Hormone replacement therapy is beneficial and safe, it turns out

 

A new study that just appeared in the Journal of the American Medical Association has some good news for women who take estrogen replacement therapy.

To jump to the punch line: estrogen therapy helps to alleviate hot flashes and other symptoms of menopause, and it carries little risk. And even better news: the study also reported that estrogen-only therapy might actually decrease the risk of breast cancer.

Why does this matter? Because about 20 years ago, millions of women stopped taking estrogen, even if it was helping them, because of a report that hormone replacement therapy might increase (not decrease) the risk of breast cancer.

These latest results come from the long-running Women’s Health Initiative, a National Institutes of Health-funded study of more than 160,000 women who were given various hormone therapies and then followed for up to 20 years. The WHI was responsible, somewhat notoriously, for the cancer scare in 2002, when the NIH reported–without consulting many of the scientists leading the study–that hormone replacement therapy increased the risk of breast cancer. This was wrong, as I explained in this column a few years ago, but as a result, many women stopped taking estrogen, and physicians stopped recommending it.

The confusion stemmed from the use of two different types of hormone therapy: (1) estrogen alone, or (2) estrogen plus progestin. The increased risk occurred solely in the combination therapy group (estrogen plus progestin), and not in the estrogen-only group. Despite this crucial difference, the WHI halted the studies of both treatments in 2002, and their press releases didn’t fully explain the difference.

And yet, as Dr. Robert Langer explained in 2017, the WHI trial of estrogen alone (without progestin) continued to track its subjects, and in 2004 that study reported that estrogen-only therapy led to a reduction in breast cancer, and a reduction in coronary heart disease as well.

(Aside: the Women’s Health Initiative website boasts that their 2002 report contains “revolutionary findings about combined hormone therapy,” emphasizing only the harm. I couldn’t find any comparable highlight describing the benefits of estrogen-only therapy.)

The new study, which appeared in JAMA on May 1, confirms several earlier studies that have reported a cancer benefit for estrogen therapy. In addition to its beneficial effects on menopause symptoms (which are widely acknowledged), the new study found that, after an average of 10.7 years, “rates of breast cancer were significantly lower in the CEE group [estrogen only] compared with the placebo group (HR, 0.77).” That HR value means that women who took estrogen had a 23% reduction in their risk of breast cancer.

Further supporting these findings is a 2022 study from NIH, available as a preprint in medRxiv here, which found that women taking estrogen only, compared to no hormones at all, had “significant risk reductions for all study cancers, breast, lung, endometrial, colorectal and ovarian” as well as a 20% reduction in mortality. The 2022 NIH study also found, similarly to the 2002 findings from WHI, that when estrogen was combined with progestin, the risk of breast cancer increased.

And there’s more. This 2012 study out of Denmark studied women who received estrogen-only therapy for 10 years starting in the early 1990s. They then followed these women for another 16 years, and found that women taking estrogen had a lower risk of heart attack, heart failure, or death–and no increased risk of cancer.

(As another aside: the new JAMA paper also reported results on a completely separate study of calcium plus vitamin D. They found that taking supplemental calcium+D didn’t provide any benefit in reducing the risk of bone fractures, confirming what I wrote in a recent column, here.)

So what’s the bottom line? We now have a raft of evidence showing that for post-menopausal women, estrogen therapy can offer significant benefits not only in treating hot flashes and other “bothersome menopausal symptoms” (to quote JAMA), but also in reducing the risk of some types of cancer. In contrast, hormone replacement therapies that use progestin, which is commonly used in birth control pills, might increase the risk of cancer and should be avoided.

As with most medical treatments, the true picture is complicated, but millions of women today might benefit from estrogen therapy. If you think you might be one of them, talk to your physician.

$3.7 million to study quack medicine at a leading cancer center

Sometimes I'm not sure whether the best response to pseudoscience is to ignore it, or to patiently try to explain why it's wrong, or to get mad.

This week I'm mad.

My anger and frustration was triggered by a tweet from Memorial Sloan-Kettering's Integrative Medicine account, shown here:

For those who don't know, Memorial Sloan-Kettering Cancer Center is one of the world's leading cancer centers, both for treatment and research. If you are diagnosed with cancer, MSK is one of the best places to go.

But not everything at MSK is world class. Unfortunately, they have an "integrative medicine" center that offers a mixture of therapies ranging from helpful to benign to useless. One of their biggest activities is acupuncture, which they claim offers a wide range of benefits to cancer patients.

