Bernard Ewigman, MD, MSPH

Illustrative case

A healthy 60-year-old Chicago woman who takes 1500 mg calcium and a multi vitamin daily tells you she has read that extra vitamins prevent cancer. She is particularly concerned about cancer because of her strong family history. Should you recommend that she take any additional vitamins to reduce her risk of cancer?

Background: Will this trial pass the test of time? We think so

Wouldn’t it be nice if we could recommend something as simple and safe as a daily vitamin to reduce the risk of cancer? Until now, we have had no definitive evidence to support such a recommendation. The Lappe et al trial, however, concluded that improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women.¹ Will this single, relatively small study pass the test of time and be confirmed by future clinical trials? We think so.

• The estimated relative risk reduction was dramatic (0.232) and the 95% confidence interval was 0.09 to 0.60, meaning that the true relative risk reduction has a 95% probability of being in the range of 40% to 91%. The P value of <.005 suggests that the probability of this finding occurring by chance alone is less than 1 in 200.
• Our critical appraisal found no significant flaws in this randomized controlled trial.
• Vitamin D is known to have cancer protective effects at the cellular level.
• Prior population based studies support the association between vitamin D and cancer prevention.

For these reasons—and the fact that 1000 IU vitamin D is very safe for most patients—we find this single RCT convincing as a practice changer. For us, the potential benefit outweighs the potential harm.

United States Preventive services Task Force. A 2003 report on “routine vitamin supplementation to prevent cancer and cardiovascular disease” cited insufficient evidence to recommend the use of supplemental vitamins A, C, E, multivitamins with folic acid, or antioxidants to prevent cancer or cardiovascular disease; vitamin D is not mentioned.³

Institute of medicine. In 2005, the IOM suggested an Adequate Intake (AI) of vitamin D of 400 IU for women from 51 to 70 years of age, and 600 IU for women over 70 years of age, to maintain bone health and normal calcium metabolism in healthy women. The IOM cited epidemiologic studies showing an inverse association between either increased sun exposure or higher vitamin D levels and decreased risk of cancer, and included the caveat that it was premature to recommend taking vitamin D for cancer prevention until well-designed trials prove that vitamin D is protective against cancer.⁴

Electronic knowledge resources that are evidence-based and frequently updated did not recommend vitamin D for cancer prevention on the dates we searched.^5-8

Clinical Context: Food, sun, supplements may not deter deficiency

Few people get enough vitamin D to match the dosage that reduced cancer incidence in this trial. In fact, inadequate vitamin D intake, even to meet current standards, is surprisingly common—even in people who are apparently conscious of their nutritional needs. A Boston hospital found that 32% of healthy students, physicians, and resident physicians were vitamin-D deficient, despite drinking a glass of milk daily, taking a daily multivitamin, and eating salmon at least once a week.⁹ An estimated 1 billion people worldwide have vitamin D deficiency or insufficiency.⁹

Many factors affect vitamin D levels (TABLE).⁹ Foods that contain vitamin D₃ include fortified milk (100 IU per cup) and oily fish, including salmon, tuna, sardines, mackerel, and herring (200–300 IU per 3.5-oz serving). Sun exposure for 10 to 15 minutes (without sunscreen) at least twice a week to the face, arms, hands, or back is considered sufficient to provide adequate vitamin D during summer or in warm climates.

Many patients need supplements to reach the levels provided by 1000 IU daily, especially in colder climates. Most over-the-counter supplements containing vitamin D alone contain 400 to 1000 IU vitamin D₃. Prescription vitamin D₂ capsules contain 50,000 IU.⁹ Vitamin D is available as vitamin D₂ and D₃:

• Vitamin D₂ is usually labeled vitamin D or calciferol. Vitamin D₂ is only 30% as effective as vitamin D₃ (doses should be adjusted accordingly).
• Vitamin D₃ is labeled vitamin D₃ or cholecalciferol.

TABLE
3 ways to get vitamin D: Food, sun, and supplements⁹

Study Summary: Cancer was a secondary outcome

This trial was well designed and executed, with impressive findings. The primary outcomes were related to skeletal status and calcium economy. Cancer incidence was one of the secondary outcomes.

This population-based study was randomized, double-blinded, and placebo-controlled, with concealed allocation. The researchers enrolled 1180 women older than 55 years of age, with no known cancer, and with adequate mental and physical health to allow an expected 4 years of participation in the trial. The trial was conducted in rural Nebraska. Eighty-six percent of the participants completed the study. Participants were randomly assigned to 3 groups:

• Placebo (calcium placebo plus vitamin D placebo, n=266)
• calcium-only (1400 mg calcium citrate or 1500 mg calcium carbonate plus vitamin D placebo, n=416)
• Calcium + D (1000 IU [25 mcg] vitamin D plus calcium [as above], n=403)

Every 6 months, adherence was assessed by bottle weight. Mean adherence (taking ≥80% of assigned doses) was 85.7% for vitamin D and 74.4% for calcium. Serum samples were analyzed for 25(OH)D at baseline and then yearly.¹

Key results

Fifty women developed non-skin cancer during the study: 13 in the first year, and 37 during the second to fourth years. Excluding cancer diagnosed in the first year (it was assumed that these cancers were present, though undiagnosed, at entry), the relative risk reduction (RRR) for the calcium + D group was 0.232 (confidence interval [CI], 0.09–0.60; P<.005), and the RRR for the calcium-only group was 0.587 (95% CI, 0.29–1.21; P=.147) compared with the placebo group.

Number needed to treat (NNT) to prevent 1 case of cancer for the calcium + D group is 21, with an absolute risk reduction of 0.048, or approximately 5%.

Risk reduction. Using baseline 25(OH)D concentration as the predictor variable and cancer as the outcome variable in logistic regression, Lappe et al predicted a 35% reduced cancer risk for every 25 nmol/L (10 ng/mL) increase in serum 25(OH)D.¹

What’s New? First RCT to show reduced cancer incidence

This is the first randomized-controlled clinical trial to show that vitamin D reduces cancer risk. (It is important to note that one prior randomized controlled trial¹⁰ found no impact on cancer incidence; however, that trial used a vitamin D₃ dose of 400 IU, which is lower than the 1000 IU dose used by Lappe et al.)

Vitamin D curbs carcinogenic potential. The new findings build on prior basic research, which established the pathophysiologic process by which vitamin D may prevent cancer in humans. Vitamin D receptors are found not only in the small intestines, bones, and kidneys, but also in most other tissues, including skin, colon, prostate, breast, and brain. The interaction of 1,25(OH)₂D with vitamin D receptors induces terminal differentiation and apoptosis and inhibits cellular growth, angiogenesis, and metastatic potential.¹⁰

Other studies suggest vitamin d plays a part. Previous population-based studies also suggested an association between vitamin D and reduced cancer incidence.

