Category Archives: Asthma

Mode of delivery and childhood illness: A randomized trial in 2004.

03c62f38ce31d41b01e1b5a4031bf11aOne of the biggest difficulties in proving a causal link between cesarean birth and chronic health problems in childhood is the type of research studies that can practically and ethically be done during pregnancy.

The gold standard in medical research is the randomized controlled trial (RCT). In an RCT researchers randomly place subjects into either “treatment” or “control” groups, then expose the treatment group to something—a new vaccine for Infection X, for example—and then compare outcomes in the two groups later on. (In this example, how many kids in the treatment [vaccinated] group came down with Infection X versus how many in the unvaccinated control group?) If there’s a significant difference in outcomes between the two groups, you’ve got a strong argument that the treatment made the difference.

How a randomized controlled trial works. (Credit: SUNY Downstate Medical Center)

How a randomized controlled trial works.**

As you can imagine, randomly assigning pregnant women to cesarean (treatment) or vaginal birth (control) groups is nigh onto impossible—ergo, you can’t do an RCT. This means that virtually all research studies on the issue of cesareans and chronic childhood have been observational in nature—looking backward in time at databases, for example, or trying to fish significant trends out of hospital registries, birth cohorts and the like. The best an observational study can tell you is that A and B are associated with one another, but that’s it—you can’t prove that A actually causes B. An observational study can’t prove that cesareans are a cause of asthma; it can only say that cesareans are associated with an increased risk of childhood asthma.*

So mode-of-delivery RCTs are out of the question…or are they? Actually, in 2004, a Canadian research team did one.

Well done, Northern Neighbors!

Well done, Northern Neighbors!

The multi-center, multi-nation Term Breech Trial wasn’t about whether cesareans might increase the risk of childhood asthma, diabetes and such. It was about trying to figure out whether elective cesarean section or vaginal birth was the safest way to deliver a breech baby at term. Since the existing research was somewhat murky at the time, it was considered ethical (with informed consent) to randomize women to have either a planned cesarean or attempt a vaginal birth.

The particulars of the breech birth debate are best left for another post, but tucked away in the study’s results section was this little nugget:

“…more parents in the planned cesarean birth group than the planned vaginal birth group reported that their children had had medical problems in the past several months…relative risk, 1.41; 95% CI, 1.05-1.89; P=0.2.”

Plain English version (mine): The toddlers who had been in the planned cesarean group were about 40% more likely to have been sick in the previous few months than those in the planned vaginal birth group. The types of medical problems—typical 2 year-old stuff like colds, ear infections and stomach flu—were no different between the groups. The only difference was in the numbers of children who’d gotten sick.

As is the case with all medical research, you can find things in the study to complain about: relatively small numbers, for example, the use of parental questionnaires and the fact that some mothers in planned vaginal birth group ended up having cesareans (and vice-versa), etc.

But here’s my bottom line:

In a randomized trial of pretty well-matched subjects, those babies whose mothers were in the planned cesarean group tended to get sick more often than those in the planned vaginal birth group.

This doesn’t address the issue of chronic illnesses like asthma, type 1 diabetes and the like, but it does support the theory that cesarean birth can mess with a baby’s developing immune system.

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*Here’s an exaggerated example of the trouble with mistaking association for causation: Virtually all adults who die suddenly of heart attacks drank water in the 24 hours before they died. So, drinking water is associated (time-wise) with heart attacks. But you would be wayyyy wrong to say that, based on that association, a glass of water can cause a heart attack.

**Credit: SUNY Downstate Medical Center

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Filed under Asthma, Canada, Cesareans, Immune system, Maternal-child health, Newborns, Vaginal birth

Cesareans and chronic childhood disease: Time for a public discussion

From the Ishinhō, Japanese medical text, 1860

From the Ishinhō, Japanese medical text, 1860

In an analysis published in the most recent edition of The BMJ, Drs. Jan Blustein and Jianming Liu examine the evidence that cesarean delivery is associated with an increased risk of chronic childhood diseases like asthma, type 1 diabetes, and obesity. Their conclusion: the bulk of the evidence suggests that the association is real.

