Antimicrobials in pregnancy

Safe and unsafe antibiotics in pregnancy

How key drugs work

• Trimethoprim inhibits bacterial dihydrofolate reductase (DHFR); at high doses or with low folate it also affects human folate metabolism, which matters while the neural tube closes (weeks 3–4). In a woman with cystitis at 7 weeks, nitrofurantoin or cefalexin is used instead. Trimethoprim with methotrexate (also a DHFR inhibitor) causes marrow suppression.
• Folate synthesis blockers: sulphonamides (block dihydropteroate synthase) and trimethoprim (DHFR). Metronidazole is not a folate blocker.
• Metronidazole is a prodrug: only anaerobes and protozoa reduce its nitro group to toxic radicals that break DNA. It is the drug of choice for trichomoniasis (partners treated together) and bacterial vaginosis. Metallic taste, disulfiram-like reaction with alcohol.
• Nitrofurantoin is concentrated in bladder urine with low plasma and kidney tissue levels, so it is first line for uncomplicated cystitis and asymptomatic bacteriuria but not pyelonephritis. It fails in poor renal function.
• Asymptomatic bacteriuria is treated in pregnancy because ureteric dilatation and stasis favour ascent to pyelonephritis.

Cephalosporin generations

• No cephalosporin covers enterococci or Listeria (use amoxicillin). ESBL producers destroy third-generation cephalosporins; use carbapenems.

Infections around delivery

• Group B streptococcus colonising the vagina causes early-onset neonatal sepsis. IV benzylpenicillin in labour, ideally 4 hours or more before birth. Penicillin allergy: cefuroxime or clindamycin.
• Caesarean prophylaxis is given before the skin incision, so tissue levels are high at contamination.
• Post-caesarean endometritis is polymicrobial; the classic regimen is clindamycin plus gentamicin.
• Puerperal mastitis not settling with frequent feeding is usually penicillinase-producing Staphylococcus aureus: oral flucloxacillin for 10–14 days, with continued breastfeeding. A fluctuant, persistent lump needs ultrasound and drainage of an abscess. Penicillin allergy: erythromycin or clarithromycin.
• Necrotising fasciitis: add clindamycin to suppress toxin production.
• Clindamycin-associated colitis: diarrhoea, fever and whitish pseudomembranes after a course of clindamycin mean Clostridioides difficile; treat with oral vancomycin or fidaxomicin (oral metronidazole is an older choice for mild disease) and stop the culprit.
• A mild delayed rash with amoxicillin does not rule out cephalosporins (cross-reactivity about 1–2%); anaphylaxis does.

Anti-D immunoglobulin

• What it is: pooled IgG anti-D from sensitised donors. Given to a Rh D-negative woman without immune anti-D when fetal Rh D-positive cells may have entered her circulation.
• Why anti-D matters: maternal anti-D is IgG and crosses the placenta, coating fetal D-positive cells and causing haemolytic disease of the fetus and newborn (anaemia, hydrops, jaundice) in later pregnancies. The first pregnancy is usually spared because the primary response is slow and mainly IgM.
• How prophylaxis works: passive anti-D coats fetal D-positive red cells, which are removed by the spleen before they can stimulate a primary immune response. It is useless once the woman is sensitised.
• When: within 72 hours of a sensitising event: delivery of a D-positive baby, miscarriage after 12 weeks, ectopic pregnancy, termination, amniocentesis or CVS, antepartum haemorrhage, abdominal trauma, external cephalic version, intrauterine death.
• Routine antenatal prophylaxis at 28 weeks (single dose, or 28 and 34 weeks) in every D-negative non-sensitised woman, including her second pregnancy, covers silent third-trimester bleeds; postnatal anti-D is still given if the baby is D-positive.

• 500 IU neutralises 4 mL of fetal red cells. The Kleihauer test relies on HbF resisting acid elution: fetal cells stay pink while adult cells become ghosts.
• Antibody in the newborn: anti-D given to the mother is IgG, so small amounts of passive IgG anti-D cross to the baby; the baby may have a weakly positive direct antiglobulin test without significant haemolysis.
• False positive anti-D in an antibody screen: the commonest cause is recent anti-D prophylaxis (passive anti-D detected for up to about 8–12 weeks). It must not be mistaken for immune sensitisation; a falling titre and the timing of the injection distinguish them.
• If the baby is also Rh D-negative, no anti-D is needed.

Remember Cell-wall drugs (penicillins, cephalosporins) are the safest antibiotics in pregnancy because human cells have no cell wall.

Exam trap Anti-D prevents sensitisation; it cannot treat a woman who already has immune anti-D.

Exam trap Nitrofurantoin treats cystitis but not pyelonephritis, and is avoided at term.

How FCPS asks about this

• Why trimethoprim is avoided in the first trimester: it inhibits dihydrofolate reductase (folate antagonist).
• Drug of choice for trichomoniasis: metronidazole, with the partner treated.
• Nitrofurantoin is first line for: uncomplicated cystitis and asymptomatic bacteriuria.
• Puerperal mastitis with penicillinase-producing S. aureus: oral flucloxacillin for 10–14 days.
• Cephalosporin with best anti-Pseudomonas activity: cefepime (fourth generation).
• Routine antenatal anti-D in a D-negative woman: at 28 weeks, and within 72 hours of any sensitising event.
• False positive anti-D result: passive anti-D from recent prophylaxis.