Lin et al, as part of the Women’s Health Study, found that higher intake of calcium and vitamin D was associated with a lower risk of breast cancer in premenopausal but not in postmenopausal women. The highest dosage quintile was >548 IU; therefore, many if not most women likely ingested an inadequate dose of vitamin D to reduce risk of cancer.¹¹

The Health Professionals Follow-up Study, which followed a cohort of 47,800 men, from 1986 until 2000, found that low levels of vitamin D were associated with increased incidence of cancer and mortality.¹²

In the only other randomized controlled trial of vitamin D and cancer (also part of the Women’s Health Initiative), Wactawski-Wende et al found no difference in the risk of colorectal cancer between women taking calcium and vitamin D and women taking placebo, over an average of 7 years of follow-up. However, the vitamin D dose was only 400 IU daily, the dosage recommended for general health and bone health.¹³

Caveats: Consider toxicity unlikely

Although excess vitamin D intake, leading to a serum level of 25-hydroxyvitamin D (25[OH]D) >150 ng/mL, can cause toxicity, the IOM has set the tolerable upper intake level of vitamin D (a fat-soluble vitamin stored in the liver) at 2000 IU (50 mcg) for adults and children older than 1 year. Moreover, studies have shown that adults can tolerate doses as high as 10,000 IU per day.⁴

Symptoms of toxicity include nausea, vomiting, poor appetite, constipation, weakness, and weight loss as well as signs and symptoms of hypercalcemia, including mental status changes, renal failure, and arrhythmias.⁴

Diseases and drugs that affect serum levels. Patients with mild to moderate renal failure or chronic granulomatous diseases, such as sarcoidosis, are at higher risk of developing vitamin D toxicity. Patients with malabsorption syndromes, mild or moderate hepatic failure, or who take certain medications, like anticonvulsants or glucocorticoids, that increase vitamin D metabolism may need higher doses of vitamin D.⁹

The good sun. Exposure to sunlight never leads to vitamin D toxicity, as UV radiation destroys any excess vitamin D that is produced.¹⁰

Challenges To Implementation: A matter of time

The primary challenge is likely to be the competing demands and limited resources inherent in delivering all preventive health services in the primary care setting. By one estimate, implementing all preventive health services recommended by the US Preventive Services Task Force would require 7.4 hours per day, leaving little if any time to address the acute and chronic care needs of each individual patient.¹⁴

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.

Illustrative case

A healthy 60-year-old Chicago woman who takes 1500 mg calcium and a multi vitamin daily tells you she has read that extra vitamins prevent cancer. She is particularly concerned about cancer because of her strong family history. Should you recommend that she take any additional vitamins to reduce her risk of cancer?

Background: Will this trial pass the test of time? We think so

Wouldn’t it be nice if we could recommend something as simple and safe as a daily vitamin to reduce the risk of cancer? Until now, we have had no definitive evidence to support such a recommendation. The Lappe et al trial, however, concluded that improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women.¹ Will this single, relatively small study pass the test of time and be confirmed by future clinical trials? We think so.

• The estimated relative risk reduction was dramatic (0.232) and the 95% confidence interval was 0.09 to 0.60, meaning that the true relative risk reduction has a 95% probability of being in the range of 40% to 91%. The P value of <.005 suggests that the probability of this finding occurring by chance alone is less than 1 in 200.
• Our critical appraisal found no significant flaws in this randomized controlled trial.
• Vitamin D is known to have cancer protective effects at the cellular level.
• Prior population based studies support the association between vitamin D and cancer prevention.

For these reasons—and the fact that 1000 IU vitamin D is very safe for most patients—we find this single RCT convincing as a practice changer. For us, the potential benefit outweighs the potential harm.

United States Preventive services Task Force. A 2003 report on “routine vitamin supplementation to prevent cancer and cardiovascular disease” cited insufficient evidence to recommend the use of supplemental vitamins A, C, E, multivitamins with folic acid, or antioxidants to prevent cancer or cardiovascular disease; vitamin D is not mentioned.³

Institute of medicine. In 2005, the IOM suggested an Adequate Intake (AI) of vitamin D of 400 IU for women from 51 to 70 years of age, and 600 IU for women over 70 years of age, to maintain bone health and normal calcium metabolism in healthy women. The IOM cited epidemiologic studies showing an inverse association between either increased sun exposure or higher vitamin D levels and decreased risk of cancer, and included the caveat that it was premature to recommend taking vitamin D for cancer prevention until well-designed trials prove that vitamin D is protective against cancer.⁴

Electronic knowledge resources that are evidence-based and frequently updated did not recommend vitamin D for cancer prevention on the dates we searched.^5-8

Clinical Context: Food, sun, supplements may not deter deficiency

Few people get enough vitamin D to match the dosage that reduced cancer incidence in this trial. In fact, inadequate vitamin D intake, even to meet current standards, is surprisingly common—even in people who are apparently conscious of their nutritional needs. A Boston hospital found that 32% of healthy students, physicians, and resident physicians were vitamin-D deficient, despite drinking a glass of milk daily, taking a daily multivitamin, and eating salmon at least once a week.⁹ An estimated 1 billion people worldwide have vitamin D deficiency or insufficiency.⁹

Many factors affect vitamin D levels (TABLE).⁹ Foods that contain vitamin D₃ include fortified milk (100 IU per cup) and oily fish, including salmon, tuna, sardines, mackerel, and herring (200–300 IU per 3.5-oz serving). Sun exposure for 10 to 15 minutes (without sunscreen) at least twice a week to the face, arms, hands, or back is considered sufficient to provide adequate vitamin D during summer or in warm climates.

Many patients need supplements to reach the levels provided by 1000 IU daily, especially in colder climates. Most over-the-counter supplements containing vitamin D alone contain 400 to 1000 IU vitamin D₃. Prescription vitamin D₂ capsules contain 50,000 IU.⁹ Vitamin D is available as vitamin D₂ and D₃:

• Vitamin D₂ is usually labeled vitamin D or calciferol. Vitamin D₂ is only 30% as effective as vitamin D₃ (doses should be adjusted accordingly).
• Vitamin D₃ is labeled vitamin D₃ or cholecalciferol.

TABLE
3 ways to get vitamin D: Food, sun, and supplements⁹

Study Summary: Cancer was a secondary outcome

This trial was well designed and executed, with impressive findings. The primary outcomes were related to skeletal status and calcium economy. Cancer incidence was one of the secondary outcomes.