The MSK tweet shown here was boasting about a new, $3.7 million study funded by NIH to study the effect of acupuncture on pain that cancer patients experience from chemotherapy and bone-marrow transplants.

Here's why I'm mad: cancer patients are extremely vulnerable, often suffering the most frightening and difficult experience of their lives. They are completely dependent on medical experts to help them. When a place like MSK suggests a treatment, patients take it very seriously–as they should. But they really have no choice: a cancer patient cannot easily look for a second opinion, or switch hospitals or doctors. Even if they have the money (and cancer treatment is extremely expensive), switching hospitals might involve a long interruption with no treatment, during which they could die, and it might also involve traveling far from their home.

Offering these patients ineffective treatments based on pseudoscience–and make no mistake, that's what acupuncture is–is immoral. Now, I strongly suspect that the MSK's "integrative medicine" doctors sincerely believe that acupuncture works. Their director, Jun Mao, is clearly a true believer, as explained in this profile of him on the MSK website. But that doesn't make it okay.

I've written about acupuncture many times before (here, here, here, and here, for example), but let me explain afresh why it is nonsense.

Acupuncture is based on a pre-scientific notion, invented long before humans understood physiology, chemistry, neurology, or even basic physics, which posits that a mysterious life force, called "qi," flows through the body on energy lines called meridians. As explained in this article by MSK's Jun Mao:

"According to traditional Chinese medicine ... interruption or obstruction of qi was believed to make one vulnerable to illness. The insertion of needles at specific meridian acupoints was thought to regulate the flow of qi, thus producing therapeutic benefit."

Today we know that none of this exists. There is no qi, and there are no meridians. In that same article, Jun Mao continued by admitting that

"the ideas of qi and meridians are inconsistent with the modern understanding of human anatomy and physiology."

And yet this is what they offer to patients at MSK.

Just to be certain, I read one of the latest studies from MSK, published early this year, which claims to show that acupuncture relieves nausea, drowsiness, and lack of appetite in multiple myeloma patients who were going through stem cell transplants.

It's a mess: totally unconvincing, and a textbook case of p-hacking (or data dredging). The paper describes a very small study, with just 60 patients total, in which they measured literally dozens of possible outcomes: overall symptom score at 3 different time points, a different score at 3 time points, each of 13 symptoms individually, and more. I counted 24 different p-values, most of them not even close to significant, but they fixated on the 3 that reached statistical significance. The two groups of 30 patients weren't properly balanced: the sham acupuncture group started out with more severe symptoms according to their own scoring metric, and Figure 2 in the paper makes it pretty clear that there was no genuine difference in the effects of real versus sham acupuncture.

But they got it published (in a mediocre journal), so now they point to it as "proof" that acupuncture works for cancer patients. This study, bad as it is, appears to be the basis of the $3.7 million NIH grant that they're now going to use, they say, in "a larger study in 300 patients to confirm these previous findings."

And there you go: the goal of the new study, according to the scientists themselves, is not to see if the treatment works, but to confirm their pre-existing belief that acupuncture works. Or, as one scientist remarked on Twitter, "they already have a result in mind, the whole wording of this suggests that they EXPECT a positive outcome. How did this get funded exactly?"

Good question.

So I'm mad. I'm mad that NIH is spending millions of dollars on yet another study of a quack treatment (acupuncture) that should have been abandoned decades ago, but that persists because people make money off it. (And, as others have explained in detail, acupuncture is actually a huge scam that former Chinese dictator Mao Zedong foisted on his own people, because he couldn't afford to offer them real medicine. For a good exposé of Chairman Mao's scam, see this 2013 Slate piece.)

But I'm even more upset that doctors at one of the world's leading cancer centers are telling desperately ill patients, who trust them with their lives, that sticking needles into their bodies at bogus "acupuncture points" will relieve the pain and nausea of chemotherapy, or help them with other symptoms of cancer. I'm willing to bet that most MSK doctors don't believe any of this, but they don't want to invest the time or energy to try to stop it.

(I am somewhat reassured by the fact that MSK's Twitter account has nearly 75,000 followers, while it's integrative medicine Twitter account has just 110.)

Or perhaps they are "shruggies": doctors who don't believe in nonsense, but figure it's probably harmless so they don't really object. To them I suggest this: read Dr. Val Jones's account of how she too was a shruggie, until she realized that pseudoscience causes real harm.

