By Todd Harrison & Michelle Jackson, Venable06.01.18
On behalf of the Organic and Natural Health Association, we recently drafted a new health claim petition for vitamin D3 and reducing the risk of preterm birth, for which pregnant women in the U.S. are at risk. We are asking the U.S. Food and Drug Administration (FDA), conventional medicine, and the healthcare industry to consider a health claim petition in a manner that is consistent with an individual’s nutrient status rather than rely on the strictures of randomized controlled trials (RCTs).
If you read this column on a regular basis, you know I am highly critical of the RCT approach especially when it comes to the health benefits of essential nutrients. Indeed, RCTs may not indicate a benefit because the dosage level necessary to increase an individual’s serum level is largely dependent on that individual’s initial status and ability or inability to absorb that nutrient.
With regard to Organic and Natural’s health claim petition, we found that neutral or negative RCTs on their face are a poor predictor of an outcome without knowing or understanding the woman’s baseline 25(OH)D levels in the first instance and whether that particular dose of vitamin D3 used in the RCT was able to increase a woman’s serum 25(OH)D levels, at a minimum, above 30 ng/mL (100 nmol/L).
Scientific Consensus
More specifically, when one reviews the literature in the first instance, there is general consensus that for pregnant women with serum 25(OH)D levels of less than 40 ng/mL (100 nmol/L), there is a benefit to raising serum 25(OH)D levels; specifically, there is a decreased risk of preterm birth. However, because pregnant women have different starting serum 25(OH)D levels, the level of vitamin D3 necessary to increase their serum levels (and thereby reduce the risk of preterm birth) is patient-specific and cannot be judged simply by the dose level. In other words, those RCTs that simply provided every woman in the study the same dose are flawed because they failed to take into account the women’s initial 25(OH)D levels. The vitamin D3 dose necessary to increase the level of 25(OH)D to at least 30 ng/mL—and preferably above 40 ng/mL (100 nmol/L)—will depend on the particular woman’s ability to absorb the nutrient, and cannot be generalized across the board. Because the dose level necessary to increase 25(OH)D in a particular woman cannot be generalized, the proposed health claim petition specifically recommends that a woman work with her healthcare practitioner to determine the appropriate dose levels.
Addressing Health Concerns
The U.S. Centers for Disease Control (CDC) reported that, in 2015, the U.S. birth rate was 12.4 per 1,000 and there were almost 4 million births. The CDC also reported that approximately one in 10 births are preterm, and each day in North America, more than 1,000 babies are born prematurely. Preterm birth is generally defined as birth before 37 weeks of pregnancy are completed.
According to Save the Children, the March of Dimes, and others, the U.S. is among the top 10 countries where preterm birth occurs, and 130 countries have a lower preterm birth rate than the U.S. Preterm (or premature) birth is an adverse pregnancy outcome that is the leading cause of perinatal morbidity and mortality. Of particular concern is that 2016 marked a second consecutive year of increasing preterm birth rates, and the trend is expected to increase once 2017 data is assessed. In 2015, the CDC reported that preterm birth and low birth weight were responsible for approximately 17% of infant deaths. Preterm birth is a leading cause of many long-term health-related conditions (e.g., neurological and respiratory disorders, learning difficulties, and behavioral challenges), according to March of Dimes. Preterm birth also has significant economic impacts (e.g., healthcare costs, lost income, special education services).
While preterm birth is a heterogeneous health-related condition, several risk factors are known and are routinely addressed during antenatal care (e.g., age, economic status and workplace conditions, inflammation and infection, and diet and nutrition). As diet and nutrition advice—including recommendations for dietary supplements—is routinely given to ensure maternal and fetal health with the goal of achieving a healthy full term pregnancy, research has necessarily focused on better understanding the role of nutrients. Out of this research, vitamin D has emerged as an important nutrient for lowering the risk of preterm birth.
Despite the established RDI, and though vitamin D may be synthesized in the dermis upon sun exposure and is found in some foods, recent reports have revealed that almost half of the U.S. population is deficient in vitamin D. The prevalence of vitamin D deficiency is even higher in certain subgroups of the U.S. population (74% among the elderly and 82% among Americans with dark skin).
