To the Editor: A 32-year-old woman presented with fatigue and jaundice 12 days after an uncomplicated elective caesarean delivery. She had a haemoglobin level of 76 g/L (reference range [RR], 110–160 g/L), reticulocytosis (202 × 109/L, 12.6%; RR, 20–100 × 109/L) and hyperbilirubinaemia (139 μmol/L, 97% unconjugated; RR, < 20 μmol/L).

Within 24 hours, her haemoglobin level fell to 37 g/L, and a blood film showed spherocytes and polychromasia consistent with haemolysis (Box). A direct antiglobulin test was strongly positive for IgG and complement. The patient’s obstetric case notes revealed administration of a single intravenous dose of cefotetan at the time of delivery. Donor red cells treated in vitro with this antibiotic reacted dramatically with the patient’s serum, indicating the presence of antibody to the drug–red cell combination.

The patient was admitted to the intensive care unit and received 6 units of red cells over 24 hours, until the haemolysis resolved.

Cefotetan disodium is a broad-spectrum second-generation cephalosporin commonly used as prophylaxis in abdominal and pelvic surgery. It is given as a single intravenous dose at the start of the operation, and 50%–80% of the dose is excreted within 24 hours.1-3 A positive direct antiglobulin test is seen in one in 250 patients treated with cefotetan, although this in itself does not always imply active haemolysis.

The true incidence of symptomatic haemolysis is difficult to determine for several reasons: the severity of haemolysis varies between patients, and, if mild, may go undiagnosed; the process is self-limiting; and, when the drug has been used perinatally, symptoms may not be distinguished from the fatigue and anaemia expected (and therefore accepted) by most new mothers. Furthermore, as in our case of caesarean delivery, the obstetrician is not always aware of drugs administered by the anaesthetist, making the link between the antibiotic and haemolysis easy to miss.

The Adverse Drug Reactions Advisory Committee has 15 listings of haemolytic anaemia caused by cefotetan in Australia, which probably represents significant under-reporting. Indeed, the recognition of cefotetan-induced haemolysis prompted a US Food and Drug Administration review of its incidence in 2002, which revealed more than 85 reports worldwide, including 15 fatal cases.4 Cephalosporins are the most common group of drugs to cause haemolytic anaemia (93% of all cases), with cefotetan alone accounting for 83%.5 A patient with haemolytic anaemia induced by one cephalosporin carries a 10% risk of cross-reactivity with other cephalosporins and consequently should avoid further exposure if possible.

First-generation cephalosporins are less likely to cause significant haemolysis than second- and third-generation cephalosporins, yet are equally efficacious in surgical prophylaxis.1,3 We therefore recommend the use of cefazolin as an alternative to cefotetan.