus arteriosus in utero, which may result in PPHN (18–22). The dose, duration, and period of gestation are important determinants of these effects. Most studies of NSAIDs used as tocolytics have indicated that the fetus is relatively resistant to premature closure of the ductus before the 34th or 35th week of gestation (see Indomethacin). However, three fetuses (one set of twins) exposed to naproxen at 30 weeks for 2–6 days in an unsuccessful attempt to halt premature labor had markedly decreased plasma concentrations of prostaglandin E. PPHN with severe hypoxemia, increased blood clotting times, hyperbilirubinemia, and impaired renal function were observed in the newborns. One infant died 4 days after birth, probably because of subarachnoid hemorrhage. Autopsy revealed a short and constricted ductus arteriosus. Use in other patients for premature labor at 34 weeks or earlier has not resulted in neonatal problems (23,24).
In a case report published in 2000, a mother took an OTC preparation of naproxen 220 mg twice a day over the 4 days immediately preceding birth of a term 3790-g male infant (25). Within 2 hours of birth, the infant developed typical signs and symptoms of PPHN with a closed ductus arteriosus. Conservative management was initiated and the infant was improving by the sixth postnatal day. At 6 weeks of age, the infant was doing well clinically without cyanosis (25).
A 2012 report from the National Birth Defects Prevention Study found associations between exposures to NSAIDs (aspirin, ibuprofen, and naproxen) and several birth defects (26). 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, aOR, 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 (26).
BREASTFEEDING SUMMARY
Naproxen passes into breast milk in very small quantities. The milk:plasma ratio is approximately 0.01 (1). Following 250 or 375 mg twice daily, maximum milk levels were found 4 hours after a dose and ranged from 0.7 to 1.25 mcg/mL and 1.76 to 2.37 mcg/mL, respectively (27,28). The total amount of naproxen excreted in the infant’s urine was 0.26% of the mother’s dose. The effect on the infant from these amounts is unknown.
The American Academy of Pediatrics classifies naproxen as compatible with breastfeeding (29).
References
1.Product information. Naprosyn. Roche Laboratories, 2000.
2.Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population-based observational study and case-control study. Br Med J 2001;322:266–70.
3.Anonymous. PG-synthetase inhibitors in obstetrics and after. Lancet 1980;2:185–6.
4.Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, ed. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995: 175–93.
5.Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
6.Glover DD, Amonkar M, Rybeck BF, Tracy TS. Prescription, over-the-counter, and herbal medicine use in a rural, obstetric population. Am J Obstet Gynecol 2003;188:1039–45.
7.Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20.
8.Montenegro MA, Palomino H. Induction of cleft palate in mice by inhibitors of prostaglandin synthesis. J Craniofac Genet Del Biol 1990;10:83–94.
9.Siu SSN, Yeung JHK, Lau TK. An in-vivo study on placental transfer of naproxen in early human pregnancy. Hum Reprod 2002;17:1056–9.
10.Wilkinson AR. Naproxen levels in preterm infants after maternal treatment. Lancet 1980;2:591–2.
11.Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.
12.Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. Br Med J 2003;327:368–71.
13.Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res B Dev Reprod Toxicol 2003;68:3–4.
14.Kallen B. Maternal drug use and infant cleft lip/palate with special reference to corticoids. Cleft Palate Craniofac J 2003;40:624–8.
15.Kallen BAJ, Olausson PO. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 2003;17:255–61.
16.Kajantie E, Somer M. Bilateral cleft lip and palate, hypertelorism and hypoplastic toes. Clin Dysmorphol 2004;13:195–6.
17.Ofori B, Oraichi D, Blais L, Rey E, Bérard A. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol 2006;77:268–79.
18.Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
19.Rudolph AM. The effects of nonsteroidal antiinflammatory compounds on fetal circulation and pulmonary function. Obstet Gynecol 1981;58(Suppl):63s–7s.
20.Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658–63.
21.Wilkinson AR, Aynsley-Green A, Mitchell MD. Persistent pulmonary hypertension and abnormal prostaglandin E levels in preterm infants after maternal treatment with naproxen. Arch Dis Child 1979;54:942–5.
22.Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001;107:519–23.
23.Gerris J, Jonckheer M, Sacre-Smits L. Acute hyperthyroidism during pregnancy: a case report and critical analysis. Eur J Obstet Gynecol Reprod Biol 1981;12:271–80.
24.Wiqvist N, Kjellmer I, Thiringer K, Ivarsson E, Karlsson K. Treatment of premature labor by prostaglandin synthetase inhibitors. Acta Biol Med Germ 1978;37:923–30.
25.Talati AJ, Salim MA, Korones SB. Persistent pulmonary hypertension after maternal naproxen ingestion in a term newborn: a case report. Am J Perinatol 2000;17:69–71.
26.Hernandez RK, Werler MM, Romitti P, Sun L, Anderka M, National Birth Defects Prevention Study. Nonsteroidal antiinflammatory drug use among women and the risk of birth defects. Am J Obstet Gynecol 2012;206:228.e1–8.
27.Jamali F, Tam YK, Stevens RD. Naproxen excretion in breast milk and its uptake by suckling infant (abstract). Drug Intell Clin Pharm 1982;16:475.
28.Jamali F, Stevens DRS. Naproxen excretion in milk and its uptake by the infant. Drug Intell Clin Pharm 1983;17:910–11.
29.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.