And finally, let me point to this study in JAMA Oncology from last year, by doctors from Yale, which looked at the use of so-called complementary therapies among cancer patients. They found that

"Patients who received complementary medicine were more likely to refuse other conventional cancer treatment, and had a higher risk of death than no complementary medicine."

And also see this 2017 study from the Journal of the National Cancer Institute, which found that patients who used alternative medicine were 2.5 times more likely to die than patients who stuck to modern medical treatments.

That's right, Memorial Sloan-Kettering: patients who use non-traditional therapies are twice as likely to die. That's why I'm mad. This is not okay.

How much brain damage is too much? NFL players head for the exits.

The smartest player in the NFL just quit.

Not because he was unable to play, and certainly not because of his age–he's only 26. No, Baltimore Ravens' player John Urschel decided to quit because the risk of permanent, irreversible brain damage is just not worth it.

Urschel is a very smart guy. He's currently pursuing a Ph.D. in mathematics at MIT, one of the best and most demanding science universities in the world. Until this summer, he was (impressively) balancing his studies with being a full-time NFL player.

But when Dr. Ann McKee and colleagues published a new study showing that 110 out of 111 former NFL players had suffered serious brain damage, Urschel could no longer pretend he wasn't putting his future at grave risk. McKee's study, the largest study yet of chronic traumatic encephalopathy (CTE), showed alarmingly high rates of CTE in college and high school players as well (91% of former college players).

Let's get one point out of the way: everyone involved with the study, including Dr. McKee, knows that it was biased. The scientists examined brains of deceased players that had been donated to the study because family members–or the players themselves, before they died–suspected something was wrong. So perhaps the true risk of brain damage is lower than 99%. Maybe it's only 50%, or 20%. Do young men playing football want to take that risk?

John Urschel isn't the first player to quit because of the growing realization that football may cause irreversible brain damage. In 2015, San Francisco 49ers player Chris Borland retired at the age of 24, and in 2016 Kansas City Chiefs player Hussain Abdullah retired at 30, both over concerns about concussions and brain damage.

The NFL has been denying or downplaying the risk for years. A few years ago, after the suicide of former player Junior Seau, they announced a $30 million partnership with the NIH to study the risks of football on the brain. As results started coming in, showing that the risk was far more serious than most people knew, the NFL backed out of the deal with $16 million still unspent.

Meanwhile, the chorus of warnings has been growing steadily louder from the medical community. Last year, a former team doctor and a former football player and coach wrote in JAMA that

"unless there is a way to reduce the number of TBIs [traumatic brain injuries] caused by the sport, football will remain a threat to the brains and health futures of the players, including impaired cognitive function and reasoning, memory loss, emotional depression, and other sequelae that profoundly erode quality of life."

Earlier this year, a study out of the CDC reported that "3 high school or college football players die each year from traumatic brain and spinal cord injuries that occur on the field," most them as a result of being tackled during games.

Over the years, football players have grown ever larger (the average NFL lineman today weighs over 300 pounds) and the intensity of the violence on the field has grown with them. It's not just in the NFL, either: last year, three high school teams in the state of Washington forfeited their games against a local team out of a legitimate fear that players would be badly injured by the opposing team's 300-plus pound linemen. Their fears were justified: the human head simply wasn't built to withstand the repeated blows that players endure.

All players might do themselves a favor by listening to John Urschel. He explained his decision–and his abiding love for the game of football–in a lengthy interview on the Freakonomics podcast a couple of weeks ago. That interview should be required listening for young players, and even more so for parents who might be dreaming that their sons have a future career in football.

Fish really is brain food

Everyone has heard that eating fish is good for the brain. This notion goes back at least a century; the famous humorist and novelist P.G. Wodehouse often mentioned it in his books. In one scene, after Jeeves (the butler) describes a clever scheme to escape a ticklish problem, Bertie Wooster reacts:

I stared at the the man.
'How many tins of sardines did you eat, Jeeves?'
'None, sir. I am not fond of sardines.'
'You mean, you thought of this great, this ripe, this amazing scheme entirely without the impetus given to the brain by fish?'
'Yes, sir.' [From Very Good, Jeeves, (c) 1930 by P.G. Wodehouse]

A century ago, the evidence that fish is brain food was virtually nonexistent. Researchers have been looking at this question ever since, and the evidence has been mixed. Even if fish is good for the brain, the mercury content in some fish might have the opposite effect.

