Friday, May 23, 2014

Overselling the microbiome award - many - for stories about placental vs. oral microbiomes

A few days ago on Twitter I was pointed to a news story about the human microbiome:

I looked at the article and definitely agreed with Ed. So I responded
And then a mini conversation happened

And I pondered writing up an "overselling the microbiome award" but I got caught up in other things. And then today some people (including Jens Walter) pointed me to this New York Times article about the same topic: Study Sees Bigger Role for Placenta in Newborns’ Health - And I decided I had to write something up because too many news stories were not doing a great job with the science here.

So here goes. First, the Science news (UPDATE - NOTE this is the news part of Science magazine, not ScienceNewsOrg) story Ed Yong pointed to originally and the parts I have problems with.
  • Sentence 1Researchers have discovered a small community of bacteria living in a most unlikely place: the placenta, the organ that nourishes a developing fetus through the umbilical cord.  No - not really.  They did not discover this.  They did a more detailed characterization of the community.
  • Sentence 2The finding overturns the conventional wisdom that the placenta is sterile.  No - the study is another piece of evidence that argues against the "conventional wisdom"
  • Sentence 3 is OK.
  • Sentence 4.  Medical experts have long assumed that any bacteria found in the organ must have been picked up when it passed through the vagina after delivery.  Sure - some "experts" have assumed this.  But there has been growing evidence for many years that this is a bad assumption.  
I could go on and on.  Actually though I won't.  Becuase every news story can have some limitations.  I don't like inaccurate statements but it is a part of life I guess.  But the part that drives me batty in this story is the inclusion of a discussion about oral health.  Here are the two paragraphs that are the crux of my concern (with bold emphasizing the worst parts).
Surprisingly, the mix of bacteria in the placenta looked more like the microbiome in an adult human’s mouth than the vaginal, skin, gut, or other body microbiomes, Aagaard’s team reports today in Science Translational Medicine. The researchers think the microbes may get to the placenta from the mother’s mouth through her bloodstream, perhaps when she brushes her teeth and dislodges them into the blood. That possibility is intriguing, because there’s a well-known correlation between gum disease and preterm birth. Indeed, the array of bacteria in the placenta differed in women who gave birth early, before 37 weeks. 
“This reemphasizes the importance of oral healthduring pregnancy, Aagaard says. In fact, women may need to pay attention to their teeth even before they may become pregnant, because the placenta develops early in pregnancy, she says. That may be a challenge for low-income women who can’t afford dental care, Aagaard adds. The team also found a correlation between the composition of the placental microbiome and urinary tract infections, which suggests that such illnesses or antibiotics taken to treat them could alter the microbiome in unhealthy ways.
I have read and reread the paper (which I note - is not open access - making it hard to the public to actually dig into the paper if they wanted to).  And I see no evidence presented anywhere of the importance of oral health or any causal connection between oral health and the placental microbiome or risks to pregnancies. The claims made about this here in this news story are irresponsible.  Yes, there have been some other studies about dental health and birth issues.  But nothing in this paper.  And to imply otherwise is misleading at best.  And then to go on with "That may be a challenge for low-income women who can’t afford dental care" is really not appropriate.  And to then go on about UTIs and how treating them may "alter the microbiome in unhealthy ways" is also misleading and not supported.  

Where is the critical evaluation of such claims?  Certainly the paper is very interesting.  Among the findings of interest to me: (1) that low amounts of DNA from diverse microbes is found even in the placentas from healthy pregnancies and (2) that in their analysis these microbes were most similar to those from the mouth.  But how we get from those findings (and some others) to "the importance of oral health during pregnancy" and "such illnesses or antibiotics could alter the microbiome in unhelathy ways" is, well, not in the realm of scientific research.  This is in the realm of speculation.  And speculation is fine -IF YOU TELL PEOPLE YOU ARE SPECULATING.  If you don't tell people you are speculating I have another term for it - it is called misleading.  I assume the researchers and reporter did not intend to be misleading but that is the end result of excessive speculation without making it clear what one is doing.