There is also vitamin D deficiency among pregnant women in the U.S., according to CDC statistics and the American College of Obstetricians and Gynecologists; and this has serious consequences for pregnancy outcomes. Among black American women of child-bearing age, the prevalence of vitamin D deficiency has been shown to be as high as 42%, according to National Health and Nutrition Examination Survey (NHANES) data.
Many Americans limit sun exposure because of the well-known serious health-related outcomes. Sunscreen, which is consistently recommended to mitigate the harmful effects of sun exposure, may also limit the body’s ability to absorb the sunlight needed for vitamin D synthesis. Skin pigmentation has a limiting effect on vitamin D synthesis in the dermis, and it is thought to be the main reason for a higher proportion of vitamin D deficiency among dark-skinned people. That the U.S. is in a temperate region also impacts sun exposure levels and therefore the body’s ability to synthesize its own vitamin D.
A Nutrient of Need
As for other sources of vitamin D3, few foods are good sources of vitamin D. Fatty fish, egg yolks, beef liver, and fortified dairy and cereals are commonly available sources of vitamin D3, but a serving of many of these foods does not provide the currently-established or previous RDI. Other well-known and frequently recommended sources of vitamin D3 are, in fact, dietary supplements such as fish liver oils.
Pregnant women in the U.S. are often advised by healthcare professionals to restrict consumption of certain foods, including fish, because of concerns about contamination with heavy metals. Pregnant women may also be advised to limit sun exposure because of increased skin sensitivity that can cause dermatitis or discoloration. Within this context, then, dietary supplements are clearly an important way for the general U.S. population, and pregnant women in particular, to get necessary amounts of vitamin D3. Indeed, researchers, healthcare professionals, and the U.S. federal government’s own Dietary Guidelines generally accept, and recommend, dietary supplements as an affordable and accessible way to ensure appropriate nutrient intake.
Moreover, consumption of vitamin D3 supplements will be an important way for certain segments of the subpopulation of pregnant women (e.g., low-income women or women of color) who may be more at risk for preterm birth to access an affordable means of improving nutrient intake more easily. Supplementation with vitamin D3—a commonly available and relatively cheap nutrient already recognized by FDA as an essential nutrient and a nutrient of concern—is an efficient and accessible way for pregnant women to increase their serum vitamin D levels, thereby decreasing the risk of experiencing a preterm birth.
Petition Support
It is clear that serum vitamin D levels are a modifiable risk factor that can influence maternal and perinatal outcomes. Vitamin D supplements are generally affordable, safe, and as discussed, effective for modifying maternal serum vitamin D levels to improve pregnancy outcomes. A health claim about vitamin D3 supplementation as part of a healthy maternal diet, and the impact that supplementation could have on lowering the risk of preterm birth, is a relatively low-cost way to have significant impact on overall U.S. maternal health and pregnancy outcomes.
Organic and Natural understands it is asking the agency to get out of its comfort zone of RCTs and to assess this petition differently. However, as explained previously, 24(OH)D serum levels are inversely associated with the rate of preterm births. We ask everyone, particularly our industry, to fully support the petition. My hope is that the industry will think outside the conventional paradigm of RCTs to support this petition, because if industry is incapable of thinking outside the traditional paradigm, then how can we expect the agency to do so? Of course, if you believe 20 years of RCTs are necessary on a specific dose level of vitamin D to support a health claim petition, then, by all means stay with the status-quo and do nothing in support of a petition that will provide women of child-bearing age with the necessary tools to make informed decisions about the health of their unborn child.
Todd Harrison
Venable
Todd Harrison is partner with Venable, which is located in Washington, D.C. He advises food and drug companies on a variety of FDA and FTC matters, with an emphasis on dietary supplement, functional food, biotech, legislative, adulteration, labeling and advertising issues. He can be reached at 575 7th St. NW, Washington, D.C. 20004, Tel: 202-344-4724; E-mail: taharrison@venable.com.