This population-based study was randomized, double-blinded, and placebo-controlled, with concealed allocation. The researchers enrolled 1180 women older than 55 years of age, with no known cancer, and with adequate mental and physical health to allow an expected 4 years of participation in the trial. The trial was conducted in rural Nebraska. Eighty-six percent of the participants completed the study. Participants were randomly assigned to 3 groups:

• Placebo (calcium placebo plus vitamin D placebo, n=266)
• calcium-only (1400 mg calcium citrate or 1500 mg calcium carbonate plus vitamin D placebo, n=416)
• Calcium + D (1000 IU [25 mcg] vitamin D plus calcium [as above], n=403)

Every 6 months, adherence was assessed by bottle weight. Mean adherence (taking ≥80% of assigned doses) was 85.7% for vitamin D and 74.4% for calcium. Serum samples were analyzed for 25(OH)D at baseline and then yearly.¹

Key results

Fifty women developed non-skin cancer during the study: 13 in the first year, and 37 during the second to fourth years. Excluding cancer diagnosed in the first year (it was assumed that these cancers were present, though undiagnosed, at entry), the relative risk reduction (RRR) for the calcium + D group was 0.232 (confidence interval [CI], 0.09–0.60; P<.005), and the RRR for the calcium-only group was 0.587 (95% CI, 0.29–1.21; P=.147) compared with the placebo group.

Number needed to treat (NNT) to prevent 1 case of cancer for the calcium + D group is 21, with an absolute risk reduction of 0.048, or approximately 5%.

Risk reduction. Using baseline 25(OH)D concentration as the predictor variable and cancer as the outcome variable in logistic regression, Lappe et al predicted a 35% reduced cancer risk for every 25 nmol/L (10 ng/mL) increase in serum 25(OH)D.¹

What’s New? First RCT to show reduced cancer incidence

This is the first randomized-controlled clinical trial to show that vitamin D reduces cancer risk. (It is important to note that one prior randomized controlled trial¹⁰ found no impact on cancer incidence; however, that trial used a vitamin D₃ dose of 400 IU, which is lower than the 1000 IU dose used by Lappe et al.)

Vitamin D curbs carcinogenic potential. The new findings build on prior basic research, which established the pathophysiologic process by which vitamin D may prevent cancer in humans. Vitamin D receptors are found not only in the small intestines, bones, and kidneys, but also in most other tissues, including skin, colon, prostate, breast, and brain. The interaction of 1,25(OH)₂D with vitamin D receptors induces terminal differentiation and apoptosis and inhibits cellular growth, angiogenesis, and metastatic potential.¹⁰

Other studies suggest vitamin d plays a part. Previous population-based studies also suggested an association between vitamin D and reduced cancer incidence.

Lin et al, as part of the Women’s Health Study, found that higher intake of calcium and vitamin D was associated with a lower risk of breast cancer in premenopausal but not in postmenopausal women. The highest dosage quintile was >548 IU; therefore, many if not most women likely ingested an inadequate dose of vitamin D to reduce risk of cancer.¹¹

The Health Professionals Follow-up Study, which followed a cohort of 47,800 men, from 1986 until 2000, found that low levels of vitamin D were associated with increased incidence of cancer and mortality.¹²

In the only other randomized controlled trial of vitamin D and cancer (also part of the Women’s Health Initiative), Wactawski-Wende et al found no difference in the risk of colorectal cancer between women taking calcium and vitamin D and women taking placebo, over an average of 7 years of follow-up. However, the vitamin D dose was only 400 IU daily, the dosage recommended for general health and bone health.¹³

Caveats: Consider toxicity unlikely

Although excess vitamin D intake, leading to a serum level of 25-hydroxyvitamin D (25[OH]D) >150 ng/mL, can cause toxicity, the IOM has set the tolerable upper intake level of vitamin D (a fat-soluble vitamin stored in the liver) at 2000 IU (50 mcg) for adults and children older than 1 year. Moreover, studies have shown that adults can tolerate doses as high as 10,000 IU per day.⁴

Symptoms of toxicity include nausea, vomiting, poor appetite, constipation, weakness, and weight loss as well as signs and symptoms of hypercalcemia, including mental status changes, renal failure, and arrhythmias.⁴

Diseases and drugs that affect serum levels. Patients with mild to moderate renal failure or chronic granulomatous diseases, such as sarcoidosis, are at higher risk of developing vitamin D toxicity. Patients with malabsorption syndromes, mild or moderate hepatic failure, or who take certain medications, like anticonvulsants or glucocorticoids, that increase vitamin D metabolism may need higher doses of vitamin D.⁹

The good sun. Exposure to sunlight never leads to vitamin D toxicity, as UV radiation destroys any excess vitamin D that is produced.¹⁰

Challenges To Implementation: A matter of time

The primary challenge is likely to be the competing demands and limited resources inherent in delivering all preventive health services in the primary care setting. By one estimate, implementing all preventive health services recommended by the US Preventive Services Task Force would require 7.4 hours per day, leaving little if any time to address the acute and chronic care needs of each individual patient.¹⁴

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.

Illustrative case

A healthy 60-year-old Chicago woman who takes 1500 mg calcium and a multi vitamin daily tells you she has read that extra vitamins prevent cancer. She is particularly concerned about cancer because of her strong family history. Should you recommend that she take any additional vitamins to reduce her risk of cancer?

Background: Will this trial pass the test of time? We think so

Wouldn’t it be nice if we could recommend something as simple and safe as a daily vitamin to reduce the risk of cancer? Until now, we have had no definitive evidence to support such a recommendation. The Lappe et al trial, however, concluded that improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women.¹ Will this single, relatively small study pass the test of time and be confirmed by future clinical trials? We think so.

• The estimated relative risk reduction was dramatic (0.232) and the 95% confidence interval was 0.09 to 0.60, meaning that the true relative risk reduction has a 95% probability of being in the range of 40% to 91%. The P value of <.005 suggests that the probability of this finding occurring by chance alone is less than 1 in 200.
• Our critical appraisal found no significant flaws in this randomized controlled trial.
• Vitamin D is known to have cancer protective effects at the cellular level.
• Prior population based studies support the association between vitamin D and cancer prevention.

For these reasons—and the fact that 1000 IU vitamin D is very safe for most patients—we find this single RCT convincing as a practice changer. For us, the potential benefit outweighs the potential harm.

United States Preventive services Task Force. A 2003 report on “routine vitamin supplementation to prevent cancer and cardiovascular disease” cited insufficient evidence to recommend the use of supplemental vitamins A, C, E, multivitamins with folic acid, or antioxidants to prevent cancer or cardiovascular disease; vitamin D is not mentioned.³

Institute of medicine. In 2005, the IOM suggested an Adequate Intake (AI) of vitamin D of 400 IU for women from 51 to 70 years of age, and 600 IU for women over 70 years of age, to maintain bone health and normal calcium metabolism in healthy women. The IOM cited epidemiologic studies showing an inverse association between either increased sun exposure or higher vitamin D levels and decreased risk of cancer, and included the caveat that it was premature to recommend taking vitamin D for cancer prevention until well-designed trials prove that vitamin D is protective against cancer.⁴

Electronic knowledge resources that are evidence-based and frequently updated did not recommend vitamin D for cancer prevention on the dates we searched.^5-8

Clinical Context: Food, sun, supplements may not deter deficiency

Few people get enough vitamin D to match the dosage that reduced cancer incidence in this trial. In fact, inadequate vitamin D intake, even to meet current standards, is surprisingly common—even in people who are apparently conscious of their nutritional needs. A Boston hospital found that 32% of healthy students, physicians, and resident physicians were vitamin-D deficient, despite drinking a glass of milk daily, taking a daily multivitamin, and eating salmon at least once a week.⁹ An estimated 1 billion people worldwide have vitamin D deficiency or insufficiency.⁹

Many factors affect vitamin D levels (TABLE).⁹ Foods that contain vitamin D₃ include fortified milk (100 IU per cup) and oily fish, including salmon, tuna, sardines, mackerel, and herring (200–300 IU per 3.5-oz serving). Sun exposure for 10 to 15 minutes (without sunscreen) at least twice a week to the face, arms, hands, or back is considered sufficient to provide adequate vitamin D during summer or in warm climates.