Now this brings me to other articles about this study.  There are many out there.  And most seem to have eaten up this oral health connection without questioning it.  For example, consider the artilce in the New York Times yesterday:Study Sees Bigger Role for Placenta in Newborns’ Health - by Denise Grady.  Some issues I have with this article:
  • Let's start with the title "Study Sees Bigger Role for Placenta in Newborns’ Health."  Well, no - there was nothing in this study that showed any evidence about a new connection between the placenta and newborns' health.  
  • NYTimes: "During pregnancy, the authors of the new study suspect, the wrong mix of bacteria in the placenta may contribute to premature births." Sure - they suspect it.  Would have been good to point out they have no evidence for this.
  • NYTimes: Although the research is preliminary, it may help explain why periodontal disease and urinary infections in pregnant women are linked to an increased risk of premature birth.  Again, may help explain - sure.  But it also may have no connection whatsoever.  There is no evidence presented in the paper connecting periodontal disease and UTIs and the placental microbiome.  So this is pure speculation.  And it should have been met with some discussion of all the other ways that periodontal disease and UTIs could lead to risk of premature birth.  Like leading to increased inflammation in the mother.  Or affecting blood flow in the mother.  Or other things.  There is actually a TON of research in this area.  Below are some of the factors that affect preterm labor, as listed by the Mayo Clinic - are we now discounting the years and years of work on this and going whole hog into proposing a new cause without any evidence?
    • Previous preterm labor or premature birth, particularly in the most recent pregnancy or in more than one previous pregnancy
    • Pregnancy with twins, triplets or other multiples
    • Certain problems with the uterus, cervix or placenta
    • Smoking cigarettes, drinking alcohol or using illicit drugs
    • Certain infections, particularly of the genital tract
    • Some chronic conditions, such as high blood pressure and diabetes
    • Being underweight or overweight before pregnancy, or gaining too little or too much weight during pregnancy
    • Stressful life events, such as the death of a loved one
    • Domestic violence or any form of abuse during pregnancy
    • Multiple miscarriages
    • Red blood cell deficiency (anemia), particularly during early pregnancy
    • Too much amniotic fluid (polyhydramnios)
    • Pregnancy complications, such as preeclampsia
    • Vaginal bleeding during pregnancy
    • Presence of a fetal birth defect
    • Little or no prenatal care
    • An interval of less than six months since the last pregnancy
    • Also, having a short cervical length or the presence of fetal fibronectin — a substance that acts like a glue between the fetal sac and the lining of the uterus — in your vaginal discharge might be linked to an increased risk of preterm labor. 
  • I note - the authors even say in their paper "Although this study is not able to address the relationship between periodontal disease and the placental microbiome, we, as a community of obstetricians, have appreciated for decades the association between periodontal disease and preterm birth". Clearly the paper received more scrutiny that the quotes and the news stories. 
  • NYTimes: The new study suggests that babies may acquire an important part of their normal gut bacteria from the placenta. No.  Nothing in this study showed any connection between what is in the placenta and what is in the babies guts.  None.
  • NYTimes: If further research confirms the findings, that may be reassuring news for women who have had cesareans. Some researchers have suggested that babies born by cesarean miss out on helpful bacteria that they would normally be exposed to in the birth canal.  Again - there is no evidence that babies pick up microbes from the placenta.  So speculating that this may reassure women who have C- sections is way way way too premature.
  • NYTimes: “I think women can be reassured that they have not doomed their infant’s microbiome for the rest of its life,  said Dr. Kjersti Aagaard.  Wow. Now we have gone from "if further research confirms" to just flat out reassuring women who have had C-sections that there are no effects on the microbiome.
  • NYTimes: It didn’t make a whole lot of sense to us,” she said. “It’s not like babies are hanging out in the vagina. They come shooting out pretty fast.” Also, she said, they emerge covered in a waxy substance called vernix, which most likely helps keep bacteria from latching on. Wow.  So babies come shooting out of the vegina and therefore cannot get microbes from the vagina.  This despite the massive amounts of evidence that they in fact do get microbes from the vagina and that C-section born babies get a different community (see for example this).  (UPDATE 5/26 - see UPDATE below with some comments / papers about C-sections vs. vaginal birth and how my use of "massive" here may be an overstatement itself).
I could go on and on.  But I won't.  I am pleased the reporter talked to Martin Blaser who puts some damping on the speculation:
Dr. Martin J. Blaser, director of the human microbiome program at NYU Langone Medical Center, and the author of a recently published book, “Missing Microbes,” said that Dr. Aagaard’s study was important, but preliminary, and that it did not provide information that could be used in treating pregnant women. 
Thank you Martin.  But even with this, these articles leave me very frustrated.  The best I can do I guess is give out an award or two. So, for their reporting on the topic I am giving Denise Grady of the New York Times and Jocelyn Kaiser of Science News an Overselling the Microbiome award since they oversell the potential connection between oral health and infant health as mediated by the placenta.  And I am also giving this award to  Kjersti Aagaard, the first author of the paper, for her comments on the topic.

For more examples of "Overselling the Microbiome" awards see my page here.

