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POSSIBLY EFFECTIVE

• Diarrhea. Oral hyperimmune bovine colostrum seems to help prevent infectious diarrhea and reduces the duration of infectious diarrhea in children. Details: An open-label study in children aged 1-6 years with a history of recurrent diarrhea shows that taking hyperimmune bovine colostrum daily for 4 weeks decreases the number of infectious diarrhea episodes during a 6-month period by around 2 episodes when compared to baseline (95924). Clinical research in infants also shows that drinking formula containing hyperimmune bovine colostrum for 1 week decreases the frequency of infectious diarrhea at 6 months by 1.5 episodes when compared to baseline (101801). Taking bovine colostrum might also reduce the duration of infectious diarrhea related to Escherichia coli. Two small clinical studies in children aged 1 month to 18 years show that bovine colostrum reduces the duration of diarrhea caused by enterotoxigenic E. coli when compared with placebo (2067,101796). The studies used hyperimmune colostrum, which provides high antibody titers against organisms for which the cow has been immunized (4905). Doses studied include hyperimmune bovine colostrum 7 grams three times daily for 14 days in children aged 1 month to 18 years (2067); a specific hyperimmune bovine colostrum product (ImmuGuard, NMI) 3 grams daily if less than 2 years of age, or 3 grams twice daily if over 2 years of age, for 1-4 weeks (95924,101796); and infant formula containing hyperimmune bovine colostrum 0.5 grams/kg for one week (101801).
• Exercise-induced respiratory infections. Small clinical studies suggest that oral bovine colostrum reduces the risk of exercise-induced respiratory infection in healthy adults. Details: While results from individual clinical studies are mixed (92413,92416), a meta-analysis of 5 small clinical trials in healthy adults shows that taking bovine colostrum 10 or 20 grams daily for 8-12 weeks during exercise training reduces the rate of upper respiratory symptom days by 44% and the rate of episodes of upper respiratory symptoms by 38% when compared with placebo (92417).
• HIV/AIDS-related diarrhea. Small clinical studies suggest that oral bovine colostrum reduces the frequency of diarrhea in patients with HIV/AIDS-related diarrhea. Details: Several very small clinical trials in patients with HIV/AIDS-related diarrhea show that taking bovine colostrum daily for up to 3 weeks seems to reduce the frequency of diarrhea when compared to baseline (4905,4906,4907,4908,92415). The validity of these findings is limited by lack of control group. Hyperimmune bovine colostrum had FDA orphan status for HIV-related diarrhea (9840); however, it has not been FDA-approved for this indication. Most clinical trials have used colostrum from pregnant cows that have been immunized against specific pathogens. The hyperimmune colostrum provides high antibody titers against organisms for which the cow has been immunized (4905). Specific hyperimmune colostrum products showing benefit include ColoPlus by ColoPlus AB and Lactobin by Biotest AG (4907,92415).
• Rotaviral diarrhea. Small clinical studies suggest that oral hyperimmune bovine colostrum is effective for treating rotaviral diarrhea in infants and children. Details: Several small clinical studies in infants and children with rotaviral diarrhea show that taking hyperimmune bovine colostrum decreases stool frequency and volume and speeds up the clearance of rotavirus when compared with placebo or baseline (4903,4904,4909,36999,37022,101796). Most clinical trials have used colostrum from pregnant cows that have been immunized against specific pathogens. This hyperimmune colostrum provides high antibody titers against organisms for which the cow has been immunized (4905). Doses studied include hyperimmune bovine colostrum powder 10 grams daily in divided doses for 4 days, hyperimmune bovine colostrum 100 mL three times daily for 3 days, and hyperimmune bovine colostrum 20 mL daily for 2 weeks in infants and children up to 30 months old (4903,4904,4909,36999). A specific hyperimmune bovine colostrum product (ImmuGuard, NMI) 3 grams daily if less than 2 years of age, or 3 grams twice daily if over 2 years of age, for 1 week has also been used (101796).