Michelle Jackson
Venable
Michelle Jackson’s practice is focused on regulatory counseling concerning the development, formulation, manufacture, distribution, and promotion of foods, dietary supplements, drugs, medical devices, and cosmetics. She handles matters involving regulation and enforcement by federal and state agencies, including the FDA, FTC, USDA, and Consumer Product Safety Commission.
If you read this column on a regular basis, you know I am highly critical of the RCT approach especially when it comes to the health benefits of essential nutrients. Indeed, RCTs may not indicate a benefit because the dosage level necessary to increase an individual’s serum level is largely dependent on that individual’s initial status and ability or inability to absorb that nutrient.
With regard to Organic and Natural’s health claim petition, we found that neutral or negative RCTs on their face are a poor predictor of an outcome without knowing or understanding the woman’s baseline 25(OH)D levels in the first instance and whether that particular dose of vitamin D3 used in the RCT was able to increase a woman’s serum 25(OH)D levels, at a minimum, above 30 ng/mL (100 nmol/L).
Scientific Consensus
More specifically, when one reviews the literature in the first instance, there is general consensus that for pregnant women with serum 25(OH)D levels of less than 40 ng/mL (100 nmol/L), there is a benefit to raising serum 25(OH)D levels; specifically, there is a decreased risk of preterm birth. However, because pregnant women have different starting serum 25(OH)D levels, the level of vitamin D3 necessary to increase their serum levels (and thereby reduce the risk of preterm birth) is patient-specific and cannot be judged simply by the dose level. In other words, those RCTs that simply provided every woman in the study the same dose are flawed because they failed to take into account the women’s initial 25(OH)D levels. The vitamin D3 dose necessary to increase the level of 25(OH)D to at least 30 ng/mL—and preferably above 40 ng/mL (100 nmol/L)—will depend on the particular woman’s ability to absorb the nutrient, and cannot be generalized across the board. Because the dose level necessary to increase 25(OH)D in a particular woman cannot be generalized, the proposed health claim petition specifically recommends that a woman work with her healthcare practitioner to determine the appropriate dose levels.
Addressing Health Concerns
The U.S. Centers for Disease Control (CDC) reported that, in 2015, the U.S. birth rate was 12.4 per 1,000 and there were almost 4 million births. The CDC also reported that approximately one in 10 births are preterm, and each day in North America, more than 1,000 babies are born prematurely. Preterm birth is generally defined as birth before 37 weeks of pregnancy are completed.
According to Save the Children, the March of Dimes, and others, the U.S. is among the top 10 countries where preterm birth occurs, and 130 countries have a lower preterm birth rate than the U.S. Preterm (or premature) birth is an adverse pregnancy outcome that is the leading cause of perinatal morbidity and mortality. Of particular concern is that 2016 marked a second consecutive year of increasing preterm birth rates, and the trend is expected to increase once 2017 data is assessed. In 2015, the CDC reported that preterm birth and low birth weight were responsible for approximately 17% of infant deaths. Preterm birth is a leading cause of many long-term health-related conditions (e.g., neurological and respiratory disorders, learning difficulties, and behavioral challenges), according to March of Dimes. Preterm birth also has significant economic impacts (e.g., healthcare costs, lost income, special education services).
While preterm birth is a heterogeneous health-related condition, several risk factors are known and are routinely addressed during antenatal care (e.g., age, economic status and workplace conditions, inflammation and infection, and diet and nutrition). As diet and nutrition advice—including recommendations for dietary supplements—is routinely given to ensure maternal and fetal health with the goal of achieving a healthy full term pregnancy, research has necessarily focused on better understanding the role of nutrients. Out of this research, vitamin D has emerged as an important nutrient for lowering the risk of preterm birth.
Despite the established RDI, and though vitamin D may be synthesized in the dermis upon sun exposure and is found in some foods, recent reports have revealed that almost half of the U.S. population is deficient in vitamin D. The prevalence of vitamin D deficiency is even higher in certain subgroups of the U.S. population (74% among the elderly and 82% among Americans with dark skin).
