TRIMETHOPRIM

Fetal Risk Summary

Trimethoprim is available as a single agent and in combination with various sulfonamides (see also Sulfonamides). Because trimethoprim is a folate antagonist, caution has been advocated for its use in pregnancy (1,2 and 3). Published case reports and placebo-controlled trials involving several hundred patients, during all phases of gestation, have failed to demonstrate an increase in fetal abnormalities (4,5,6,7,8,9,10,11,12 and 13). However, other reports (14,15,16 and 17) and the unpublished data cited below are suggestive that trimethoprim use during the 1st trimester may result in structural defects. Maternal supplementation with multivitamins that contain folic acid may reduce this risk (16).

Trimethoprim (200 mg/kg) given to pregnant rats resulted in cleft palates (18). The no-effect dose was 192 mg/kg. When trimethoprim (88 mg/kg) was combined with sulfamethoxazole (355 mg/kg), cleft palates were observed in one litter out of nine. In two other rat studies, however, no teratogenic effects were seen at a combined dose of 128 and 512 mg/kg, respectively. In some studies with pregnant rabbits, a trimethoprim dose 6 times the human therapeutic dose was associated with resorptions, fetal death, and malformations (18).

Trimethoprim (molecular weight about 290) crosses the placenta, producing similar levels in fetal and maternal serum and in amniotic fluid (19,20 and 21). Using an in vitro perfused human cotyledon, both trimethoprim and sulfamethoxazole were shown to cross the placenta (22). After 1 hour in a closed system at maternal trimethoprim concentrations of 7.2 and 1.0 µg/mL, concentrations on the fetal side were 1.4 (19%) and 0.08 µg/mL (8%), respectively. Under similar conditions, maternal sulfamethoxazole levels of 29.6, 112.6, and 127.7 µg/mL produced fetal levels of 5.1 (17%), 9.6 (9%), and 14.8 µg/mL (12%). (Note: The mean steady state serum levels following 160 mg/800 mg trimethoprim/sulfamethoxazole orally twice daily are 1.72 and 68 µg/mL, respectively [18].) A 27-year-old woman consumed a low-calorie (Nutra System) diet 10 months before conception through the 4th gestational week (14). Her pregnancy was complicated by otitis, treated with a combination of trimethoprim-sulfamethoxazole for 10 days beginning in the 3rd week, and the onset of hyperemesis gravidarum at 5–6 weeks' gestation that lasted until the 8th month. Dimenhydrinate was taken intermittently as an antiemetic from the 7th week through the 8th month. She gave birth at 38 weeks' gestation to a 3225-g, female infant with a lobar holoprosencephaly. The malformations included a median cleft lip and palate, a flat nose without nostrils, hypoplasia of the optic discs, and a single ventricle and midline fused thalami. The infant developed progressive hydrocephalus, myoclonic jerks, intractable seizures, and muscle tone that changed from hypotonic to hypertonic at 2 months of age (14). Although the critical period for development of holoprosencephaly was thought to be during the period of gastrulation (i.e., the 3rd week of pregnancy), the cause of the defects was unknown (14).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 2,296 newborns had been exposed to the combination of trimethoprim-sulfamethoxazole during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 126 (5.5%) major birth defects were observed (98 expected). This incidence is suggestive of an association between the drug combination and congenital defects. Specific data were available for six defect categories, including (observed/expected) 37/23 cardiovascular defects, 3/4 oral clefts, 1/1 spina bifida, 7/7 polydactyly, 3/4 limb-reduction defects, and 7/5 hypospadias. Only the cardiovascular defects are suggestive of an association among the six specific malformations, but other factors such as the mother's disease, concurrent drug use, and chance may be involved.

A 2000 case report described the adverse pregnancy outcomes, including neural tube defects (NTDs), of two pregnant women with human immunodeficiency virus (HIV) infection who were treated with the anti-infective combination trimethoprim/sulfamethoxazole for prophylaxis against Pneumocystsis carinii, concurrently with antiretroviral agents (15). In the first case, a 32-year-old woman with a 3-year history of HIV and recent diagnosis of acquired immunodeficiency syndrome was treated before and throughout gestation with the antiinfective combination plus zidovudine and zalcitabine. Folic acid 10 mg/day was added after the diagnosis of pregnancy (gestational age not specified). At term, a female infant was delivered by cesarean section without HIV infection, but with a bony mass in the lumbar spine (identified by ultrasound at 32 weeks' gestation). A diagnostic evaluation revealed that the second lumbar vertebra consisted of hemivertebrae and projected posteriorly into the spinal canal. A slightly malformed and displaced first lumbar vertebra was also noted. Surgery was planned to correct the defect. The second case involved a 31-year-old woman who presented at 15 weeks' gestation (15). She was receiving trimethoprim/sulfamethoxazole, didanosine, stavudine, nevirapine, and vitamin B supplements (specific vitamins and dosage not given) that had been started before conception. A fetal ultrasound at 19 weeks' gestation revealed spina bifida and ventriculomegaly. The patient elected to terminate her pregnancy. The fetus did not have HIV infection. Defects observed at autopsy included ventriculomegaly, an Arnold-Chiari malformation, sacral spina bifida, and a lumbosacral meningomyelocele. The authors attributed the NTDs in both cases to the antifolate activity of trimethoprim (15).