POSSIBLY INEFFECTIVE

• Necrotizing enterocolitis (NEC). Small clinical studies suggest that oral bovine colostrum does not prevent NEC in preterm or very low birth weight infants. Details: A small clinical study in very low birth weight infants shows that giving bovine colostrum (Pedimmune, Merk India Ltd.) 1.2 or 2 grams enterally four times daily until discharge or death does not reduce the risk of NEC when compared with placebo (92411). Another small clinical study in formula-fed, preterm neonates also shows that giving bovine colostrum (Immuguard, Dulex-Lab) for 2 weeks has no effect on the incidence of NEC when compared with a control group (105755). An open-label trial in very preterm infants shows that adding 1-2.8 grams of powdered bovine colostrum to each 100 mL of breastmilk until 35 weeks' postmenstrual age does not reduce the risk of NEC when compared with a conventional milk fortifier (111140). Additionally, a large clinical study in very preterm infants shows that adding bovine colostrum to breastmilk feeding during the first 14 days of life does not reduce the risk of NEC or shorten the time to full enteral feeding when compared with preterm formula added to breastmilk (114816).
• Sepsis. Small clinical studies suggest that oral bovine colostrum does not prevent sepsis in preterm or very low birth weight infants. Details: A small clinical study in low birth weight infants shows that giving bovine colostrum (Pedimmune, Merk India Ltd.) 1.2 or 2 grams enterally four times daily until discharge or death does not reduce the risk of sepsis when compared with placebo (92411). Another small clinical study in formula-fed, preterm neonates also shows that giving bovine colostrum (Immuguard, Dulex-Lab) for 2 weeks has no effect on the incidence of late-onset sepsis when compared with a control group. While the severity of sepsis appeared to be higher in the control group, the study was underpowered to assess this outcomes (105755). An open-label trial in very preterm infants shows that adding 1-2.8 grams of powdered bovine colostrum to each 100 mL of breastmilk until 35 weeks' postmenstrual age does not reduce the risk of sepsis when compared with a conventional milk fortifier (111140).
• Short bowel syndrome. Small clinical studies suggest that oral bovine colostrum is not beneficial in children or adults with short bowel syndrome. Details: A very small crossover study in children with short bowel syndrome shows that administering bovine colostrum enterally at a dose that comprises 20% of a child's daily basal fluid requirement does not improve growth or intestinal function when compared with a control diet (92410). Another very small crossover study in adults with short bowel syndrome shows that taking bovine colostrum 250 mL twice daily for 4 weeks does not improve intestinal absorption or body composition when compared with an isocaloric control supplement (92423).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral bovine colostrum for aging, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Athletic performance. Small clinical studies suggest that oral bovine colostrum might improve some measures of athletic performance; however, results are mixed, and any benefit appears to be small. Details: Several small clinical studies show that taking bovine colostrum 10-60 grams daily for up to 8 weeks increases power and improves cycling and sprint time following an initial bout of exercise, but not during a normal training period (11453,16532,36988,36991,36995). Another small clinical study in elite soccer players shows that a lower dose of 3.2 grams daily for 6 weeks modestly attenuates muscle damage, muscle soreness, and decreases in squat jump performance after simulated soccer matches (98820). However, bovine colostrum does not appear to improve rowing performance, anaerobic work capacity, endurance, or strength training (11453,16532,36980,36992,36995,37000,37006,92419,114817). Differences are possibly explained by the variation in exercise and recovery protocols used (16533).
• Autism spectrum disorder. Oral bovine colostrum has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical trial in children aged 3-11 years with autism spectrum disorder shows that taking bovine colostrum (Immucon) 5.1-10.8 grams daily with Bifidobacterium infantis for 5 weeks improves measures of irritability and hyperactivity and symptoms of autism-associated gastrointestinal problems such as stool consistency and frequency of diarrhea when compared to baseline (101792). The validity of these findings is limited by a lack of placebo control. Also, it is unclear if these findings are due to bovine colostrum, Bifidobacterium infantis, or the combination.
• Benign prostatic hyperplasia (BPH). Oral bovine colostrum has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An open-label study in males with lower urinary tract symptoms related to BPH shows that taking bovine colostrum 30 mg and saw palmetto extract 320 mg plus tamsulosin 0.4 mg daily for 12 months does not improve overall symptoms when compared with tamsulosin alone. However, the combination improved storage symptoms more than tamsulosin alone, without affecting urinary flow rate, postvoid residual volume, or prostate volume (101795). This study is limited by the lack of a placebo group.
• Chemotherapy-related infection. It is unclear if oral bovine colostrum is effective for the prevention of chemotherapy-related infection. Details: A small clinical study in children with leukemia shows that taking bovine colostrum (Biofiber-Damino) 0.5-1 gram/kg daily during chemotherapy treatment for 4 weeks does not reduce the incidence of fever, neutropenic fever, bacteremia, fungaemia, or the need for antibiotics when compared with placebo (101797). It is possible that this study was underpowered to detect between-group differences.
• Child growth. Oral bovine colostrum has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical trial in 9-month-old breastfed infants at high risk for stunted growth shows that giving bovine colostrum 5.7 grams with whole egg powder 4.3 grams twice daily for 3 months reduces stunting and linear growth faltering, as measured by mean length-for-age z-score, when compared with placebo. These effects are sustained for up to 5 months following discontinuation of bovine colostrum (105754). It is unclear if these effects are due to bovine colostrum, whole egg powder, or the combination.
• Cognitive function. It is unclear if oral bovine colostrum is effective for improving cognitive function. Details: A small clinical study in older adults shows that taking a specific bovine colostrum product (Eterna Gold, Saskatoon Colostrum Co. Ltd.) 60 grams daily for 8 weeks does not improve cognitive function when compared with whey protein (92414).
• Critical illness (trauma). It is unclear if oral bovine colostrum is beneficial in patients with critical illness. Details: A small clinical trial in critically ill patients shows that taking bovine colostrum 20 grams daily in enteral formula reduces the median length of stay by around 7 days and reduces risk of diarrhea by 72% when compared with placebo. There was no effect on vomiting, abdominal distention, constipation, sepsis, or mortality (101799).
• Dental plaque. Although there has been interest in using topical bovine colostrum for dental plaque, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Diabetes. It is unclear if oral bovine colostrum is beneficial in patients with type 2 diabetes. Details: A very small clinical study in patients with type 2 diabetes shows that taking bovine colostrum (Immuno-Dynamics, Inc.) 5 grams twice daily on an empty stomach for 4 weeks decreases postprandial blood glucose by 11% to 14% and cholesterol levels by 8% when compared to baseline (92418). The validity of these findings is limited by a lack of comparator group.
• Dry eye. Although there has been interest in using topical bovine colostrum for dry eye, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Graft-versus-host disease (GVHD). Although there has been interest in using oral bovine colostrum for diarrhea associated with GVHD, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Hematopoietic stem cell transplant (HSCT). Oral and topical bovine colostrum have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: A small clinical study in patients undergoing HSCT shows that taking a specific combination product containing bovine colostrum and aloe (Remargin Colostrum Gastro-Gel, Solimè srl) and rinsing with a specific mouthwash containing bovine colostrum and aloe (Remargin Colostrum OS, Solimè srl) modestly reduces the risk and duration of severe oral mucositis and febrile neutropenia when compared with historical values. There was no effect on duration of neutropenia, length of hospital stay, pain, or duration of medication use. All patients were also given standard care. The mouthwash was used after each oral hygiene session, and the oral treatment was taken 3 to 5 times daily depending on symptoms (110211,111135). The validity of these findings is limited by a lack of control group. Additionally, it is unclear if these findings are due to bovine colostrum, aloe, or the combination.