A new study that appeared last week in JAMA answers this question: fish is indeed good for the brain. More precisely, eating fish regularly was associated with a reduced risk of Alzheimer's disease. This benefit occurred despite the fact that people who ate more fish did have higher levels of mercury in the brain. Apparently, the levels of mercury were too low to cause harm, and the benefits of eating fish easily outweighed any risks.

The new study, by Martha Clare Morris and colleagues at Rush Medical Center in Chicago, looked at 554 Chicago residents, all part of a long-term aging study, who died over a ten-year period. The scientists conducted autopsies to look directly in the brain for physiological changes such as neuritic plaques, which are signs of Alzheimer's or other disease. They used questionnaire data, which they collected for everyone in the study, to measure how much fish people had been eating–an imperfect way to measure eating habits, but it's often the only realistic way to gather this information.

Here's what they found: people who ate seafood at least once per week had lower levels of three different physiological signs of Alzheimer's, but only in people with a genetic marker known as APOE ε4, which itself carries an increased risk of Alzheimer's. (None of the people in the study had dementia when they first enrolled, starting in 1997.) Somehow, then, eating fish seems to counteract the effects of this harmful genetic mutation.

Bad news for fish oil supplement makers: the study found that "fish oil supplementation had no statistically significant correlation with any neuropathologic marker." In other words, people who took supplements got no benefit. You just have to eat fish.

This isn't the first study to show a positive benefit to brain health from eating fish. The authors cite 13 previous studies that reported "protective relations between seafood consumption and n-3 fatty acids with cognitive decline and incident dementia." The JAMA study is the first to include mercury levels, brain changes associated with Alzheimer's, and diet all in the same study. It's reassuring to learn that despite the increased mercury caused (probably) by eating more fish, the overall effect is beneficial.

The authors also pointed out that as we age, our brains lose DHA, a critical lipid in the brain, and that therefore "fish consumption may be more beneficial with older age." The FDA already recommends that pregnant women and young children eat more fish for its nutritional benefits. Now there's evidence that older people should eat fish regularly too.

So it seems that Wodehouse's character Bertie Wooster might have been right: fish really is brain food.

Over-hyped claims that antidepressants cause autism and antidepressants

Over-hyped, overstated, and probably just wrong.

That's my summary of the latest high-profile study of autism, which reports that mothers who take antidepressants increase the risk of autism in their unborn children by up to 87%. The new study, which appeared this week in the journal JAMA Pediatrics, received widespread attention, both uncritical (Washington Post, Huffington Post) and more cautious (CBS News). But it was that 87% increase that caught most people's attention.

Many scientists, including me, read this news with skepticism. It seems particularly unlikely given that exactly two years ago, another large study reported exactly the opposite conclusion. The 2013 study, published in the New England Journal of Medicine, found that antidepressant use during pregnancy was NOT associated with an increased risk of autism. What's more, the 2013 study looked at exactly the same class of antidepressants, selective serotonin uptake inhibitors (SSRIs), as the new study.

So what's going on? Was the 2013 study just wrong? It seemed the only way to answer this was to read the new study, written by Anick Bérard and colleagues. Looking over the new numbers, my conclusion is that Bérard simply tortured the data until she got the results–and the press headlines–that they wanted. Let's look a bit more closely.

Bérard and colleagues looked at 145,456 children born in Quebec between 1998 and 2009. From this total, 4,724 were born to mothers who took antidepressants (SSRIs) at some time during their pregnancy. The number of children diagnosed with autism was 1,054, about 0.7% of all babies. Only 46 of the 1,054 were born to mothers who had taken antidepressants. The study's main results concerns mothers who took antidepressants in the second or third trimester: these women accounted for 2,532 infants, of whom 31 were diagnosed with autism.

If these numbers seem confusing, try focusing on just one number: 31. The study's main conclusion–and all the headlines–are based on those 31 children diagnosed with autism whose mothers took antidepressants in their second or third trimesters.

The key results are found in Table 2 of the study. Out of 9207 infants whose mothers took antidepressants one year before getting pregnant, 82 were later diagnosed with autism. Bérard et al. found that, after adjusting for various confounders, this group of infants had no increased risk of autism. Another group was infants whose mothers took antidepressants, in the first trimester: of these 4200 infants, 40 were diagnosed with autism. Bérard et al. computed that the adjust risk for this group was 16% lower than average. This difference was not statistically significant, though.