The time has come, Blustein and Liu write, for maternity care providers to include the risk of chronic childhood disease in their discussions with women considering a “non-essential” cesarean, such as when the choice is between a VBAC or repeat cesarean, or in the case of a woman choosing a medically unneccessary cesarean in lieu of vaginal birth—the so-called “maternal request” cesarean.

This topic has intrigued me for some time now. As part of my recently completed MPH program at the University of Minnesota, I wrote a paper titled, “Do Cesarean Sections Increase the Risk of Child Asthma? A Systematic Literature Review.”

In writing the paper I read and analyzed every research study on the subject since 2001. Roughly two-thirds of those studies detected a small-to-moderate association between cesarean birth and childhood asthma. (In fact, 90% of the studies detected an association between the two, but not all were statistically significant.) Most of the studies that didn’t find the association were seriously flawed—too few subjects, for example, or ignoring possible confounders, like prematurity or a history of maternal asthma. Three meta-analyses (two in 2008, one in 2014) all reached similar conclusions: cesarean section is associated with about a 20% increase in the risk of child asthma.

My paper was limited to asthma, but as described in the BMJ analysis there’s evidence that cesareans increase the risk of other chronic childhood illnesses, too–type 1 diabetes and obesity. A 2015 study by Sevelsted et. al. analyzed a cohort of two million Danish children and found small-to-moderately increased risks of juvenile rheumatoid arthitis, connective tissue disorders, inflammatory bowel diseases, immune deficiencies, and even leukemia.

Given that body of evidence, you’d think that organizations like ACOG (the American Congress of Obstetricians and Gynecologists) and the U.K.’s National Institute for Health and Care Excellence would be pushing their members to share this information with their pregnant patients. But they’re not. According to Blustein and Liu,

“…knowledge about chronic disease risks could affect decision making in non-essential caesarean. The American College of Obstetrics and Gynecology and the UK’s National Institute for Health and Care Excellence recently issued consensus statements on caesarean delivery at maternal request. Based on evidence about maternal and perinatal outcomes, both groups concluded that a pregnant woman requesting caesarean should have that choice, if she still desires it after discussion of the risks and benefits of the procedure. Importantly, neither group acknowledged the long term risk of chronic disease. [Emphasis mine.]

Critics can (and do) point to the uneven quality and designs of the studies that support such links—it’s association versus causation all over again—but that’s not entirely fair. To prove beyond doubt that cesarean birth increases the risk of child asthma, you’d have to do trials where women are randomly assigned to cesarean or vaginal birth…which, as you can imagine, is a practical and ethical non-starter. That leaves us with observational studies, which can only point out that two things seem to be related, not that they definitely are.

Ah, but there has been a randomized study of the long-term effects of cesareans versus vaginal birth in term, breech deliveries, and at least one research team has made the case that randomized trials of mode of delivery aren’t really unethical. More on those topics soon.

Finally, just to re-re-reiterate: I’m not anti-cesarean. My wife and son are alive and well today thanks to a medically necessary cesarean. But the cesarean rate today is 6 times higher than it was when I was a junior in high school (1970, if you must know…). As Blustein and Liu point out in their analysis:

“We live in a world where caesarean rates cannot be explained by compelling medical indications.”

Perhaps increased awareness of the potentially negative impact of cesareans on child health will help reverse that decades-long trend.

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Filed under Asthma, Cesareans, Diabetes, Obesity, VBAC

Is it the cesarean, or the absence of labor?

Stem cells, pondering the future

Stem cells, pondering the future

I’ve written a fair amount about the association between cesarean birth and the increased risk of immune-related diseases like asthma, diabetes, celiac disease, and even obesity. Most of the research out there has focused on the newborn gut microbiota—the collection of bacteria that colonize a baby’s intestines at birth and play a key role in the development of the immune system. These bacteria are primarily acquired from the mother’s birth canal and rectum during a vaginal birth, but for cesarean-born babies those “pioneer” bacteria are often derived from the hospital environment. Such “wrong” bacteria in the bowel early on can lead to inflammation and, the theories go, to immune-related diseases later in life.