• Human papillomavirus (HPV). It is unclear if intravaginal bovine colostrum is beneficial in patients with HPV infection. Details: Observational research in patients with HPV infection has found that vaginal application of bovine colostrum-containing tablets (Ginedie, Tfarma) twice weekly for 6 months is associated with regression of low grade cervical lesions in 76% of patients (92424). The validity of these findings is limited by the observational nature of the study and a lack of comparator group.
• Influenza. It is unclear if oral bovine colostrum is effective for the prevention of influenza in adults. Details: A small clinical study in healthy Italian adults shows that taking a specific type of defatted freeze-dried bovine colostrum (ARd Colostrum, Corcon srl) 400 mg daily for 8 weeks reduces the rate of self-reported flu symptoms by approximately 70% to 75% when compared with no prophylaxis or receiving the influenza vaccine. In high-risk patients with cardiovascular disease, taking bovine colostrum, with or without influenza vaccination, reduces the rate of self-reported flu symptoms by up to 22% when compared with vaccination alone. However, viral testing was not conducted and some patients reported more than one incidence of flu symptoms during the study period, indicating that the reported symptoms might not have been caused by influenza infection (92412).
• Lichen planus. Although there has been interest in using topical bovine colostrum for lichen planus, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Malnutrition. It is unclear if oral bovine colostrum is beneficial in children with malnutrition. Details: A small clinical study in children with nonorganic failure to thrive shows that taking bovine colostrum 40 mg/kg daily for 3 months, along with routine treatment, modestly increases weight but not height when compared with routine treatment alone. Failure to thrive resolves in approximately 10-fold more patients treated with bovine colostrum and routine treatment when compared with routine treatment alone (92420).
• Multiple sclerosis (MS). It is unclear if oral bovine colostrum is beneficial in patients with MS. Details: A very small clinical study in patients with MS shows that taking hyperimmune bovine colostrum 100 mL daily for about 4 weeks improves symptoms of MS when compared with non-hyperimmune bovine colostrum (37039). However, another very small clinical study in patients with MS shows that taking hyperimmune bovine colostrum about 120 mL daily for 4 weeks does not improve symptoms of MS when compared with placebo (37024).
• Muscle strength. Although there has been interest in using oral bovine colostrum for muscle strength, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Oral mucositis. It is unclear if oral bovine colostrum is effective for the prevention of chemotherapy-induced oral mucositis. Details: A small clinical study in children with leukemia shows that taking bovine colostrum (Biofiber-Damino) 0.5-1 gram/kg daily during chemotherapy for 4 weeks reduces the peak severity of oral mucositis, but not the overall risk of oral mucositis, when compared with placebo (101797).
• Physical performance. It is unclear if oral bovine colostrum is effective for improving physical performance in older adults. Details: A small clinical study in older adults participating in resistance training shows that taking a specific bovine colostrum product (Eterna Gold, Saskatoon Colostrum Co. Ltd.) 60 grams daily for 8 weeks might improve leg strength, but not upper body strength or body composition, when compared with placebo (92414).
• Prematurity. It is unclear if oral bovine colostrum improves outcomes in very preterm infants. Details: An open-label trial in very preterm infants shows that adding 1-2.8 grams of powdered bovine colostrum to each 100 mL of breastmilk until 35 weeks' postmenstrual age does not increase weight, length, or head circumference, but slightly improves bowel habits, when compared with a conventional milk fortifier (111140,111141). A large, multi-center, clinical study conducted in 7 neonatal intensive care units in China among very preterm infants shows that adding bovine colostrum to breastmilk, when maternal milk supply was insufficient, until postnatal day 14does not reduce time to full enteral feeding, feeding intolerance, risk of morbidity or mortality, or improve infant growth when compared with preterm formula added to breastmilk (114816). However, results significantly varied by study site where different feeding protocols were used. Additionally, blinding of clinical personnel was inadequate due to color, odor, and viscosity differences between bovine colostrum and preterm formula.
• Psychological well-being. Although there has been interest in using oral bovine colostrum for psychological well-being, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Shigellosis. It is unclear if oral bovine colostrum is beneficial in children with shigellosis. Details: A small clinical study in children aged 1-12 years with shigellosis shows that taking hyperimmune bovine colostrum 100 mL three times daily for 3 days along with the antibiotic pivmecillinam for 5 days does not reduce the duration of Shigella dysenteriae infection when compared with a control group taking non-hyperimmune bovine colostrum and pivmecillinam (36986).
• Sjogren syndrome. Although there has been interest in using topical bovine colostrum for Sjogren syndrome, there is insufficient reliable information about the clinical effects of bovine colostrum for this purpose.
• Travelers' diarrhea. Several very small clinical studies suggest that oral hyperimmune bovine colostrum is beneficial for the prevention of travelers' diarrhea in adults. Details: Three very small clinical studies in healthy adults show that taking hyperimmune bovine colostrum reduces the risk of diarrhea due to pathogens that commonly cause travelers' diarrhea such as enterotoxigenic Escherichia coli (2068,2069) and Shigella flexneri (2070).
• Ulcerative colitis. It is unclear if rectal bovine colostrum is beneficial in patients with ulcerative colitis. Details: A very small clinical study in patients with distal ulcerative colitis shows that rectal administration of bovine colostrum 10% solution, as an enema, twice daily along with oral mesalamine for 4 weeks improves symptom and histological scores when compared with a placebo enema plus mesalamine (9730).
• Upper respiratory tract infection (URTI). It is unclear if oral bovine colostrum is effective for preventing or treating URTIs in children or adults. Details: A small clinical study in healthy adult males shows that taking a specific bovine colostrum product (Intact, Numico Research Australia Pty. Ltd.) 30 grams twice daily for 8 weeks reduces the incidence of URTIs by about 33% when compared with whey protein. However, it does not appear to reduce the duration of URTIs if they do occur (36998). However, another small clinical study in healthy medical and health sciences students shows that taking bovine colostrum 500 mg once or twice daily for 45 days, then again for 7 days starting at day 87, does not reduce the frequency or severity of URTI symptoms when compared with placebo (111139). In children aged 1-6 years with a history of recurrent URTIs, a small clinical study shows that taking hyperimmune bovine colostrum (ImmuGuard, NMI) 3 grams once or twice daily for 4 weeks decreases the occurrence of URTIs during a 6-month period by about 4 episodes when compared to baseline (95924). The validity of this finding is limited by the lack of a control group. However, another small clinical study in healthy children aged 3-7 years shows that taking bovine colostrum 500 mg twice daily for 15 days followed by 500 mg once daily for 30 days preventatively, and 500 mg twice daily for 4 days if URTI symptoms develped, does not decreases the frequency of days with any URTI symptoms and symptom severity over 21 weeks when compared with whey-based control. (114819). The validity of the study is limited by the lack of a true placebo and absence of investigator-rated outcomes. Frequency of URTIs and symptom severity was reported by the child's parents or guardians via online survey every 2-4 weeks throughout the duration of the trial.
• Vaginal atrophy. Intravaginal bovine colostrum has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in postmenopausal patients with vulvovaginal atrophy shows that inserting 2 mL of a combination cream (Refeel, IDI Pharma) containing bovine colostrum, visnadine, and prenylflavonoids into the vagina once daily for 15 days improves overall symptoms when compared to baseline (98819). A larger clinical study in postmenopausal patients shows that using an intravaginal gel containing bovine colostrum 2.3% and other ingredients (Monurelle Biogel, Zambon SpA) daily for 12 weeks improves overall vaginal health scores by approximately 54%, increasing the number of patients engaging in regular sexual activity to 84% from 59% at baseline. Use of the gel also appears to reduce urinary incontinence (101794). The validity of these findings is limited by the lack of control groups. Also, it is unclear if these effects are due to bovine colostrum, other ingredients, or the combination.
• Wound healing. It is unclear if oral bovine colostrum is beneficial for wound healing. Details: A small non-randomized open-label intervention in patients with chronic non-healing wounds suggests that adding powdered bovine colostrum 500 mg to wound dressings for 21 days is associated with improved wound healing when compared with conventional wound dressings (114821). More evidence is needed to rate bovine colostrum for these uses.