Finally, there's the third group of 2,532 children whose mothers took antidepressants during the 2nd or 3rd trimesters. 31 of these children were later diagnosed with autism, which worked out to an increase in relative risk of 87%.

The first thing to note here is that the increase is relative, not absolute. The overall risk of autism in this study, which was consistent with other studies, was 0.7%. An 87% increase works out to a risk of 1.3% – that's an increase of 0.6% in the rate of autism. This doesn't sound nearly so dramatic as 87%.

But keep in mind that this supposed increased risk of autism is based on just 31 cases. Digging a bit deeper, we find that the way these 31 children were diagnosed was not so clear: the authors wrote that

"Autism spectrum disorder was defined as a medical service claim or hospitalization with a diagnosis of ASD."

Apparently this means only that the children were evaluated for autism, as Dr. Alison Stuebe at The Huffington Post pointed out. Bérard et al. admit this in their paper, where they report that when they restricted their analysis to children whose diagnoses were confirmed by a psychiatrist or neurologist, the number of children with autism was smaller and the increased risk was not statistically significant. In other words, if they looked only at children with confirmed autism, their main conclusion would fade away.

You also might have noticed that Bérard divided the data up in multiple ways to look for an increase in autism: they looked at mothers who took antidepressants before getting pregnant, during the first trimester, and during the 2nd and 3rd trimesters. They don't report any findings for the 2nd trimester alone, or for the 3rd trimester alone, which would have certainly involved smaller (and probably less significant) numbers.

This raises a potentially fatal problem with the study: multiple testing. Whenever a study considers more than one hypothesis, the statistics must be adjusted to account for that. If you look for an effect in ten different ways, you're more likely to find something by chance alone, so you have to find a much stronger effect in order for it to be valid. (The web comic xkcd has a great explanation of this.) Bérard doesn't explain how many hypotheses she tested, but she does write that:

"No adjustment was made for multiple comparisons; hence, we cannot rule out chance findings given the number of comparisons made."

No kidding! Upon reading this, my main question was how the journal editors let them get away with this. I guess JAMA's editors like headlines, perhaps a bit too much.

The senior author of the study, Anick Bérard, appears to have an agenda, as Slate's David Auerbach explained. Last year, she testified in a lawsuit against Pfizer, claiming that their antidepressant Zoloft caused birth defects. The judge in that case, Cynthia Rufe, threw out Bérard's testimony with the explanation that her methods were unscientific:

"Dr. Bérard’s opinions regarding Zoloft are only made possible by her departure from use of well-established epidemiological methods." 

Now, the fact that Bérard has previously testified in court cases doesn't prove that her current study is flawed, but it does indicate that she has a bias against antidepressants. This bias might explain why her study looked so hard to find an effect when the data don't seem to support it.

Finally, I should note that even if the new study is correct (and I doubt it), it completely ignores the risk of stopping medication for pregnant women with severe depression, as Dr. Alison Stuebe discussed at length at the Huffington Post. (Recall that the 2013 study I mentioned above found that there was no increased risk of autism in women taking SSRIs.) No woman should go off her medication based on this study, although I fear that the headlines from last week will have exactly that effect.

MMR vaccine (still) doesn't cause autism, new study finds

Nope.

We’re still spending vast amounts of time and money trying to counter the ill effects of a discredited, retracted paper from 1998 that claimed to find a link between the MMR (measles, mumps, and rubella) vaccine and autism. Even after the The Lancet retracted the study, and even after the British Medical Council revoked the medical license of its lead author, Andrew Wakefield, many people continue to withhold vaccines from their children because of a fear that somehow, despite all the evidence to the contrary, vaccines might cause autism. Vaccines, I hasten to add, have saved millions of lives and are probably the greatest medical advance of the past two centuries.

Now another study has appeared to add more weight to the evidence about the safely of the MMR vaccine. The new study by Anjali Jain and colleagues, just published in the Journal of the American Medical Association, looked at a huge number of children–95,727–for evidence of any link between autism and the MMR vaccine.

The results were not surprising, to those who have been following the science. To quote the conclusions directly: 

“Receipt of the MMR vaccine was not associated with increased risk of ASD [autism spectrum disorder], regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.”

That should settle it, right? But then, dozens of previous studies should have already settled this question. Unfortunately, due to the ongoing activism of anti-vaccine groups such as Age of Autism, (who already attacked this new study) and to conspiracy theorists such as Robert F. Kennedy Jr. (whom I wrote about last summer, and who was campaigning against vaccines in Vermont just last week), misguided claims that vaccines cause autism or neurological problems persist.

