Randomized controlled trials (RCTs) have long been heralded as the gold standard for evaluating whether interventions are effective. As a result, medical advice and public health policies are often made based on their outcomes. But what if the gold standard is actually leading us astray? 

By design, RCTs isolate the intervention that is under consideration and hold the other variables constant. This is necessary to ensure that one is measuring the impact of the intervention, and that the results of the study are not due to confounding factors. It’s a highly effective way to isolate the variable in question. 

While scientifically that may be appropriate, it’s not how the real world works. In reality, and especially when it comes to our health, we cannot always isolate variables in a modular way. Our bodies are interdependent systems, and as a result, what we do for one body system affects the others too. 

RCTs have provided countless insights to better our medical care and public health landscape. However, they are not without negative externalities. In this piece I’ll highlight how RCTs’ failure to ask interdependent questions in the case of folic acid is negatively impacting health, and I’ll also propose a better path forward. 

What is folic acid and why do we consume it?  

Folic acid is the synthetic, man-made, version of folate, which is also known as Vitamin B9. Folate, not folic acid, occurs naturally in foods and is necessary for a number of bodily processes. In its active form, folate is known as 5-methyltetrahydrofolate (5-MTHF). 

Two RCTs in the early 1990s demonstrated folic acid’s ability to reduce neural tube defects (NTDs) in pregnancy. As a result of these studies, starting in 1991, the CDC recommended women with a history of NTDs in pregnancy take 4000 mg of folic acid when they began planning a pregnancy. And in 1992, a recommendation for all women of childbearing age to take 400 mg of folic acid was recommended by the U.S. Public Health Service. In 2009, these recommendations were reinforced by the U.S. Preventive Services Task Force’s updated guidelines. 

But it’s not just pregnant women who are consuming this man-made supplement. The US and Canada began mandatory grain fortification programs in 1998, with other countries following afterwards. As a result, most people consuming grains in the US consume folic acid (organic producers are not required to fortify grains). 

That might not be an issue if 30-60% of the population didn’t have a gene mutation (a.k.a. MTHFR polymorphism) that inhibited their ability to metabolize folic acid into its bioactive form (5-MTHF). But they do. For individuals who have one or more of these gene mutations, consuming folic acid results in unmetabolized folic acid (UMFA) being left to circulate in the bloodstream. Effectively, their bodies can’t use the folic acid the way they can use bioactive folate (5-MTHF). 

When individuals consume foods with—or supplement with—the bioactive form of folate (5-MTHF), UMFA does not result. But most prenatal vitamins, and our national fortification program, use folic acid. It is more stable and cheaper. 

So, while they demonstrated a reduction in NTDs, what did those RCTs upon which we’ve based decades of medical recommendations and public health interventions not ask? What else does the folic acid do? 

The Theory of Interdependence and Modularity 

The Theory of Interdependence and Modularity helps to explain this situation. It states that when a system’s components are unpredictably interdependent—that is, the way one part is designed and functions depends on the way another part is designed and functions and vice versa—the only way forward is to manage the system as a whole. This requires addressing every critical component in the system so that it will function adequately. The reason is this: treating any given problem in a modular fashion by just improving a specific component of the system will have unpredictable spillover effects into other parts of the system. 

By preventing leaders—or medical providers—from addressing the whole system, a modular approach hamstrings their ability to address these unpredictable interdependencies. Modular thinking takes away too many degrees of freedom from the approach and the whole set of tools they need to succeed.

This applies to businesses operating in situations characterized by performance gaps, where the functionality or reliability of something is falling short. It also applies to providers treating and caring for the human body, and officials making public health policy. Our bodies are interdependent, with spillover effects between our different physiological and psychological functions. As a result, treating people in a modular fashion creates externalities. 

The downfall of applying modular thinking to an interdependent system

Folic acid supplementation and fortification is a modular solution targeted at reducing NTDs. And reducing and eliminating NTDs is a worthy goal. But, folic acid doesn’t just impact NTDs. With new studies—though most not RCTs—performed since the early 1990s, we now know that those incapable of metabolizing folic acid into its bioactive form (5-MTHF) are left with UMFA circulating in their body. 

Studies highlight that this circulating UMFA likely has negative consequences. A few of these negative spillover effects include: 

The tough question is whether these spillover effects are due to correlation or causation. Whichever the answer, there are associations with enough negative outcomes that our modular approach to an interdependent problem requires a second look. When the available research is inconclusive about negative outcomes, it means we must dive deeper. 

The path to better health 

The negative impacts of UMFA can be characterized as unintended consequences. No one intended to create other harms in preventing NTDs, but this is what the RCT model predisposes our medical and public health advice to do: treat an interdependent problem modularly, and create spillover effects as a result. 

Yet, the litany of negative outcomes associated with excess folic acid intake, especially for those with MTHFR gene mutations, begs the question of how we might minimize the harms going forward. Below are three suggestions. 

First, CMS and private insurers should cover the cost of MTHFR testing for all women seeking to conceive as part of routine gynecological exams. If not completed at a routine exam, it should be part of the standard of care at the first prenatal visit. As a result of the test, OBGYNs and midwives should counsel patients on the appropriate dietary choices and vitamins to minimize their risk of complications from UMFA. If we counsel all pregnant women to avoid a lengthy list of foods due to the 0.005% of pregnancies that will encounter listeriosis, it makes sense to advise them to take the type of vitamin 30-60% of people are better able to absorb.

Second, on the basis of additional evidence, the American College of Obstetrics and Gynecology (ACOG) should reconsider its 2013 decision not to test patients for MTHFR status. They should now establish clinical practice guidelines for the differential treatment of those with MTHFR polymorphisms.  

Third, for the benefit of all people, questions for health care decision makers and policy makers to explore should include: 

  1. If a RCT highlights certain benefits of a supplement, intervention, lifestyle change, etc., what are the potential negative externalities that the study didn’t examine? How can we put a system into place to monitor for those spillover effects and respond accordingly?
  2. At what point should medical advice and public health interventions be based on scientific evidence, even if it’s not from an RCT? 

In serving the public’s health, practitioners pledge to do the greatest good for the greatest number. In light of Modularity Theory and the application of RCT findings, specifically in the case of folic acid, it’s time to ask, “Are we?”.


  • Ann Somers Hogg
    Ann Somers Hogg

    Ann Somers Hogg is the director of health care at the Christensen Institute. She focuses on business model innovation and disruption in health care, including how to transform a sick care system to one that values and incentivizes total health.