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POSSIBLY EFFECTIVE

• Pregnancy-related iron deficiency. Oral lactoferrin seems to improve hemoglobin levels similarly to oral or parenteral iron therapy in patients with pregnancy-related iron deficiency. Details: A meta-analysis of 4 clinical studies in patients with pregnancy-related iron deficiency anemia shows that taking bovine lactoferrin 200-250 mg daily for 4-8 weeks during the second or third trimester is equally effective to ferrous sulfate 150-520 mg for improving hemoglobin levels (97788). Another meta-analysis of 6 mostly small, low-quality clinical studies in pregnant patients with iron deficiency anemia, iron deficiency, or hereditary thrombophilia shows that taking lactoferrin improves hemoglobin and serum iron, but not serum ferritin, when compared with ferrous sulfate (110773). However, the validity of these findings is limited by the heterogeneity of the included studies and lack of information about lactoferrin and iron doses.
• Sepsis. Oral lactoferrin seems to reduce the risk of late-onset sepsis in some premature infants. However, the optimal dosing regimen and patient population is unclear. Details: A meta-analysis of 12 clinical studies in premature infants shows that lactoferrin 150-200 mg/kg daily reduces the risk of late-onset sepsis by 20%, largely due to reductions in fungal infections specifically (104868). In contrast, other meta-analyses have reported conflicting findings (97783,104856) and some suggest that any benefits may be relegated to certain sub-groups of premature infants, including infants fed with bovine formula (104856,104868) or those with very low birth weight or extremely low birth weight (104856,104868,104869). These groups seemed to obtain greater benefits than other premature infants or those fed exclusively or almost exclusively with breast milk. Early data from one meta-analysis also suggests that lactoferrin may be more effective at preventing late-onset sepsis when combined with probiotics (104868). Fixed doses of 100-250 mg daily and weight-based doses up to 300 mg/kg daily have been studied (97783,104856,104868,104869,104870). However, many individual clinical studies, including 3 large studies, have failed to demonstrate clear benefits of lactoferrin. These clinical trials, one in very premature infants and the others in very low birthweight infants, show that lactoferrin 150 mg/kg daily, 200 mg/kg daily, or 100 mg daily does not reduce late-onset sepsis when compared with control (104857,104858,110771). Two of these trials had very few infants exclusively fed bovine formula, which may have limited potential benefits. Subgroup analyses from these trials also suggest that extremely low birth weight and/or extremely premature infants may have benefited from lactoferrin (104857,104858).