The effects of exposure (at any time during the 2nd or 3rd month after the last menstrual period) to folic acid antagonists on embryo/fetal development were evaluated in a large, multicenter, case-control surveillance study published in 2000 (16). The report was based on data collected between 1976 and 1998 by the Slone Epidemiology Unit Birth Defects Study from 80 maternity or tertiary care hospitals in Boston, Philadelphia, Toronto, and Iowa. Mothers were interviewed within 6 months of delivery about their use of drugs during pregnancy. Folic acid antagonists were categorized into two groups: group I—dihydrofolate reductase inhibitors (aminopterin, methotrexate, sulfasalazine, pyrimethamine, triamterene, and trimethoprim); group II—agents that affect other enzymes in folate metabolism, impair the absorption of folate, or increase the metabolic breakdown of folate (carbamazepine, phenytoin, primidone, and phenobarbital) (16). The case subjects were 3,870 infants with cardiovascular defects, 1,962 with oral clefts, and 1,100 with urinary tract malformations. Infants with defects associated with a syndrome were excluded, as were infants with coexisting neural tube defects (NTDs; known to be reduced by maternal folic acid supplementation). Too few infants with limb-reduction defects were identified to be analyzed. Controls (N=8,387) were infants with malformations other than oral clefts and cardiovascular, urinary tract, and limb-reduction defects and NTDs, but included infants with chromosomal and genetic defects. The risk of malformations in control infants would not have been reduced by vitamin supplementation, and none of the controls used folic acid antagonists (16). For group I cases, the relative risks (RRs) of cardiovascular defects and oral clefts were 3.4 (95% confidence interval [CI] 1.8–6.4) and 2.6 (95% CI 1.1–6.1), respectively. For group II cases, the RRs of cardiovascular and urinary tract defects, and oral clefts were 2.2 (95% CI 1.4–3.5), 2.5 (95% CI 1.2–5.0), and 2.5 (95% CI 1.5–4.2), respectively. Maternal use of multivitamin supplements reduced the risks in group I cases, but not in group II cases (16).

Additional data related to the above study appeared in a reply to correspondence (17). Analysis for trimethoprim exposure resulted in a RR of 4.2 (95% CI 1.5–11.5) for cardiovascular defects based on 12 cases. Additional analysis for oral clefts (three cases) and urinary tract defects (one case) was not conducted because of the small number of exposures (17).

A case of Niikawa-Kuroki syndrome (i.e., Kabuki make-up syndrome) has been described in a non-Japanese girl whose mother had a viral and bacterial infection during the 2nd month of pregnancy (23). The bacterial infection was treated with trimethoprim-sulfamethoxazole. The syndrome is characterized by mental and growth retardation and craniofacial malformations (23). The cause of the defects in this patient, as in all cases of this syndrome, was unknown. Some have speculated, however, that the syndrome is caused by autosomal dominant inheritance (24).

Sulfonamide-trimethoprim combinations have been shown to cause a drop in the sperm count after 1 month of continuous treatment in males (25). Decreases varied between 7% and 88%. The authors theorized that trimethoprim deprived the spermatogenetic cells of active folate by inhibiting dihydrofolate reductase.

No interaction between trimethoprim-sulfamethoxazole and oral contraceptives was found in one study (26). Short courses of the anti-infective combination are unlikely to affect contraceptive control.

Breast Feeding Summary

Trimethoprim is excreted into breast milk in low concentrations. Following 160 mg twice daily for 5 days, milk concentrations varied between 1.2 and 2.4 µg/mL (average 1.8 µg/mL) with peak levels occurring at 2–3 hours (27). No adverse effects were reported in the infants. Nearly identical results were found in a study with 50 patients (28). Mean milk levels were 2.0 µg/mL, representing a milk:plasma ratio of 1.25. The authors concluded that these levels represented a negligible risk to the suckling infant. The American Academy of Pediatrics considers the combination of trimethoprim-sulfamethoxazole to be compatible with breast feeding (29).