Many patients need supplements to reach the levels provided by 1000 IU daily, especially in colder climates. Most over-the-counter supplements containing vitamin D alone contain 400 to 1000 IU vitamin D₃. Prescription vitamin D₂ capsules contain 50,000 IU.⁹ Vitamin D is available as vitamin D₂ and D₃:

• Vitamin D₂ is usually labeled vitamin D or calciferol. Vitamin D₂ is only 30% as effective as vitamin D₃ (doses should be adjusted accordingly).
• Vitamin D₃ is labeled vitamin D₃ or cholecalciferol.

TABLE
3 ways to get vitamin D: Food, sun, and supplements⁹

Study Summary: Cancer was a secondary outcome

This trial was well designed and executed, with impressive findings. The primary outcomes were related to skeletal status and calcium economy. Cancer incidence was one of the secondary outcomes.

This population-based study was randomized, double-blinded, and placebo-controlled, with concealed allocation. The researchers enrolled 1180 women older than 55 years of age, with no known cancer, and with adequate mental and physical health to allow an expected 4 years of participation in the trial. The trial was conducted in rural Nebraska. Eighty-six percent of the participants completed the study. Participants were randomly assigned to 3 groups:

• Placebo (calcium placebo plus vitamin D placebo, n=266)
• calcium-only (1400 mg calcium citrate or 1500 mg calcium carbonate plus vitamin D placebo, n=416)
• Calcium + D (1000 IU [25 mcg] vitamin D plus calcium [as above], n=403)

Every 6 months, adherence was assessed by bottle weight. Mean adherence (taking ≥80% of assigned doses) was 85.7% for vitamin D and 74.4% for calcium. Serum samples were analyzed for 25(OH)D at baseline and then yearly.¹

Key results

Fifty women developed non-skin cancer during the study: 13 in the first year, and 37 during the second to fourth years. Excluding cancer diagnosed in the first year (it was assumed that these cancers were present, though undiagnosed, at entry), the relative risk reduction (RRR) for the calcium + D group was 0.232 (confidence interval [CI], 0.09–0.60; P<.005), and the RRR for the calcium-only group was 0.587 (95% CI, 0.29–1.21; P=.147) compared with the placebo group.

Number needed to treat (NNT) to prevent 1 case of cancer for the calcium + D group is 21, with an absolute risk reduction of 0.048, or approximately 5%.

Risk reduction. Using baseline 25(OH)D concentration as the predictor variable and cancer as the outcome variable in logistic regression, Lappe et al predicted a 35% reduced cancer risk for every 25 nmol/L (10 ng/mL) increase in serum 25(OH)D.¹

What’s New? First RCT to show reduced cancer incidence

This is the first randomized-controlled clinical trial to show that vitamin D reduces cancer risk. (It is important to note that one prior randomized controlled trial¹⁰ found no impact on cancer incidence; however, that trial used a vitamin D₃ dose of 400 IU, which is lower than the 1000 IU dose used by Lappe et al.)

Vitamin D curbs carcinogenic potential. The new findings build on prior basic research, which established the pathophysiologic process by which vitamin D may prevent cancer in humans. Vitamin D receptors are found not only in the small intestines, bones, and kidneys, but also in most other tissues, including skin, colon, prostate, breast, and brain. The interaction of 1,25(OH)₂D with vitamin D receptors induces terminal differentiation and apoptosis and inhibits cellular growth, angiogenesis, and metastatic potential.¹⁰

Other studies suggest vitamin d plays a part. Previous population-based studies also suggested an association between vitamin D and reduced cancer incidence.

Lin et al, as part of the Women’s Health Study, found that higher intake of calcium and vitamin D was associated with a lower risk of breast cancer in premenopausal but not in postmenopausal women. The highest dosage quintile was >548 IU; therefore, many if not most women likely ingested an inadequate dose of vitamin D to reduce risk of cancer.¹¹

The Health Professionals Follow-up Study, which followed a cohort of 47,800 men, from 1986 until 2000, found that low levels of vitamin D were associated with increased incidence of cancer and mortality.¹²

In the only other randomized controlled trial of vitamin D and cancer (also part of the Women’s Health Initiative), Wactawski-Wende et al found no difference in the risk of colorectal cancer between women taking calcium and vitamin D and women taking placebo, over an average of 7 years of follow-up. However, the vitamin D dose was only 400 IU daily, the dosage recommended for general health and bone health.¹³

Caveats: Consider toxicity unlikely

Although excess vitamin D intake, leading to a serum level of 25-hydroxyvitamin D (25[OH]D) >150 ng/mL, can cause toxicity, the IOM has set the tolerable upper intake level of vitamin D (a fat-soluble vitamin stored in the liver) at 2000 IU (50 mcg) for adults and children older than 1 year. Moreover, studies have shown that adults can tolerate doses as high as 10,000 IU per day.⁴

Symptoms of toxicity include nausea, vomiting, poor appetite, constipation, weakness, and weight loss as well as signs and symptoms of hypercalcemia, including mental status changes, renal failure, and arrhythmias.⁴

Diseases and drugs that affect serum levels. Patients with mild to moderate renal failure or chronic granulomatous diseases, such as sarcoidosis, are at higher risk of developing vitamin D toxicity. Patients with malabsorption syndromes, mild or moderate hepatic failure, or who take certain medications, like anticonvulsants or glucocorticoids, that increase vitamin D metabolism may need higher doses of vitamin D.⁹

The good sun. Exposure to sunlight never leads to vitamin D toxicity, as UV radiation destroys any excess vitamin D that is produced.¹⁰

Challenges To Implementation: A matter of time

The primary challenge is likely to be the competing demands and limited resources inherent in delivering all preventive health services in the primary care setting. By one estimate, implementing all preventive health services recommended by the US Preventive Services Task Force would require 7.4 hours per day, leaving little if any time to address the acute and chronic care needs of each individual patient.¹⁴

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.