LIKELY INEFFECTIVE

• Fetal and premature infant mortality. Oral lactoferrin does not reduce the risk of all-cause mortality in premature infants. Details: Many meta-analyses and large clinical trials show that taking lactoferrin does not reduce the risk of mortality from any cause in premature infants (104856,104857,104858,104868,110771).
• Necrotizing enterocolitis (NEC). Most research shows that oral lactoferrin does not reduce the incidence of NEC in premature infants. Details: Many meta-analyses and large clinical studies show that lactoferrin does not reduce the incidence of NEC in premature infants (104856,104857,104858,104868,110771). Exploratory data from one meta-analysis suggest that lactoferrin combined with probiotics may reduce the incidence of NEC when compared with control (104868). However, since probiotics alone have demonstrated benefit for the prevention of NEC in clinical trials, it is unclear if lactoferrin confers any additional benefit.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral lactoferrin has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in adult females with acne shows that taking an oral supplement containing lactoferrin, zinc, niacinamide, and prebiotics once daily for 12 weeks, in addition to applying a topical combination retinoid-based cream, modestly improves the number of acne lesions (i.e., non-inflammatory, inflammatory, and total) when compared with the topical combination retinoid-based cream alone (112915). It is unclear if these effects are due to lactoferrin, other ingredients, or the combination.
• Anemia of chronic disease. Oral lactoferrin might improve hemoglobin levels in some patients with anemia of chronic disease. However, the optimal patient population is unclear. Details: One nonrandomized clinical study evaluated bovine lactoferrin in patients with anemia of chronic disease. In pregnant patients with anemia related to beta-thalassemia or hereditary thrombophilia, taking a specific bovine lactoferrin 100 mg capsule (Lattoglobina, Aqma Italia) twice daily with meals, starting at 6-8 weeks' gestation and continuing until delivery, improves hemoglobin levels by 50% and 15%, respectively, when compared with baseline. In non-pregnant patients, taking this same product twice daily for 30 days improves hemoglobin levels by 18% in patients with hereditary thrombophilia, but not in those with beta-thalassemia. The study may have been inadequately powered to detect a difference from baseline (104865).
• Antibiotic-associated diarrhea. It is unclear if oral lactoferrin is beneficial for preventing antibiotic-associated diarrhea in children or adults. Details: A very small clinical study in long-term care patients shows that adding lactoferrin at an unspecified dose to 600 mL of gastronomy tube solution daily for 56 days reduces the risk for antibiotic-associated diarrhea when compared with placebo (97782). Conversely, a clinical study in children aged 1-18 years receiving antibiotic therapy for an acute respiratory or urinary tract infection shows that those taking bovine lactoferrin 100 mg twice daily are more than twice as likely to develop antibiotic-associated diarrhea during or for the two weeks following antibiotic therapy when compared with those taking placebo (106729). However, the validity of these findings is limited by differences in baseline characteristics between groups.
• Atopic dermatitis (eczema). Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults with atopic dermatitis shows that taking a combination of lactoferrin 250 mg and a whey derived immunoglobulin-rich fraction 250 mg daily for 56 days improves symptoms in 13 of 22 patients, compared with 4 of 13 patients taking placebo (97789).
• Bacterial vaginosis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent bacterial vaginosis shows that adding a specific combination capsule (Respecta, Giellepi Spa Health Science) containing bovine lactoferrin 50 mg and 5 billion colony-forming units of Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001 on a varying schedule over 6 months, in conjunction with metronidazole 500 mg twice daily for the first 7 days, reduces the proportion of patients with vaginal discharge by 63%, itching by 57%, and a recurrent episode by 50% when compared with placebo. Patients took 2 capsules daily for 5 days, then 1 capsule daily for 10 days, followed by 1 capsule daily for 10 days of each month, beginning on the first day of the menstrual cycle. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104872).
• Chemotherapy-induced anemia. It is unclear if oral lactoferrin is beneficial for chemotherapy-induced anemia. Details: An open-label clinical study in adults with advanced cancer and chemotherapy-induced anemia who are receiving treatment with recombinant human erythropoietin shows that taking oral lactoferrin (Lattoglobina, Grunenthal-Formenti) 200 mg daily for 12 weeks is as effective as intravenous ferric gluconate 125 mg weekly for improving hemoglobin and iron levels (97781).
• Cognitive function. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in healthy adults shows that taking a product containing a combination of lactoferrin 10 mg, probiotics, prebiotics, minerals, and glutathione (Puraflor, GSK Consumer Healthcare, Milano, Italy) daily for 4 weeks does not affect cognitive performance during acute stress when compared with placebo (110923). It is unclear if this effect is due to lactoferrin, other ingredients, or the combination.
• Common cold. It is unclear if oral lactoferrin is beneficial for preventing the common cold. Details: A clinical study in healthy adults shows that taking bovine lactoferrin 200 mg or 600 mg daily for 12 weeks does not reduce the frequency or duration of self-reported symptoms of the common cold when compared with placebo (104859). Another clinical study in adults with frequent colds shows that taking a combination of bovine lactoferrin 400 mg and whey protein immunoglobulin-rich fraction 200 mg daily for 90 days reduces the number of colds by 57% when compared with placebo. There was no effect on cold severity (97786). It is not clear if this effect is due to lactoferrin, whey protein fraction, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral lactoferrin is beneficial for the treatment or prevention of COVID-19. Details: A small clinical study in adults hospitalized with mild-to-moderate COVID-19 receiving hydroxychloroquine, vitamin C, zinc, and acetylcysteine shows that taking lactoferrin 200 mg once or twice daily does not improve symptoms when compared with placebo (106731). Similarly, a large clinical study in adults hospitalized with moderate-to-severe COVID-19 receiving standard therapy shows that taking a specific product containing bovine lactoferrin (Mosaic, Pharmaguida) 400 mg twice daily for 30 days does not reduce intensive care unit admission or death, nor improve illness severity scores or discharge within 2 weeks when compared with placebo (112913). However, observational research with this product in outpatient adults with asymptomatic to moderately symptomatic COVID-19 suggests that taking 200-1000 mg daily is associated with a median of 15 days to a negative SARS-CoV-2 test, compared with 24 days in a historical control group (106732). The validity of these findings is limited by the retrospective nature of the study and differences in symptom severity between the groups at baseline. There is also interest in oral lactoferrin for prevention of COVID-19. A large clinical study conducted in healthcare workers in Peru who were screened and tested for COVID-19 shows that taking bovine lactoferrin 600 mg once daily for 65 days does not reduce the number of SARS-CoV-2 cases when compared with placebo (112914). However, the study was stopped prematurely due to vaccine availability; it may not have been powered to detect a difference between groups.
• Diarrhea. It is unclear if oral lactoferrin is beneficial for reducing the incidence of diarrhea in children or adults. Details: A large clinical study in weaned children 12-18 months of age shows that taking bovine lactoferrin 500 mg twice daily for 6 months does not reduce the incidence of diarrhea when compared with placebo (97787). However, a clinical study in infants with anemia who were exclusively breast-fed from 4-6 months before weaning and transitioning to infant formula from 6-9 months shows that fortification of each 100 grams of formula with 38 mg of bovine lactoferrin for 3 months improves vomiting and nausea when compared with formula without fortification. Similarly, fortification of each 100 grams of formula with 76 mg of bovine lactoferrin for 3 months improves diarrhea-related illness, diarrhea, vomiting, and nausea when compared with formula without fortification (106726). Lactoferrin has also been evaluated in adults. A large clinical study in healthy adults working at kindergartens or nursery schools in the winter shows that taking bovine lactoferrin 600 mg daily for 12 weeks is associated with a 1-day duration of diarrhea, compared with 2 days in those taking placebo (106728).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral lactoferrin prevents the development of gastroenteritis-associated nausea and vomiting in children or adults. Details: A large clinical study in children aged 3-6 years shows that consuming yogurt fortified with bovine lactoferrin 100 mg 3-5 days weekly for 15 weeks reduces the odds of school absence due to vomiting by 19% when compared with consuming the yogurt less than 3 days per week. However, consuming the yogurt did not reduce absences due to gastroenteritis, the presumed cause of vomiting (104862). A large clinical study in healthy adults working at kindergartens or nursery schools in the winter shows that taking bovine lactoferrin 200 or 600 mg daily for 12 weeks is associated with a 12% prevalence of acute gastrointestinal symptoms, compared with a prevalence of 22% in those taking placebo (106728).