There is also vitamin D deficiency among pregnant women in the U.S., according to CDC statistics and the American College of Obstetricians and Gynecologists; and this has serious consequences for pregnancy outcomes. Among black American women of child-bearing age, the prevalence of vitamin D deficiency has been shown to be as high as 42%, according to National Health and Nutrition Examination Survey (NHANES) data.
Many Americans limit sun exposure because of the well-known serious health-related outcomes. Sunscreen, which is consistently recommended to mitigate the harmful effects of sun exposure, may also limit the body’s ability to absorb the sunlight needed for vitamin D synthesis. Skin pigmentation has a limiting effect on vitamin D synthesis in the dermis, and it is thought to be the main reason for a higher proportion of vitamin D deficiency among dark-skinned people. That the U.S. is in a temperate region also impacts sun exposure levels and therefore the body’s ability to synthesize its own vitamin D.
A Nutrient of Need
As for other sources of vitamin D3, few foods are good sources of vitamin D. Fatty fish, egg yolks, beef liver, and fortified dairy and cereals are commonly available sources of vitamin D3, but a serving of many of these foods does not provide the currently-established or previous RDI. Other well-known and frequently recommended sources of vitamin D3 are, in fact, dietary supplements such as fish liver oils.
Pregnant women in the U.S. are often advised by healthcare professionals to restrict consumption of certain foods, including fish, because of concerns about contamination with heavy metals. Pregnant women may also be advised to limit sun exposure because of increased skin sensitivity that can cause dermatitis or discoloration. Within this context, then, dietary supplements are clearly an important way for the general U.S. population, and pregnant women in particular, to get necessary amounts of vitamin D3. Indeed, researchers, healthcare professionals, and the U.S. federal government’s own Dietary Guidelines generally accept, and recommend, dietary supplements as an affordable and accessible way to ensure appropriate nutrient intake.
Moreover, consumption of vitamin D3 supplements will be an important way for certain segments of the subpopulation of pregnant women (e.g., low-income women or women of color) who may be more at risk for preterm birth to access an affordable means of improving nutrient intake more easily. Supplementation with vitamin D3—a commonly available and relatively cheap nutrient already recognized by FDA as an essential nutrient and a nutrient of concern—is an efficient and accessible way for pregnant women to increase their serum vitamin D levels, thereby decreasing the risk of experiencing a preterm birth.
Petition Support
It is clear that serum vitamin D levels are a modifiable risk factor that can influence maternal and perinatal outcomes. Vitamin D supplements are generally affordable, safe, and as discussed, effective for modifying maternal serum vitamin D levels to improve pregnancy outcomes. A health claim about vitamin D3 supplementation as part of a healthy maternal diet, and the impact that supplementation could have on lowering the risk of preterm birth, is a relatively low-cost way to have significant impact on overall U.S. maternal health and pregnancy outcomes.
Organic and Natural understands it is asking the agency to get out of its comfort zone of RCTs and to assess this petition differently. However, as explained previously, 24(OH)D serum levels are inversely associated with the rate of preterm births. We ask everyone, particularly our industry, to fully support the petition. My hope is that the industry will think outside the conventional paradigm of RCTs to support this petition, because if industry is incapable of thinking outside the traditional paradigm, then how can we expect the agency to do so? Of course, if you believe 20 years of RCTs are necessary on a specific dose level of vitamin D to support a health claim petition, then, by all means stay with the status-quo and do nothing in support of a petition that will provide women of child-bearing age with the necessary tools to make informed decisions about the health of their unborn child.
Todd Harrison
Venable
Todd Harrison is partner with Venable, which is located in Washington, D.C. He advises food and drug companies on a variety of FDA and FTC matters, with an emphasis on dietary supplement, functional food, biotech, legislative, adulteration, labeling and advertising issues. He can be reached at 575 7th St. NW, Washington, D.C. 20004, Tel: 202-344-4724; E-mail: taharrison@venable.com.
Michelle Jackson
Venable
Michelle Jackson’s practice is focused on regulatory counseling concerning the development, formulation, manufacture, distribution, and promotion of foods, dietary supplements, drugs, medical devices, and cosmetics. She handles matters involving regulation and enforcement by federal and state agencies, including the FDA, FTC, USDA, and Consumer Product Safety Commission.
