USE OF TRIMETHOPRIM IN PREGNANCY

Trimethoprim is an antibiotic used to treat a variety of bacterial infections, but most commonly in the treatment or prophylaxis of urinary tract infections. It acts as a selective inhibitor of dihydrofolate reductase to prevent folic acid synthesis, thereby inhibiting DNA replication. It is available for use as a single agent and in combination with sulfamethoxazole (co-trimoxazole), which also inhibits folate metabolism, producing a synergistic antimicrobial effect.

Much of the available pregnancy exposure safety data are provided from studies which have investigated gestational co-trimoxazole use and, as such, do not assess the risk of trimethoprim exposure alone. The available data are limited by small study sample sizes, the possibility of data confounding from the underlying maternal illness for which trimethoprim/co-trimoxazole was prescribed, and study design methodologies which may have increased the possibility of chance findings.

As trimethoprim is a folic acid antagonist, there are concerns that periconceptual/perinatal use may limit the availability of folic acid and impact the developing fetus. Several studies investigating overall malformation risks have demonstrated possible associations with both first trimester and pre-conception trimethoprim exposure, however data are conflicting. A larger number of studies are available which have investigated specific anomalies following periconceptual/perinatal trimethoprim use, with several providing evidence of associations with neural tube defects, cardiac defects and facial clefts. Studies have also described increased risks of spontaneous miscarriage, low birth weight and preterm delivery. However, there are conflicting results for all of these findings, and given the limitations described above, any causal association with trimethoprim use remains unconfirmed.

Where trimethoprim use during the first trimester is considered necessary, there may be an advantage to taking high dose (5mg) folic acid, although no UK guideline currently recommends this and any benefit over standard dose supplementation is theoretical and scientifically unproven. Women prescribed trimethoprim who are trying to conceive or who are not using a reliable form of contraception should be made aware of the available data regarding possible fetal risk and advised to delay conception until treatment is completed. Pre-conceptual folic acid supplementation should also be discussed. 

Trimethoprim is frequently used in combination with the sulphonamide, sulfamethoxazole. There have been concerns that use of sulphonamide-containing medicines near delivery may increase the risk of hyperbilirubinemia and neonatal haemolysis in the neonate, particularly in premature infants or infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, the majority of population studies do not show an increased risk of neonatal hyperbilirubinemia following in utero sulphonamide exposure and this may therefore only be a concern in neonates with other risk factors (preterm/G6PD deficiency).

The treatment of infection in pregnancy should be guided by the results of culture and sensitivity tests, in accordance with local prescribing guidelines. Data concerning the safety of first trimester use of trimethoprim are conflicting and, as such, increased risks of congenital malformation or other adverse pregnancy outcomes cannot be excluded. An earlier detailed anomaly ultrasound (from 12-16 weeks onwards) may be considered following inadvertent use in the first trimester to exclude major structural problems. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.