• Gingivitis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild gingivitis shows that taking bovine lactoferrin 60 mg, bovine lactoperoxidase 7.8 mg, and glucose oxidase 7.8 mg daily for 12 weeks improves gingival health and plaque index scores when compared with placebo. A lower dose product containing bovine lactoferrin 20 mg, bovine lactoperoxidase 2.6 mg, and glucose oxidase 2.6 mg daily for 12 weeks improves plaque index scores, but not gingival health scores, when compared with placebo. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104867).
• Helicobacter pylori. Research on the use of oral lactoferrin as an adjunct for H. pylori eradication is inconclusive and conflicting. Details: Monotherapy with human recombinant lactoferrin, even at high doses of 5 grams daily, does not suppress or eradicate H. pylori infection (13317). However, research on its use as an adjunct to standard therapy is conflicting. Some studies suggest that lactoferrin improves efficacy when added to a triple therapy regimen of rabeprazole, clarithromycin, and tinidazole (13316,13332). However, research using lactoferrin with a triple therapy regimen of esomeprazole, clarithromycin, and amoxicillin found no difference in eradication rates. It is possible that lactoferrin activity on the bacterial cell wall interferes with the cell wall activity of amoxicillin (13315). Other research shows that using lactoferrin in addition to a sequential therapy regimen of esomeprazole, amoxicillin, metronidazole, and clarithromycin or a triple therapy regimen of esomeprazole, amoxicillin, and clarithromycin is associated with eradication rates of 95% or 86%, respectively, compared with eradication rates of 83% and 70%, respectively, with the use of either regimen alone (106730). However, using lactoferrin in addition to a sequential therapy regimen (esomeprazole, amoxicillin, tinidazole, and clarithromycin) and probiotics does not increase eradication more than sequential therapy and probiotics alone (97790).
• Hepatitis C. It is unclear if oral lactoferrin is beneficial for hepatitis C. Details: Some clinical research shows that lactoferrin decreases serum levels of hepatitis C virus RNA and alanine aminotransferase (ALT) in adults with hepatitis C (13320,13321). Some experts recommend starting lactoferrin 1 to 3 months before starting interferon to identify lactoferrin responders (13321,13322,13323,13324). Lactoferrin doses of 1.8 or 3.6 grams daily appear to be necessary for efficacy (13323,13324); lower doses don't seem to have any effect (13313,13314).
• Infant development. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in healthy, full-term, exclusively formula-fed infants shows that taking a formula fortified with bovine lactoferrin 0.6 grams/L and bovine milk fat globule membrane 5 grams/L for 12 months improves cognitive development scores by about 8% after 12 months, but not after 18 months, when compared with control formula. This study may have been inadequately powered to detect a difference between groups at 18 months. It is unclear if any effect is due to lactoferrin, milk fat globule membrane, or the combination (104866).
• Iron deficiency anemia. It is unclear if oral lactoferrin is beneficial for the treatment or prevention of iron deficiency anemia in infants and children. Details: An open-label clinical study in children aged 1-10 years with cerebral palsy and iron deficiency anemia shows that taking bovine lactoferrin (Pravotin, Hygint) 100 mg twice daily for 4 weeks improves hemoglobin by 1.4 grams/dL, compared with 0.8 grams/dL in those taking iron hydroxide polymaltose complex providing elemental iron 3 mg/kg twice daily. Lactoferrin also improves serum ferritin, but not the rest of the serum iron profile (106725). Conversely, a small open-label clinical study in children aged 1-18 years with iron deficiency anemia in Egypt shows that the improvement in hemoglobin, serum iron, ferritin, or transferrin saturation is less with lactoferrin 100 mg daily, or twice daily if over age 3, when compared with iron bisglycinate chelate 0.75 mg/kg daily or iron polymaltose complex 6 mg/kg daily for a month. However, improvement in hemoglobin and iron studies was similar when comparing 30% iron saturated lactoferrin (100 mg lactoferrin and 30 mg iron) daily, or twice daily if over age 3 years, with iron bisglycinate chelate or iron polymaltose complex (110189). Lactoferrin has also been evaluated for the prevention of iron deficiency anemia. A clinical study in healthy, full-term formula-fed infants aged 6 weeks to 6 months shows that feeding a low-iron infant formula supplemented with lactoferrin has no effect on iron status or incidence of iron deficiency when compared with the low-iron formula alone (106724).
• Preterm labor. It is unclear if vaginal lactoferrin is beneficial for preventing preterm labor. Details: Observational research in patients diagnosed with bacterial vaginosis in the first trimester of pregnancy and a previous history of preterm labor has found that using a lactoferrin vaginal tablet 300 mg daily for 21 days is associated with a 44% reduced incidence of preterm birth when compared with no intervention. The validity of this study is limited by the use of a retrospective chart review (105405).
• Psoriasis. It is unclear if topical lactoferrin is beneficial in psoriasis. Details: A small open-label clinical study in patients with mild to moderate stable plaque-type psoriasis shows that applying lactoferrin 10% or 20% ointment topically daily in addition to taking bovine lactoferrin 100 mg orally daily (Lattoglobina, Grünenthal-Formenti) for 4 weeks improves symptoms of psoriasis, such as redness and scaling, by up to 37% when compared with use of oral lactoferrin alone (97784).
• Respiratory tract infections. It is unclear if oral lactoferrin is beneficial for treating or preventing respiratory tract infections. Details: A clinical study in healthy children aged 12-32 months shows that taking bovine lactoferrin 48 mg daily for 13 weeks does not reduce symptoms of respiratory tract infections when compared with placebo (104861). However, a clinical study in infants with anemia who were exclusively breast-fed from 4-6 months before weaning and transitioning to infant formula from 6-9 months shows that fortification of each 100 grams of formula with 38 mg of bovine lactoferrin for 3 months improves rhinorrhea, wheezing, and skin rash when compared with formula without fortification. Similarly, fortification of each 100 grams of formula with 76 mg of bovine lactoferrin for 3 months improves respiratory-related illness and wheezing when compared with formula without fortification (106726). There is also interest in oral lactoferrin for prevention of respiratory tract infections. However, two meta-analyses that each included 6 clinical studies in infants, children, and adults who consumed a bovine lactoferrin supplement or bovine lactoferrin enhanced formula, with some studies included in both analyses, have conflicting results. One meta-analysis of 1194 patients shows that lactoferrin reduces the risk of developing a respiratory infection by 43% when compared with placebo or various controls (110774). Conversely, the second meta-analysis of 1157 patients shows that lactoferrin does not reduce the risk of developing a respiratory infection in adults but may reduce the risk by 22% in infants and children when compared with placebo or unenhanced formula (110775). The validity of the findings from these meta-analyses is limited by the heterogeneity of the included studies, which enrolled patients of a broad age range and utilized widely varying dosing regimens. Furthermore, some studies are of poor quality.
• Vaginal candidiasis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent vaginal candidiasis shows that taking a specific combination capsule (Respecta, Giellepi Spa Health Science) containing bovine lactoferrin 50 mg and 5 billion colony-forming units of Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001 on a varying schedule over 6 months, in conjunction with clotrimazole 100 mg daily for the first 7 days, reduces the proportion of patients with vaginal discharge by 63%, itching by 100%, and a recurrent infection by 71% when compared with placebo. Patients took 2 capsules daily for 5 days, then 1 capsule daily for 10 days, followed by 1 capsule daily for 10 days of each month, beginning during the premenstrual phase. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104863).
• Ventilator-associated pneumonia (VAP). It is unclear if oral lactoferrin is beneficial for preventing VAP. Details: A clinical study in critically ill, mechanically ventilated adults shows that taking lactoferrin 500 mg four times daily for up to 28 days does not reduce the incidence of VAP or other infections, or increase antibiotic-free days, when compared with placebo (104873). More evidence is needed to rate lactoferrin for these uses.