In this issue of JFP, 2 well-known family physician leaders, Carol Herbert and Stephen Spann,^1,2 describe a variety of threats to the specialty of family practice, warn of its potential demise, and call for its reinvention. The threats include new knowledge in genomics, new technologies, increasing patient desire for direct access to other physician specialists, increased access to information by patients through the Internet and media, evidence-based medicine (EBM), alternative and complementary medicine, nurse practitioners and physicians assistants, nurse triage systems, the abandonment of traditional roles such as hospital care, the push for higher quality of care, and the demand that costs be contained. For tangible evidence of a threat, the authors cite the decreased numbers of medical students entering family practice, decreased satisfaction among physicians, and the replacement of traditional family physician roles by other care providers.

Is our demise impending? To paraphrase Mark Twain, another Missourian: Rumors of our impending death are greatly exaggerated.

Changes offer opportunities

I agree we live in a time of dramatic reorganization of health care and tremendous growth in biologic knowledge and the capacities of information technology. One result of this is that patient expectations are increasing. At the same time, the rising cost of medical care is forcing uncomfortable choices in how we practice medicine. These changes can be seen as opportunities rather than threats. Our opportunity in family practice is threefold: to continue to respond to the need for patient-centered medical care, to translate emerging knowledge into improved patient outcomes, and to manage that knowledge through information technology to put it to the best use for our patients and communities. Pursuing these opportunities seriously will certainly require changes in strategies and roles for family physicians; in doing so, we must maintain the core function of the family physician as a personal physician and enhance the physician-patient relationship, not detract from it.

Solutions through creativity

Spann² identifies such a strategy for the discipline in his vision of information technology harnessed to help rather than threaten us. In his model, technology would be used to give health care providers and patients easier access to reliable information and more assistance with decision making and informed consent. We would thus commit fewer errors, improve access, and provide a higher quality of care. Such a system could assist us in managing genomic information, selecting diagnostic and therapeutic technologies, and managing the information overload and hype that appropriately concern Herbert.¹ Hopefully this will allow us to spend more time with patients and less time with paperwork and tracking down information, and will enable us to continue our strong focus on the physician-patient relationship. Spann’s model is an example of the creative solutions that I am confident will be generated. These solutions could enable family physicians to maintain their essential and satisfying historical roles as personal physicians in North America.

My belief that family medicine will succeed is based on my confidence in the creativity of my colleagues and of those in other disciplines, and on the fact that I find the evidence of potential demise unconvincing. Student interest fluctuates in all disciplines. Physicians in many specialties have experienced a greater relative loss of income and decreased personal satisfaction in the past decade than family physicians. Most family physicians I know welcome the opportunity to lead a more balanced life by having emergency coverage and appreciate nurse triage lines for minor problems. Many work in multidisciplinary team settings in which the burdens of care are shared. These physicians still have strong physician-patient relationships and play an important role as personal physicians. Do not misunderstand; I grumble about loss of autonomy, unfairness in the system, and the paperwork, too. I was disappointed as well when our residency program did not fill this year. But when I think about my experiences practicing medicine in Columbia, Missouri, in Sierra Leone, and in Guatemala I recognize how blessed we really are. As Ringdahl described so eloquently in her recent essay,³ we only have to step back and consider the devastating life experiences of our patients to gain proper perspective on “tragedies” like not filling our residency programs.

Family Medicine Research

I agree with Herbert’s recommendations,¹ particularly her points about the need for research career paths, the need for family medicine researchers to understand the changing landscape of health care and health care research, and the integrative and multidisciplinary nature of much of the best family medicine research. In fact, those multidisciplinary teams could, and do in many cases, productively include basic scientists, ethicists, and health promotion experts. However, I do not agree that family medicine as a discipline is particularly well trained or has a distinctive capacity to address such broad social issues as poverty, violence, pollution, and climate change beyond our roles as responsible citizens and as those issues affect our patients.

Another point in Herbert’s article with which I disagree is her criticism of EBM. Those who have articulated the concepts that fall under the rubric of EBM have acknowledged the role of patient preferences and values, pathophysiologic reasoning, and the history and physical examination as essential ingredients of clinical judgement. The clinical epidemiologic research adds the most valid and relevant findings to this mix.^4-6 Each source of “evidence” plays an important role in the management of individual patients. Unfortunately, Herbert criticizes EBM because of how it is abused and for the paucity of research available. These are certainly problems, but they are indictments of the users and of insufficient research, not of EBM. The practical application of EBM in a patient-centered fashion (referred to as information mastery⁷) is the single most important competence we need to add to our training of medical students, residents, and faculty.

Herbert’s approach of asking a basic scientist, an ethicist, and a health promotion expert to describe the role of family medicine research revealed her colleagues were uninformed. I believe her intent was to illustrate that we lack a widespread recognition for our research. That may be useful information, but given our developmental stage I do not find it surprising. For the past 5 years I have chaired the North American Primary Care Research Group’s Committee on Building Research Capacity and the Association of Family Medicine Organizations Research Subcommittee and directed 4 research capacity building workshops involving the chairs and research directors of 29 family medicine departments. I see a vision of the scope, role, and nature of family medicine research coming into sharper focus. Practice-based research is clearly a central contribution of family medicine research. Family medicine research is primarily integrative in nature, using multiple methods. The paper Stange⁸ presented on this topic at the Keystone III Conference articulates much of this vision.

The delivery of personal preventive health services is an example of an important body of knowledge to which family medicine researchers have contributed significantly. The American Academy of Family Physicians’ groundbreaking initiatives have led to the development of 3 family practice research centers, a national research network, a national policy research office, and a large number of family physicians receiving advanced research training. We are developing research in our discipline as we should; the recognition will come in due time. More important, we are producing original research and translations of that research that will provide family physicians with the knowledge that they are obligated to bring to their relationships with patients.

Conclusions

General practice was reinvented as family practice in the United States in 1969 as a response to society’s need for a personal physician to provide medical care. The need for a trusted physician-patient relationship has not changed, but that relationship will be expressed in different ways. How patients need us to serve in that relationship has changed, and we must adapt. We must embrace and contribute to emerging knowledge and translate that knowledge into beneficial care as partners with our patients, collaborate more with our colleagues in other disciplines, and add information mastery to our armamentarium. By doing so we will reinvent family practice again—and probably not for the last time.

Acknowledgments

My thanks to Robert Blake, Mary Barile, Jack Colwill, and Steven Zweig for their thoughtful review of this manuscript.

In this issue of JFP, 2 well-known family physician leaders, Carol Herbert and Stephen Spann,^1,2 describe a variety of threats to the specialty of family practice, warn of its potential demise, and call for its reinvention. The threats include new knowledge in genomics, new technologies, increasing patient desire for direct access to other physician specialists, increased access to information by patients through the Internet and media, evidence-based medicine (EBM), alternative and complementary medicine, nurse practitioners and physicians assistants, nurse triage systems, the abandonment of traditional roles such as hospital care, the push for higher quality of care, and the demand that costs be contained. For tangible evidence of a threat, the authors cite the decreased numbers of medical students entering family practice, decreased satisfaction among physicians, and the replacement of traditional family physician roles by other care providers.

