Lactoferrin safety and side effects

Randomized trials have counted adverse events on oral bovine lactoferrin in four different groups: adults in hospital with COVID-19, people on antibiotics for Helicobacter pylori, pregnant women with iron deficiency anemia, and very preterm infants. In none of them did a harm occur significantly more often on lactoferrin than on the comparison. Two findings ran the other way, with fewer digestive side effects on lactoferrin. The limit on all of this is size and time, and it has its own section below.

The trial record

Adults in hospital

The LAC trial gave 800 mg a day of bovine lactoferrin or placebo for 30 days to 218 adults admitted with moderate to severe COVID-19, and it looked for adverse events systematically. Its Table 6 lists them by arm. The total was 57 on lactoferrin and 49 on placebo, a difference the authors found not significant (p=0.58).

Most of the events in that table are complications of severe COVID-19 itself: arrhythmias, raised liver enzymes (13 in each arm), clots, kidney injury, bacterial infection. One category differed significantly. Diarrhea occurred four times on placebo and never on lactoferrin (p=0.04). The authors recorded no relevant adverse event related to lactoferrin. A population this ill tells more about whether lactoferrin adds harm to serious illness than about how a healthy adult tolerates it.

Alongside antibiotics

Two meta-analyses published in 2009 pooled trials that added lactoferrin to H. pylori eradication regimens. The larger, by Zou and colleagues, covered nine randomized trials and 1,343 people. Side effects occurred in 9.05% of those given lactoferrin (95% CI 6.83 to 11.27%) and 16.28% of those without it (95% CI 13.43 to 19.13%). Nausea showed the clearest difference, with an odds ratio of 0.15 (95% CI 0.04 to 0.54).

The second, by Sachdeva and Nagpal, pooled five trials and 682 people and found no significant difference in adverse effects. The two reviews agree that adding lactoferrin did not increase side effects. They disagree on whether it reduced them, and the side effects in question belong to the antibiotics.

Both reviews were built to answer a different question, whether lactoferrin helps clear the infection, and the tolerance figures are a secondary result. The page on lactoferrin and H. pylori eradication reports that primary outcome, along with two randomized trials published since.

Compared with iron tablets

In pregnant women treated for iron deficiency anemia, four randomized trials with 600 women compared lactoferrin with ferrous sulfate. Gastrointestinal side effects were significantly less frequent on lactoferrin. The comparison here is an iron salt known for digestive upset. The result shows lactoferrin was the better tolerated of two treatments; it says less about how lactoferrin compares with taking nothing. The iron deficiency anemia page covers what those trials found about hemoglobin.

Preterm infants

The largest single safety dataset comes from ELFIN, which randomized 2,203 infants born before 32 weeks to bovine lactoferrin at 150 mg/kg a day or to sucrose. It recorded 16 serious adverse events in the lactoferrin group against 10 in the control group. Two events in the lactoferrin group, one case of blood in stool and one death following intestinal perforation, were assessed as possibly related to the intervention. The trial was not designed to characterize rare harms, and that imbalance supports no conclusion in either direction.

The 2020 Cochrane review of enteral lactoferrin in preterm infants pooled 12 randomized trials and stated that investigators reported no adverse effects in any of them. Its late-onset sepsis analysis alone covered 5,425 infants. The review graded most of its findings as low certainty, and the safety statement rests on the same trials.

What these trials could not detect

Most lactoferrin trials are small and short. LAC ran for 30 days. The longest adult trial on this site, a COVID-19 prevention study in health care staff, ran for 90 days. A trial of a few hundred people over several weeks cannot detect a harm that affects one person in a thousand, or one that appears after two years of daily use.

So the record supports a narrow statement. At the amounts tested, over weeks to a few months, randomized trials did not find lactoferrin more harmful than placebo or the usual comparison. It says nothing about years of daily use, and absence of reported harm at this scale is weak evidence of safety.

Who should not take lactoferrin

Supplemental lactoferrin is produced from cow's milk or whey. It is therefore unsuitable for anyone with a cow's milk protein allergy, and products vary in how much residual milk protein they carry. This is the clearest contraindication and the one most often missed, because lactoferrin is frequently described as an immune ingredient rather than as a dairy protein.

Lactoferrin binds iron, which is the mechanism it is taken for. Anyone managing an iron disorder in either direction, including hemochromatosis, has reason to raise it with a clinician before starting.

Evidence in pregnancy comes from trials that treated diagnosed iron deficiency anemia under supervision, which differs from general supplementation. Evidence for infants concerns clinical administration in hospital, not products bought and given at home.