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LIKELY SAFE ...when used orally and appropriately. There are no reports of significant toxicity in multiple human trials (4901,4903,4904,4905,4906,4907,4908,4909,36980,36988) (36992,36995,36998,37000,92412,92413,92415,101799,111136,111138) (111139,114817). However, bovine colostrum is derived from animals, and there is some concern about contamination with diseased animal parts (1825). So far, there are no reports of disease transmission to humans due to use of contaminated bovine colostrum.

POSSIBLY SAFE ...when used rectally and appropriately, short-term. Bovine colostrum has been used with apparent safety when administered as a 10% enema twice weekly for up to 4 weeks (9730). ...when used intravaginally and appropriately, short-term. Bovine colostrum has been used with apparent safety when administered vaginally as a tablet twice weekly for up to 6 months, as a 1% cream once daily for up to 15 days, or as a gel containing 2.3% bovine colostrum daily for 12 weeks (92424,98819,101794). There is insufficient reliable information available about the safety of bovine colostrum when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Bovine colostrum has been used with apparent safety in children for 1-3 months (92420,95924,101797,114819). There is insufficient reliable information available about the safety of long-term use of bovine colostrum in children.

CHILDREN: POSSIBLY UNSAFE
when used enterally in very preterm infants in the first few weeks of life. Enterally, bovine colostrum added to breastmilk for very preterm infant feeding in the first 14 days of life has been associated with a higher rate of periventricular leukomalacia when compared with preterm formula added to breastmilk in one clinical trial (114816). Orally, the addition of bovine colostrum to breastmilk for very preterm infant feeding resulted in infants requiring more calcium and phosphate supplementation to maintain acceptable blood levels when compared with conventional fortifier in one clinical trial (114822).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312).