Is our demise impending? To paraphrase Mark Twain, another Missourian: Rumors of our impending death are greatly exaggerated.

Changes offer opportunities

I agree we live in a time of dramatic reorganization of health care and tremendous growth in biologic knowledge and the capacities of information technology. One result of this is that patient expectations are increasing. At the same time, the rising cost of medical care is forcing uncomfortable choices in how we practice medicine. These changes can be seen as opportunities rather than threats. Our opportunity in family practice is threefold: to continue to respond to the need for patient-centered medical care, to translate emerging knowledge into improved patient outcomes, and to manage that knowledge through information technology to put it to the best use for our patients and communities. Pursuing these opportunities seriously will certainly require changes in strategies and roles for family physicians; in doing so, we must maintain the core function of the family physician as a personal physician and enhance the physician-patient relationship, not detract from it.

Solutions through creativity

Spann² identifies such a strategy for the discipline in his vision of information technology harnessed to help rather than threaten us. In his model, technology would be used to give health care providers and patients easier access to reliable information and more assistance with decision making and informed consent. We would thus commit fewer errors, improve access, and provide a higher quality of care. Such a system could assist us in managing genomic information, selecting diagnostic and therapeutic technologies, and managing the information overload and hype that appropriately concern Herbert.¹ Hopefully this will allow us to spend more time with patients and less time with paperwork and tracking down information, and will enable us to continue our strong focus on the physician-patient relationship. Spann’s model is an example of the creative solutions that I am confident will be generated. These solutions could enable family physicians to maintain their essential and satisfying historical roles as personal physicians in North America.

My belief that family medicine will succeed is based on my confidence in the creativity of my colleagues and of those in other disciplines, and on the fact that I find the evidence of potential demise unconvincing. Student interest fluctuates in all disciplines. Physicians in many specialties have experienced a greater relative loss of income and decreased personal satisfaction in the past decade than family physicians. Most family physicians I know welcome the opportunity to lead a more balanced life by having emergency coverage and appreciate nurse triage lines for minor problems. Many work in multidisciplinary team settings in which the burdens of care are shared. These physicians still have strong physician-patient relationships and play an important role as personal physicians. Do not misunderstand; I grumble about loss of autonomy, unfairness in the system, and the paperwork, too. I was disappointed as well when our residency program did not fill this year. But when I think about my experiences practicing medicine in Columbia, Missouri, in Sierra Leone, and in Guatemala I recognize how blessed we really are. As Ringdahl described so eloquently in her recent essay,³ we only have to step back and consider the devastating life experiences of our patients to gain proper perspective on “tragedies” like not filling our residency programs.

Family Medicine Research

I agree with Herbert’s recommendations,¹ particularly her points about the need for research career paths, the need for family medicine researchers to understand the changing landscape of health care and health care research, and the integrative and multidisciplinary nature of much of the best family medicine research. In fact, those multidisciplinary teams could, and do in many cases, productively include basic scientists, ethicists, and health promotion experts. However, I do not agree that family medicine as a discipline is particularly well trained or has a distinctive capacity to address such broad social issues as poverty, violence, pollution, and climate change beyond our roles as responsible citizens and as those issues affect our patients.

Another point in Herbert’s article with which I disagree is her criticism of EBM. Those who have articulated the concepts that fall under the rubric of EBM have acknowledged the role of patient preferences and values, pathophysiologic reasoning, and the history and physical examination as essential ingredients of clinical judgement. The clinical epidemiologic research adds the most valid and relevant findings to this mix.^4-6 Each source of “evidence” plays an important role in the management of individual patients. Unfortunately, Herbert criticizes EBM because of how it is abused and for the paucity of research available. These are certainly problems, but they are indictments of the users and of insufficient research, not of EBM. The practical application of EBM in a patient-centered fashion (referred to as information mastery⁷) is the single most important competence we need to add to our training of medical students, residents, and faculty.

Herbert’s approach of asking a basic scientist, an ethicist, and a health promotion expert to describe the role of family medicine research revealed her colleagues were uninformed. I believe her intent was to illustrate that we lack a widespread recognition for our research. That may be useful information, but given our developmental stage I do not find it surprising. For the past 5 years I have chaired the North American Primary Care Research Group’s Committee on Building Research Capacity and the Association of Family Medicine Organizations Research Subcommittee and directed 4 research capacity building workshops involving the chairs and research directors of 29 family medicine departments. I see a vision of the scope, role, and nature of family medicine research coming into sharper focus. Practice-based research is clearly a central contribution of family medicine research. Family medicine research is primarily integrative in nature, using multiple methods. The paper Stange⁸ presented on this topic at the Keystone III Conference articulates much of this vision.

The delivery of personal preventive health services is an example of an important body of knowledge to which family medicine researchers have contributed significantly. The American Academy of Family Physicians’ groundbreaking initiatives have led to the development of 3 family practice research centers, a national research network, a national policy research office, and a large number of family physicians receiving advanced research training. We are developing research in our discipline as we should; the recognition will come in due time. More important, we are producing original research and translations of that research that will provide family physicians with the knowledge that they are obligated to bring to their relationships with patients.

Conclusions

General practice was reinvented as family practice in the United States in 1969 as a response to society’s need for a personal physician to provide medical care. The need for a trusted physician-patient relationship has not changed, but that relationship will be expressed in different ways. How patients need us to serve in that relationship has changed, and we must adapt. We must embrace and contribute to emerging knowledge and translate that knowledge into beneficial care as partners with our patients, collaborate more with our colleagues in other disciplines, and add information mastery to our armamentarium. By doing so we will reinvent family practice again—and probably not for the last time.

Acknowledgments

My thanks to Robert Blake, Mary Barile, Jack Colwill, and Steven Zweig for their thoughtful review of this manuscript.

In this issue of JFP, 2 well-known family physician leaders, Carol Herbert and Stephen Spann,^1,2 describe a variety of threats to the specialty of family practice, warn of its potential demise, and call for its reinvention. The threats include new knowledge in genomics, new technologies, increasing patient desire for direct access to other physician specialists, increased access to information by patients through the Internet and media, evidence-based medicine (EBM), alternative and complementary medicine, nurse practitioners and physicians assistants, nurse triage systems, the abandonment of traditional roles such as hospital care, the push for higher quality of care, and the demand that costs be contained. For tangible evidence of a threat, the authors cite the decreased numbers of medical students entering family practice, decreased satisfaction among physicians, and the replacement of traditional family physician roles by other care providers.

Is our demise impending? To paraphrase Mark Twain, another Missourian: Rumors of our impending death are greatly exaggerated.