References

1. McEwen LM. Trimethoprim/sulphamethoxazole mixture in pregnancy. Br Med J 1971;4:490–1.
2. Smithells RW. Co-trimoxazole in pregnancy. Lancet 1983;2:1142.
3. Tan JS, File TM Jr. Treatment of bacteriuria in pregnancy. Drugs 1992;44:972–80.
4. Williams JD, Condie AP, Brumfitt W, Reeves DS. The treatment of bacteriuria in pregnant women with sulphamethoxazole and trimethoprim. Postgrad Med J 1969;45(Suppl):71–6.
5. Ochoa AG. Trimethoprim and sulfamethoxazole in pregnancy. JAMA 1971;217:1244.
6. Brumfitt W, Pursell R. Double-blind trial to compare ampicillin, cephalexin, co-trimoxazole, and trimethoprim in treatment of urinary infection. Br Med J 1972;2:673–6.
7. Brumfitt W, Pursell R. Trimethoprim/sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis 1973;128(Suppl):S657–S63.
8. Brumfitt W, Pursell R. Trimethoprim/sulfamethoxazole in the treatment of urinary infection. Med J Aust 1973;1(Suppl):44–8.
9. Bailey RR. Single-dose antibacterial treatment for bacteriuria in pregnancy. Drugs 1984;27:183–6.
10. Soper DE, Merrill-Nach S. Successful therapy of penicillinase-producing Neisseria gonorrhoeae pharyngeal infection during pregnancy. Obstet Gynecol 1986;68:290–1.
11. Cruikshank DP, Warenski JC. First-trimester maternal Listeria monocytogenes sepsis and chorioamnionitis with normal neonatal outcome. Obstet Gynecol 1989;73:469–71.
12. Seoud M, Saade G, Awar G, Uwaydah M. Brucellosis in pregnancy. J Reprod Med 1991;36:441–5.
13. Frederiksen B. Maternal septicemia with Listeria monocytogenes in second trimester without infection of the fetus. Acta Obstet Gynecol Scand 1992;71:313–5.
14. Ronen GM. Holoprosencephaly and maternal low-calorie weight-reducing diet. Am J Med Genet 1992;42:139.
15. Richardson MP, Osrin D, Donaghy S, Brown NA, Hay, Sharland M. Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole. Eur J Obstet Gynecol Reprod Biol 2000;93:215–7.
16. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608–14.
17. Hernandez-Diaz S, Mitchell AA. Folic acid antagonists during pregnancy and risk of birth defects. N Engl J Med 2001;344:934–5.
18. Product information. Septra. Monarch Pharmaceuticals, 2001.
19. Ylikorkala O, Sjostedt E, Jarvinen PA, Tikkanen R, Raines T. Trimethoprim-sulfonamide combination administered orally and intravaginally in the 1st trimester of pregnancy: its absorption into serum and transfer to amniotic fluid. Acta Obstet Gynecol Scand 1973;52:229–34.
20. Reid DWJ, Caille G, Kaufmann NR. Maternal and transplacental kinetics of trimethoprim and sulfamethoxazole, separately and in combination. Can Med Assoc J 1975;112:67s–72s.
21. Reeves DS, Wilkinson PJ. The pharmacokinetics of trimethoprim and trimethoprim/sulfonamide combinations, including penetration into body tissues. Infection 1979;7(Suppl 4):S330–41.
22. Bawdon RE, Maberry MC, Fortunato SJ, Gilstrap LC, Kim S. Trimethoprim and sulfamethoxazole transfer in the in vitro perfused human cotyledon. Gynecol Obstet Invest 1991;31:240–2.
23. Koutras A, Fisher S. Niikawa-Kuroki syndrome: a new malformation syndrome of postnatal dwarfism, mental retardation, unusual face, and protruding ears. J Pediatr 1982;101:417–9.
24. Niikawa N. Kabuki make-up syndrome. In Buyse ML, Editor-in-Chief. Birth Defects Encyclopedia. Volume 2. Dover, MA: Center for Birth Defects Information Services, 1990:998–9.
25. Murdia A, Mathur V, Kothari LK, Singh KP. Sulpha-trimethoprim combinations and male fertility. Lancet 1978;2:375–6.
26. Grimmer SFM, Allen WL, Back DJ, Breckenridge AM, Orme M, Tjia J. The effect of cotrimoxazole on oral contraceptive steroids in women. Contraception 1983;28:53–9.
27. Arnauld R, Soutoul JH, Gallier J, Borderon JC, Borderon E. A study of the passage of trimethoprim into the maternal milk. Quest Med 1972;25:959–64.
28. Miller RD, Salter AJ. The passage of trimethoprim/sulphamethoxazole into breast milk and its significance. In Daikos GK, ed. Progress in Chemotherapy, Proceedings of the Eighth International Congress of Chemotherapy, Athens, 1973. Athens: Hellenic Society for Chemotherapy, 1974:687–91.
29. Committee of Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.