POSSIBLY SAFE ...when used orally in medicinal amounts. Bovine lactoferrin has been safely used at doses of up to 600 mg daily for up to 12 months (13313,13314,13315,13316,13320,13321,13322,13323,97786,104859,104860). Recombinant human lactoferrin has been used with apparent safety at a dose of 5 grams daily for up to 14 days (13317,13318,13319). There is insufficient reliable information available about the safety of lactoferrin when used topically.

CHILDREN: POSSIBLY SAFE
when used enterally in infants and children up to 6 years of age. Lactoferrin has been used safely as a part of enteral feeds in preterm infants at a dose of 250 mg daily or up to 300 mg/kg daily for up to 30 days (97783,97787,104857,104858,104870). Formula fortified with bovine lactoferrin 0.6 grams/L and bovine milk fat globule membrane 5 grams/L has also been used safely in infants for up to 12 months (104866). Bovine and recombinant human lactoferrin 1000 mg daily for up to 6 months has been used with apparent safety in weaned infants up to 18 months of age (97783,97787). Bovine lactoferrin 336-500 mg per week has been used with apparent safety in children 1-6 years of age for 13-15 weeks (104861,104862). There is insufficient reliable information available about the safety of lactoferrin in children over 6 years of age.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312).

PREGNANCY: POSSIBLY SAFE
when used orally in medicinal amounts. Lactoferrin has been used with apparent safety during the second or third trimester of pregnancy at doses of up to 250 mg daily for up to 8 weeks (97788). Also, bovine lactoferrin has been used with apparent safety throughout all trimesters of pregnancy at doses of up to 200 mg daily (104865). There is insufficient reliable information available about the safety of intravaginal lactoferrin during pregnancy and lactation; avoid using.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312). There is insufficient reliable information available about the safety of lactoferrin when used medicinally during lactation; avoid using.

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General ...Orally, bovine colostrum is well tolerated.

Endocrine ...Enterally, the addition of bovine colostrum to breastmilk for very preterm infant feeding resulted in infants requiring more calcium and phosphate supplementation to maintain acceptable blood levels when compared with conventional fortifier in one clinical trial (114822).

Gastrointestinal ...Orally, bovine colostrum has caused nausea and vomiting in an individual with HIV-related cryptosporidiosis (4905). In clinical trials of bovine colostrum, bloating, nausea, diarrhea, and unsettled stomach have been reported as mild in nature by a few patients (92414,101792) with a similar rate of occurrence as those taking a whey-based control (114819).

Hematologic ...Orally, bovine colostrum has caused decreased serum hematocrit in HIV patients treated for infectious diarrhea (4905).

Hepatic ...Orally, bovine colostrum has caused elevated liver function tests in HIV patients treated for infectious diarrhea (4905).

Immunologic ...Topically, there is a case report of anaphylaxis, urticaria, and itching related to bovine colostrum (101793).

Neurologic/CNS ...Enterally , bovine colostrum has been associated with increased risk of periventricular leukomalacia in very preterm infants. Specifically, in a large, multi-center, clinical study conducted in 7 neonatal intensive care units in China, 5 cases of periventricular leukomalacia (PVL), diagnosed with magnetic resonance imaging, were reported among the 155 infants fed bovine colostrum supplemented breastmilk until postnatal day 14, while no cases were reported among the 181 infants receiving preterm formula supplemented breastmilk. Three of the 5 infants with PVL were fed small volumes of bovine colostrum (less than 10 mL/kg daily) while 2 were fed larger volumes of bovine colostrum (18-35 mL/kg daily). in addition to preterm formula (114816).

Renal ...Enterally, bovine colostrum added to breastmilk for infant feeding until postnatal day 14 among very preterm infants has been associated with higher blood urea nitrogen levels by about 3 mg/dL when compared with preterm formula added to breastmilk (114816).

Other ...Theoretical adverse effects to bovine colostrum include an allergic reaction in individuals allergic to bovine milk products. There is also some concern that bovine colostrum that is obtained from cows in countries where bovine spongiform encephalitis (BSE) has been reported might be unsafe, however, there is no research indicating that colostrum can be contaminated with the BSE-causing prion. Countries where BSE has been reported include Great Britain, France, The Netherlands, Portugal, Luxembourg, Ireland, Switzerland, Oman, and Belgium (1825). Until more is known, tell patients to avoid these products unless country of origin can be determined. Patients should avoid products that are produced in countries where BSE has been found.

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General ...Orally, bovine and human recombinant lactoferrin are well tolerated when used in typical doses. However, hjgher doses of 7.2 grams daily increase the risk of side effects and decrease tolerability.
Topically, there is a limited amount of information on the adverse effects of lactoferrin.
Intravaginally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Constipation, diarrhea, epigastric pain, and nausea.
Topically: Burning sensation.
Serious Adverse Effects (Rare):
Orally: Bowel obstruction, intestinal perforation.

Dermatologic ...Orally, at higher doses of 7. 2 grams daily, lactoferrin has been reported to cause skin rash (13323). Topically, burning sensation has been reported (97784).

Gastrointestinal ...Orally, lactoferrin has been reported to cause diarrhea in some patients. At higher doses of 7.2 grams daily, anorexia and constipation have been reported (13323). However, gastrointestinal effects of lactoferrin, including epigastric pain, constipation, nausea, and diarrhea, are less common than with other sources of iron such as ferrous sulfate (97788). In neonates, single cases of jaundice, bloody stool, bowel obstruction, and intestinal perforation have been reported in clinical trials (104857,104858).

Neurologic/CNS ...Orally, at higher doses of 7. 2 grams daily, lactoferrin has been reported to cause fatigue and chills (13323).

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