Changes offer opportunities

I agree we live in a time of dramatic reorganization of health care and tremendous growth in biologic knowledge and the capacities of information technology. One result of this is that patient expectations are increasing. At the same time, the rising cost of medical care is forcing uncomfortable choices in how we practice medicine. These changes can be seen as opportunities rather than threats. Our opportunity in family practice is threefold: to continue to respond to the need for patient-centered medical care, to translate emerging knowledge into improved patient outcomes, and to manage that knowledge through information technology to put it to the best use for our patients and communities. Pursuing these opportunities seriously will certainly require changes in strategies and roles for family physicians; in doing so, we must maintain the core function of the family physician as a personal physician and enhance the physician-patient relationship, not detract from it.

Solutions through creativity

Spann² identifies such a strategy for the discipline in his vision of information technology harnessed to help rather than threaten us. In his model, technology would be used to give health care providers and patients easier access to reliable information and more assistance with decision making and informed consent. We would thus commit fewer errors, improve access, and provide a higher quality of care. Such a system could assist us in managing genomic information, selecting diagnostic and therapeutic technologies, and managing the information overload and hype that appropriately concern Herbert.¹ Hopefully this will allow us to spend more time with patients and less time with paperwork and tracking down information, and will enable us to continue our strong focus on the physician-patient relationship. Spann’s model is an example of the creative solutions that I am confident will be generated. These solutions could enable family physicians to maintain their essential and satisfying historical roles as personal physicians in North America.

My belief that family medicine will succeed is based on my confidence in the creativity of my colleagues and of those in other disciplines, and on the fact that I find the evidence of potential demise unconvincing. Student interest fluctuates in all disciplines. Physicians in many specialties have experienced a greater relative loss of income and decreased personal satisfaction in the past decade than family physicians. Most family physicians I know welcome the opportunity to lead a more balanced life by having emergency coverage and appreciate nurse triage lines for minor problems. Many work in multidisciplinary team settings in which the burdens of care are shared. These physicians still have strong physician-patient relationships and play an important role as personal physicians. Do not misunderstand; I grumble about loss of autonomy, unfairness in the system, and the paperwork, too. I was disappointed as well when our residency program did not fill this year. But when I think about my experiences practicing medicine in Columbia, Missouri, in Sierra Leone, and in Guatemala I recognize how blessed we really are. As Ringdahl described so eloquently in her recent essay,³ we only have to step back and consider the devastating life experiences of our patients to gain proper perspective on “tragedies” like not filling our residency programs.

Family Medicine Research

I agree with Herbert’s recommendations,¹ particularly her points about the need for research career paths, the need for family medicine researchers to understand the changing landscape of health care and health care research, and the integrative and multidisciplinary nature of much of the best family medicine research. In fact, those multidisciplinary teams could, and do in many cases, productively include basic scientists, ethicists, and health promotion experts. However, I do not agree that family medicine as a discipline is particularly well trained or has a distinctive capacity to address such broad social issues as poverty, violence, pollution, and climate change beyond our roles as responsible citizens and as those issues affect our patients.

Another point in Herbert’s article with which I disagree is her criticism of EBM. Those who have articulated the concepts that fall under the rubric of EBM have acknowledged the role of patient preferences and values, pathophysiologic reasoning, and the history and physical examination as essential ingredients of clinical judgement. The clinical epidemiologic research adds the most valid and relevant findings to this mix.^4-6 Each source of “evidence” plays an important role in the management of individual patients. Unfortunately, Herbert criticizes EBM because of how it is abused and for the paucity of research available. These are certainly problems, but they are indictments of the users and of insufficient research, not of EBM. The practical application of EBM in a patient-centered fashion (referred to as information mastery⁷) is the single most important competence we need to add to our training of medical students, residents, and faculty.

Herbert’s approach of asking a basic scientist, an ethicist, and a health promotion expert to describe the role of family medicine research revealed her colleagues were uninformed. I believe her intent was to illustrate that we lack a widespread recognition for our research. That may be useful information, but given our developmental stage I do not find it surprising. For the past 5 years I have chaired the North American Primary Care Research Group’s Committee on Building Research Capacity and the Association of Family Medicine Organizations Research Subcommittee and directed 4 research capacity building workshops involving the chairs and research directors of 29 family medicine departments. I see a vision of the scope, role, and nature of family medicine research coming into sharper focus. Practice-based research is clearly a central contribution of family medicine research. Family medicine research is primarily integrative in nature, using multiple methods. The paper Stange⁸ presented on this topic at the Keystone III Conference articulates much of this vision.

The delivery of personal preventive health services is an example of an important body of knowledge to which family medicine researchers have contributed significantly. The American Academy of Family Physicians’ groundbreaking initiatives have led to the development of 3 family practice research centers, a national research network, a national policy research office, and a large number of family physicians receiving advanced research training. We are developing research in our discipline as we should; the recognition will come in due time. More important, we are producing original research and translations of that research that will provide family physicians with the knowledge that they are obligated to bring to their relationships with patients.

Conclusions

General practice was reinvented as family practice in the United States in 1969 as a response to society’s need for a personal physician to provide medical care. The need for a trusted physician-patient relationship has not changed, but that relationship will be expressed in different ways. How patients need us to serve in that relationship has changed, and we must adapt. We must embrace and contribute to emerging knowledge and translate that knowledge into beneficial care as partners with our patients, collaborate more with our colleagues in other disciplines, and add information mastery to our armamentarium. By doing so we will reinvent family practice again—and probably not for the last time.

Acknowledgments

My thanks to Robert Blake, Mary Barile, Jack Colwill, and Steven Zweig for their thoughtful review of this manuscript.

Evidence summary

Reflux of gastric contents into the esophagus (both regurgitant [into the mouth] and nonregurgitant) is a normal physiologic event. The incidence of regurgitation is similar in breast-fed and formula-fed infants, occurring in up to 67% of 4-month-olds. In the majority of infants, regurgitation is uncomplicated and self-limited, resolving spontaneously by 6 to 12 months of age,^5,6 with 21% of 6- to 7-month-old infants and 5% of 10- to 12- month old infants experiencing regurgitant reflux.⁶ In less than 3% of infants, reflux is severe enough to result in clinically significant GERD.⁵ GERD is suggested by persistent irritability, sleep disturbance, abnormal posturing, hematemesis, excessive crying, respiratory symptoms, and failure to thrive.⁷

True allergy to cow’s milk or soy-based formulas likely occurs in less than 2% of infants,⁸ but is unlikely to present with vomiting as the only symptom. Temporary carbohydrate intolerance may occur with gastroenteritis, malnutrition, or in preterm infants, but otherwise is rare in infancy.⁹ Controlled trials have demonstrated no difference in colic, spitting-up, vomiting, fussiness, cramps, flatus, or stools frequency between iron-fortified and nonfortified formulas.^1,2

Retrospective surveys studying outcomes associated with formula change reveal that approximately one third of infants experience a formula change,³ but the retrospective nature of these studies, lack of blinding and control groups, and selflimiting nature of regurgitation makes interpretation of these studies difficult.