Here are the numbers from the new study. The authors compared vaccinated children to unvaccinated children, using a huge database of medical claims that included at least 5 years of followup. (This was an "observational" study, by necessity–it would be unethical to withhold vaccines from children on purpose.) The relative risk for autism in children who had 2 doses of the MMR vaccine (the recommended amount) compared to unvaccinated children was 0.74. In other words, a child was somewhat less likely to be diagnosed with autism if he or she were vaccinated. 

Even more surprising was the relative risk among children who had an older sibling with autism: in this smaller group, children with 2 doses of MMR were just 44% as likely to be diagnosed with autism as unvaccinated children. This statistically significant finding indicates, unexpectedly, that vaccines might actually protect children from autism.

The authors were quick to note that there are other good reasons for this apparent protective effect of vaccines: in particular, if parents of autistic children withheld vaccines from their younger children, this could explain the effect. Why? Because we know that autism has a genetic component, and that if one child has autism, his younger sibling is more likely (because they share many genes) to have autism as well. Jain and colleagues explained that if these parents withheld vaccines–because of fears spread by the anti-vaccine movement–then their children could contribute to the apparently lower rate of autism in children who were vaccinated. The authors couldn’t rule out a protective effect of vaccines, but scientifically it seems unlikely, and they wisely offered an alternative explanation.

So: once again we have a large, carefully conducted study showing that the MMR vaccine does not cause autism, and even finding evidence that vaccinated children have lower rates of autism. Let's hope this study helps to end the anti-vax movement, so that we can soon stop spending time and money trying to refute their long-discredited hypotheses and instead focus on trying to understand the true cause.

Those fish oil supplements might cause cancer

Eating fish is good for you, especially fish that contain omega-3 fatty acids.  So I was surprised last week to read a new study in the Journal of the National Cancer Institute that found that omega-3 fatty acids increase the risk of prostate cancer.  The risk for both high-grade and low-grade cancer was increased with higher levels of omega-3 fatty acids.  This is a carefully done study, and the results should make anyone who is taking fish oil pills reconsider.

One reason this study caught many people off guard is that there has been much evidence showing that a diet rich in fish that contain omega-3 oils is good for you.  The Mayo Clinic says that  "eating fish helps your heart", especially fish like salmon that contain omega-3 fatty acids.  The American Heart Association (AHA) elaborates:

"Omega-3 fatty acids benefit the heart of healthy people, and those at high risk of — or who have — cardiovascular disease. Research has shown that omega-3 fatty acids decrease risk of arrhythmias (abnormal heartbeats), which can lead to sudden death. Omega-3 fatty acids also decrease triglyceride levels, slow growth rate of atherosclerotic plaque, and lower blood pressure (slightly)."

This all sounds great.  Because of the evidence about the benefits of fatty fish, supplement manufacturers have been marketing and selling fish oil pills for years, with great success.  As I described back in 2010, GlaxoSmithKline even created a high-dose omega-3 fatty acid pill called Lovaza that has FDA approval.

But the evidence for that you can get the same benefit from supplemental omega-3 fatty acids — taking a pill, that is — is much weaker.  In fact, a large review published last year in the Journal of the American Medical Association found no connection at all between supplemental omega-3 and a lower risk of heart attacks, strokes, or death in general.  Other studies have reported similarly negative results.  So it appears that fish oil pills may not have any heart benefits.

And now, with this new study, we learn that supplemental fish oil might increase the risk of prostate cancer.

The bottom line: the AHA recommendations about eating fish are probably still good ones.  The AHA website says:

"We recommend eating fish (particularly fatty fish) at least two times (two servings) a week. Each serving is 3.5 oz. cooked, or about ¾ cup of flaked fish.  Enjoy fish baked or grilled, not fried." 

But popping a fish oil pill is not going to cut it. As we've seen before, supplements often fail to show the benefits that a healthy diet offers.  So save your money and stop buying those fish oil pills — and fire up the grill and throw on a few salmon fillets for this weekend's barbecue.

Multivitamins and cancer: a mixed bag

A major new study published this week in the Journal of the American Medical Association (JAMA)  came to the surprising conclusion that

"daily multivitamin supplementation modestly but significantly reduced the risk of total cancer."

The report included some caveats, such as the fact that all 14,641 participants were healthy male physicians.