UPDATE: Some other news stories where the headline alone is painful

UPDATE 2: Some articles that discussed placental microbes before this story came out
and many more

UPDATE 3: Paper on placental - mother - infant connection not even mentioned

Just found this paper from a Google Scholar search:  Probiotics Modulate Host-Microbe Interaction in the Placenta and Fetal Gut: A Randomized, Double-Blind, Placebo-Controlled Trial.  Seems like it is of direct relevance.  Abstract is below;
Background: Early host-microbe interaction provides important maturational stimuli for the developing immune system. The role of prenatal microbial contact remains elusive. Objectives: Our aim was to investigate whether microbes in placenta or amniotic fluid affect fetal innate immune gene expression during late pregnancy and whether innate immune gene expression profiles in the placenta and the fetal gut may be modulated by dietary supplementation with specific probiotics. Methods: Altogether 43 pregnant women were randomized to receive (1) Bifidobacterium lactis, (2) B. lactis in combination with Lactobacillus rhamnosus GG (LGG) or (3) placebo for 14 days before elective cesarian section at full term in a double-blind clinical trial. Bacteria in amniotic fluid and placenta were detected by quantitative (q)PCR. The expression of Toll-like receptor (TLR)-related genes in the placenta and meconium samples was assessed by qPCR. Gene expression patterns in meconium were interpreted to reflect immune physiology in the fetal gut. Results: The study was completed by 29 mother-infant pairs. Bacterial DNA was detected in all placenta samples. Microbial DNA in amniotic fluid and placenta was associated with changes in TLR-related gene expression in the fetal intestine. Maternal probiotic supplementation significantly modulated the expression of TLR-related genes both in the placenta and in the fetal gut. Conclusions: Microbial contact in utero is associated with changes in fetal intestinal innate immune gene expression profile. Fetal and placental immune physiology may be modulated by maternal dietary intervention using specific probiotics.

This paper was not mentioned or cited as far as I can tell in the current study.

UPDATE 4: This paper also seems relevant

Microbial contact during pregnancy, intestinal colonization and human disease.  Abstract:
Interaction with colonizing intestinal bacteria is essential for healthy intestinal and immunological development in infancy. Advances in understanding early host–microbe interactions indicate that this early microbial programming begins in utero and is substantially modulated by mode of birth, perinatal antibiotics and breastfeeding. Furthermore, it has become evident that this stepwise microbial colonization process, as well as immune and metabolic programming by the microbiota, might have a long-lasting influence on the risk of not only gastrointestinal disease, but also allergic, autoimmune and metabolic disease, in later life. Modulating early host–microbe interaction by maternal probiotic intervention during pregnancy and breastfeeding offers a promising novel tool to reduce the risk of disease. In this Review, we describe the current body of knowledge regarding perinatal microbial contact, initial intestinal colonization and its association with human disease, as well as means of modulating early host–microbe interaction to reduce the risk of disease in the child.

UPDATE 5 - more misleading quotes
  • From Time's misleadingly named article "The New Way to Predict When Pregnant Women Will Deliver": “By focusing on oral health, we may actually be optimizing the health of the pregnancy and limiting the risk of pre-term birth,” says Aagaard. After paying so much attention to the more obvious ways to make a pregnancy healthy, it may be time to consider the less obvious – and less visible ones
  • That quote is just so inappropriate ... uggh

UPDATE 6: May 24.  Some  Made a Storify with some of the Tweets related to this post. Note - November 2018 replaced with Wakelet. UPDATE 7: May 26 - some other papers of relevance to birth mode and infant microbiomes and placentas
A key question to me I guess is the following - how do differences between the microflora in babies born by C-Section vs. vaginal birth arise if the microbes in placentas have a big role in colonizing infants?  Perhaps the differences between C-section babies and vaginal birth babies are small -- I do not know -- need to dig into this more.


  1. This is wonderful, which means that the public will outright reject it. Meanwhile, the New York Times is doing a bang-up job with the bad science journalism.

  2. "Modulating early host–microbe interaction by maternal probiotic intervention during pregnancy and breastfeeding offers a promising novel tool to reduce the risk of disease."

    In a society that strongly encourages C-section deliveries, discourages breast feeding (let me count the ways), and demands that women return to work when their children are still in the primary stages of breastfeeding, it is easy to see why it is so much easier to blame pre-mature delivery and poor infant health on ORAL HYGEINE.

    This, coupled with Nicholas Wade's (chief genetics reporter at the New York Times) recent book, remind me of why I cancelled my subscription to the New York Times years ago.

