USE OF TRIMETHOPRIM IN PREGNANCY

Trimethoprim is an antibiotic used in the treatment 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 safety data relate to co-trimoxazole and may not distinguish the effects of trimethoprim alone. Interpretation of these data is limited by small sample sizes, potential confounding (particularly by underlying maternal infection), and study design limitations.

As a folic acid antagonist, use in early pregnancy, including the periconceptual period, may reduce folate availability and adversely affect fetal development. Some studies have reported associations with overall and specific congenital malformations, particularly neural tube defects (NTDs), cardiac defects and orofacial clefts; however, findings are inconsistent and likely confounded, and a causal relationship remains unconfirmed. Associations have also been reported with miscarriage, low birth weight (LBW) and preterm delivery (PTD), although evidence for these outcomes is similarly conflicting and causality has not been established.

Trimethoprim use during the first trimester should be avoided where possible. If use is necessary, high-dose folic acid supplementation (5mg daily) is recommended, although there are no data demonstrating that this reduces the likelihood of birth defects. Women prescribed trimethoprim should be advised of potential fetal risks and, where appropriate, to avoid conception until treatment is complete.

Trimethoprim is frequently used in combination with the sulphonamide, sulfamethoxazole. Treatment with a further folate antagonist may theoretically increase the risk of congenital anomalies cause by folate deficiency. There have also been concerns that use of sulphonamide-containing medicines near delivery may increase the risk of neonatal hyperbilirubinemia and haemolysis, particularly in preterm infants or those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, most population-based studies do not demonstrate an increased risk, and concern is likely limited to infants with additional susceptibility factors.

Management of infection in pregnancy should be guided by culture and sensitivity tests and local prescribing guidance. Data regarding the safety of first trimester trimethoprim use are conflicting and, as such, increased risks of congenital malformation or other adverse pregnancy outcomes cannot be excluded. Where trimethoprim exposure has occurred during the first trimester, an earlier anomaly ultrasound (from 12-16 weeks onwards) may be considered 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.