But the result is still surprising, because other recent studies, some of them even larger, have concluded that vitamin supplements do not provide any significant health benefits.  On the contrary, some studies found that supplements could actually be harmful.  As I wrote last year, a very large study of 38,772 older women, who were followed for 25 years, showed that the risk of death INCREASED with long-term use of multivitamins, vitamin B6, folic acid, iron, magnesium, zinc, and copper.  That's death, not just cancer.  The authors of that study, Jaakko Mursu and colleagues, concluded that there is

"little justification for the general and widespread use of dietary supplements."

The new study, PHS II (Physicians' Health Study II) looked at overall death rates as well as cancer, and found that men on a daily multivitamin had fewer deaths, but too few to be statistically significant.

So we have a large study in men showing that multivitamins seem to reduce overall cancer, and maybe even death, but an even larger study in women showing the opposite effect.

A second study from last year, in 35,533 men, looked at vitamin E and selenium supplements. That study, also published in JAMA, found that risk of cancer INCREASED for men taking vitamin E, selenium, or both.

The media reports aren't helping to clarify things.  The NY Times proclaimed "Multivitamin use linked to lowered cancer risk, and the Wall St. Journal reported that "Multivitamin cuts cancer risk, large study finds."  Bloomberg News went right for the business angle, announcing that "Pfizer multivitamin reduces cancer 8% in men, study finds."

Compared to Bloomberg news, Pfizer's own website was remarkably restrained, saying only

"Centrum Silver was part of the recently published landmark study evaluating the long-term benefits of multivitamins."  

No claims about reducing the risk of cancer - surprisingly, the independent media made far stronger statements than Pfizer.  Not true of supplement manufacturer GNC, which was flashing a pop-up headline that "Taking a daily multivitamin could cut cancer risk", linking to a news article at the Boston Herald.

So what do we make of this new study?  Are multivitamins good for you after all?

The new JAMA study appears to be very well done.  It's a double-blind, placebo-controlled study in which half of the physicians received a daily multivitamin, Centrum Silver, and half received a placebo.  The participants didn't know if the pill they were taking was a vitamin or a sugar pill.  The authors report some minor conflicts of interest, but none of them work for or received major funding from Pfizer (PFE, the manufacturer of Centrum).  So how to explain the seeming contradiction with two larger studies published only a year ago?

To answer this question, we must look at the details of the study itself.  This study looked at 21 different types of cancer risk.  For most cancers - colon cancer, prostate cancer, lung cancer, pancreatic cancer, lymphoma, leukemia, melanoma, and others - multivitamins did not provide a benefit.  But when all the numbers were added up, the effect was just large enough to be "significant", at a level of p=0.04.  More on that in a moment.

Here are the raw numbers: among the 7,317 men who took a daily multivitamin, there were 1,290 cases of cancer over the 11-year study.  Among the 7,324 men who took a placebo pill, there were 1,379 cases.  That's about 1.2% more - far less than the 8% reported by Bloomberg News. The statistical analysis showed that this difference had a p-value of 0.04, a result the authors considered significant. When the authors looked only at men with no history of cancer, the effect was smaller, and not statistically significant.

One explanation of the new finding is that the effects were indeed due to chance. Let's look at that p-value of 0.04. In much of the scientific literature, any p-value below 0.05 is considered "significant," but this has been widely criticized, in part because it encourages binary "true, false" thinking that is not the way scientists actually think. Also, the "0.05 threshold actually represents evidence much weaker than the number "0.05" suggests. A back-of-the-envelope Bayesian calculation shows that if the cancer-preventing power of multivitamins was a 50:50 proposition before this study, then after this study there is still a 10-26% chance that the cancer prevention claim is wrong. If we thought that prior evidence made this effect less than 50:50, (say 25:75), then the study has roughly a 25-50% chance of being wrong.* Either way, I won't be stocking up on Centrum Silver anytime soon.

Looking at this small effect, and at the contradictory results from other studies, neurologist Steven Novella writes in his blog that

"About the only thing we can say with a high degree of confidence is that there is no large risk or benefit from taking a multivitamin. There may be a small benefit, no benefit, or even a small harm."

That's a good summary.  So should men take a multivitamin?  Well, it's your money, but if you don't have a vitamin deficiency, it's probably not worth it.  Should women?  The evidence still says no.

*Thanks to Stanford biostatistician Steven Goodman (formerly of Johns Hopkins University) for crunching some numbers to produce Bayes factors.