  3. Jon (and others, but less directly);
    Dr. Miles and I have generated 454/16S + some other marker gene data from 10 patients who underwent hysterectomies and were not pregnant. There is sequence from tissue including the lower reproductive tract, various aspects of the uterus, the fallopian tubes and ovaries. There are bacterial populations across most of these tissues in most of the patients; I will not elaborate more at the moment, but the data was generated less than a year ago and we are working on an ms. If there are people with specific interests, I'm open to discussion so that human subjects are not unnecessarily inconvenienced in the conduct of our science.

    1. It would be very interesting to see if there are microbes that are specific for any site ..

  4. @BenK: "There are bacterial populations across most of these tissues . . ."

    So what. Why would anyone assume that there was *not* bacterial in the reproductive system of women?

    @Jonanthan Eisen: Jonathan, why is it such a big research topic that the reproductive system has clusters of bacterial populations? Also, do the women who participated in this research know how it is being used?

    1. 1. I have no idea if the women who participated know how it is being used.

      2. As for bigness of the research topic, I think what microbes are in the reproductive system is potentially very interesting. But I guess I am with you on the notion that just having clusters of microbes is not that interesting ...

    2. Marnie;
      Many tissues were thought to be sterile. In fact, to a decent approximation, intramuscular and many other tissues are free of bacteria in most people. Breast tissue apparently is not, which is interesting. The upper female reproductive tract is not, also interesting. Simply observing them and getting an initial sounding of the community diversity and composition is a start.

    3. Marnie;
      You raised the issue of informed consent. I'm not sure what you have in mind. Of course, for all research on human subjects, informed consent is required.

  5. I can't remember any journalist's version of a science topic where my own internal editor was not stopping after each sentence and commenting, "False." "Irrelevant." "Unsupported." "Correct but pointless" In contrast, most actual peer reviewed science literature, even the piece said journalist was writing about, get's editorial comments like, "Hmmm." "Interesting." "Didn't know that." Why is that? I think that journalism's fundamental drivers - attention, subscriptions, exposure, publicity - differ from those of science: Truth, accuracy, reputation, teaching, knowledge building.
    I really admire Jonathan for trying to stamp out this spot fire of journalistic excess, but I think...there is a lot of dry fuel out there and a lot of careless ignition sources.

    1. I disagree a bit - there are definitely some science reporters out there who I do not elicit that kind of response (at least in me)

  6. Thank you Jonathan for this dissection of the article and surrounding media hype, but despite the overselling, I do feel the article is interesting scientifically.

    One thing that interests me is that although the microbiome splits quite neatly across the different body sites by taxonomic profile, this is not so for the metabolic profile (using KEGG pathways), which appears quite consistent across all the sites. Although the placenta does look a little different in this respect, it appears simply more noisy than the other sites (Fig 2C). If the microbiome is important functionally in a location-specific manner, would you not expect different gene sets to be involved in the different body regions?

    1. Personally, I think the way most metabolic analyses are done leads to much of the variation between sites being missed and this might be an example of that. That being said, I agree with you that this is an important point that should be addressed by those that keep saying the microbiome does everything for everyone all the time.

  7. Thank you Jonathan. How do you believe this variation is missed? Just because these analyses ultimately depend on having good annotation sets, and functional annotations are likely to be missing?

    I guess a counter-argument to my point is that the broadly similar pathways across different body sites could be viewed as suggesting these are functionally important conserved pathways. Nonetheless, it's hard to see how the microbiome can contribute to tissue-specific functionality through species diversification alone if the types of genes and pathways present remain the same in different body sites.

  8. Dear Jonathan,
    Thank you for this really relevant post and discussion. I’m an associate professor at the Academic Centre for Dentistry Amsterdam (ACTA) in Amsterdam, the Netherlands, focusing on the oral microbial ecology. I happened to hear dr. Aagaard presenting this work during International Human Microbiome Conference in China in September 2013, and started brainstorming with my colleagues about the potential role of the ‘placental microbiome’ harboring oral microbes. This resulted in a hypothesis quite different from that of dr Aagaard, which we have proposed in an open access publication at Frontiers in Microbiology: . In a nutshell, we propose that development of fetal tolerance toward the microbiome of the mother during pregnancy is the major factor for a successful acquisition of a normal microbiome, where the fetal immune system is ‘trained’ by placental microbes to recognize a ‘friend’ from a ‘foe’. Of course, all of this is still a speculation, in research papers called in a much nicer term - a hypothesis, which we are eager to test.

  9. Read the actual journal review articles cited in the Wikipedia article about the topic Placental microbiome. You don't even have to read the article, just read the references and form your own conclusions. The popular press always seem to throw in their own speculation. I just wrote this article, check out the references, they answer all your questions.


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