In infants with GERD, formula thickening has numerous benefits, including reductions in frequency of regurgitation, total volume of emesis, and time spent crying by one third, and an increase in time spent sleeping by 18% per 90-minute postprandial period. Formula thickening also increases the frequency of postprandial cough, but the clinical significance of this is unclear. Aspiration was not observed on scintigraphic examination following thickened feedings.⁴

Dry rice cereal (one tablespoon per ounce of formula) is a common thickener with excellent digestibility, but increases the caloric density of formula and can cause constipation. Thickened formulas also require enlarged nipple holes to feed, potentially resulting in greater ingestion of air or formula, which can favor regurgitation. Commercially available pre-thickened formulas are nutritionally balanced, convenient, well tolerated, and do not require enlarged nipple holes to feed.⁵

Increased frequency of feedings with smaller volumes has not been proved efficacious, is difficult to implement, and may create distress in a hungry infant. In overfed infants, or infants fed large volumes at infrequent intervals, feeding volume or feeding interval should be reduced. There is no benefit to head-elevated prone versus flat-prone positioning.

Recommendations from others

The European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend parental reassurance and formula thickening as first-line therapy for the management of infants with uncomplicated regurgitation.⁵ Flat-prone positioning, further evaluation, or a trial of H2 blockers may be considered in infants not responding to first-line therapy.

Evidence summary

Reflux of gastric contents into the esophagus (both regurgitant [into the mouth] and nonregurgitant) is a normal physiologic event. The incidence of regurgitation is similar in breast-fed and formula-fed infants, occurring in up to 67% of 4-month-olds. In the majority of infants, regurgitation is uncomplicated and self-limited, resolving spontaneously by 6 to 12 months of age,^5,6 with 21% of 6- to 7-month-old infants and 5% of 10- to 12- month old infants experiencing regurgitant reflux.⁶ In less than 3% of infants, reflux is severe enough to result in clinically significant GERD.⁵ GERD is suggested by persistent irritability, sleep disturbance, abnormal posturing, hematemesis, excessive crying, respiratory symptoms, and failure to thrive.⁷

True allergy to cow’s milk or soy-based formulas likely occurs in less than 2% of infants,⁸ but is unlikely to present with vomiting as the only symptom. Temporary carbohydrate intolerance may occur with gastroenteritis, malnutrition, or in preterm infants, but otherwise is rare in infancy.⁹ Controlled trials have demonstrated no difference in colic, spitting-up, vomiting, fussiness, cramps, flatus, or stools frequency between iron-fortified and nonfortified formulas.^1,2

Retrospective surveys studying outcomes associated with formula change reveal that approximately one third of infants experience a formula change,³ but the retrospective nature of these studies, lack of blinding and control groups, and selflimiting nature of regurgitation makes interpretation of these studies difficult.

In infants with GERD, formula thickening has numerous benefits, including reductions in frequency of regurgitation, total volume of emesis, and time spent crying by one third, and an increase in time spent sleeping by 18% per 90-minute postprandial period. Formula thickening also increases the frequency of postprandial cough, but the clinical significance of this is unclear. Aspiration was not observed on scintigraphic examination following thickened feedings.⁴

Dry rice cereal (one tablespoon per ounce of formula) is a common thickener with excellent digestibility, but increases the caloric density of formula and can cause constipation. Thickened formulas also require enlarged nipple holes to feed, potentially resulting in greater ingestion of air or formula, which can favor regurgitation. Commercially available pre-thickened formulas are nutritionally balanced, convenient, well tolerated, and do not require enlarged nipple holes to feed.⁵

Increased frequency of feedings with smaller volumes has not been proved efficacious, is difficult to implement, and may create distress in a hungry infant. In overfed infants, or infants fed large volumes at infrequent intervals, feeding volume or feeding interval should be reduced. There is no benefit to head-elevated prone versus flat-prone positioning.

Recommendations from others

The European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend parental reassurance and formula thickening as first-line therapy for the management of infants with uncomplicated regurgitation.⁵ Flat-prone positioning, further evaluation, or a trial of H2 blockers may be considered in infants not responding to first-line therapy.

Evidence summary

Reflux of gastric contents into the esophagus (both regurgitant [into the mouth] and nonregurgitant) is a normal physiologic event. The incidence of regurgitation is similar in breast-fed and formula-fed infants, occurring in up to 67% of 4-month-olds. In the majority of infants, regurgitation is uncomplicated and self-limited, resolving spontaneously by 6 to 12 months of age,^5,6 with 21% of 6- to 7-month-old infants and 5% of 10- to 12- month old infants experiencing regurgitant reflux.⁶ In less than 3% of infants, reflux is severe enough to result in clinically significant GERD.⁵ GERD is suggested by persistent irritability, sleep disturbance, abnormal posturing, hematemesis, excessive crying, respiratory symptoms, and failure to thrive.⁷

True allergy to cow’s milk or soy-based formulas likely occurs in less than 2% of infants,⁸ but is unlikely to present with vomiting as the only symptom. Temporary carbohydrate intolerance may occur with gastroenteritis, malnutrition, or in preterm infants, but otherwise is rare in infancy.⁹ Controlled trials have demonstrated no difference in colic, spitting-up, vomiting, fussiness, cramps, flatus, or stools frequency between iron-fortified and nonfortified formulas.^1,2

Retrospective surveys studying outcomes associated with formula change reveal that approximately one third of infants experience a formula change,³ but the retrospective nature of these studies, lack of blinding and control groups, and selflimiting nature of regurgitation makes interpretation of these studies difficult.

In infants with GERD, formula thickening has numerous benefits, including reductions in frequency of regurgitation, total volume of emesis, and time spent crying by one third, and an increase in time spent sleeping by 18% per 90-minute postprandial period. Formula thickening also increases the frequency of postprandial cough, but the clinical significance of this is unclear. Aspiration was not observed on scintigraphic examination following thickened feedings.⁴

Dry rice cereal (one tablespoon per ounce of formula) is a common thickener with excellent digestibility, but increases the caloric density of formula and can cause constipation. Thickened formulas also require enlarged nipple holes to feed, potentially resulting in greater ingestion of air or formula, which can favor regurgitation. Commercially available pre-thickened formulas are nutritionally balanced, convenient, well tolerated, and do not require enlarged nipple holes to feed.⁵

Increased frequency of feedings with smaller volumes has not been proved efficacious, is difficult to implement, and may create distress in a hungry infant. In overfed infants, or infants fed large volumes at infrequent intervals, feeding volume or feeding interval should be reduced. There is no benefit to head-elevated prone versus flat-prone positioning.

Recommendations from others

The European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend parental reassurance and formula thickening as first-line therapy for the management of infants with uncomplicated regurgitation.⁵ Flat-prone positioning, further evaluation, or a trial of H2 blockers may be considered in infants not responding to first-line therapy.