But is the cesarean per se at the root of all this? Or might the absence of labor (or an incomplete labor) have something to do with it? Childbirth is, after all, a fabulously complicated dance of maternal and fetal hormones, anti-oxidants, and other chemicals that are known to influence the immune system. What happens to the newborn’s immune system development when that dance is cut short, or never starts in the first place?

A study from Sweden’s Karolinska Institutet published in the current issue of the American Journal of Obstetrics and Gynecology has me wondering about the “absent-labor” scenario again. The study’s authors compared cord blood samples from babies born by elective cesarean section (ECS) with those who were vaginally born (VB). They looked specifically at hematopoietic stem cells—the precursor cells that go on to become, among other things, the white blood cells that play a critical role in the human immune system.

Here’s what they found: the DNA in stem cells from ECS babies was significantly different from that of the VB babies, particularly in an area devoted to production of antibodies. The study’s genetic analysis is way above my pay grade, but boiled down to the essentials, the differences are all about epigenetics, which is defined as:

 “…the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence.”

Ouch!

Plain English version (mine): Epigenetics is the study of how genes are turned on and off, typically by the addition of methyl groups (ouch, again!) to genes. The timing of all this light-switch-like activity, and the potential for permanent change, has big-time implications for health throughout life.

The Swedish researchers found that stem cell DNA methylation (the addition of methyl groups to genes) increased steadily with the duration of labor. So one could conclude, couldn’t one, that normal labor plays an important role in preparing future white blood cells for their task, and, ergo, the absence of labor is why everyone’s so chubby these days? Sure, one could conclude that…but one would be jumping the gun, big time.

Hold that smokin' gun, pardner!

Hold that smokin’ gun, pardner!

Why? Because this was a small, observational study—the kind of study designed to make readers sit up and take notice (Hmm…that’s interesting!”) but that requires much more research before any guns start smoking. The small numbers of subjects in this study makes it easier for error to creep in, for example, and there were significant differences between the mothers as well—the ECS group was significantly older than the VB group, and their babies were born an average of a week and a half earlier, factors which might cause their own epigenetic effects.

It’s going to take much larger studies to see if these findings are in fact true, and if so to tease out how significant such cesarean-related epigenetic changes may be in the grand scheme of childhood immune system diseases. A lot of vaginally born kids end up asthma, after all. Including me.

But still, how fascinating! I’m looking forward to reading more about this.

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Photos courtesy Joseph Elsbernd, Jim Sher

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Filed under Asthma, Cesareans, Gut microbiota, Natural childbirth, Obesity

Oops…

The perils of the virtual world…

Ahem… I’ve just been told that Science & Sensibility is having some spam problems, so apparently my post went up and came down quickly. Should be up again soon. In the meantime here’s the post (below). Check in at Science & Sensibility later to follow any comments that surface, or to further sabotage the site, as you see fit.

And no, I’m not the spammer…

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Unintended consequences: Cesarean section, the gut microbiota, and child health.

When I first learned some years ago that cesarean section was associated with an increased risk of childhood asthma and eczema, I eagerly awaited the rest of the story. What could the link possibly be? Epidurals? Anesthetics? Antibiotics? Something strange and exotic was afoot, I was certain.

Imagine my surprise, then, when a growing body of evidence pointed to an unexpected source: the newborn gastrointestinal tract and the microorganisms that live there.

How might intestinal bacteria play such a major role in the health and well-being of newborns and children? The answer lies in an ancient, mutually beneficial relationship, one that modern birth technology has dramatically altered.

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Some friendly faces…

“Microbiota” is the term used to describe the community of microorganisms—bacteria, viruses, and fungi—that normally live in or on a given organ in the body. There’s a unique microbiota that inhabits the mouth, for example, another that lives on the skin, and still another that populates the intestine, or gut. Given an intestinal surface area of about 2,700 square feet—more or less the size of a tennis court—the microbiota inhabiting the gut is the largest and most diverse in the body.

How large and diverse? The gut microbiota contains roughly one quadrillion cells—at least ten times as many cells as does the human body itself. More than 1,000 bacterial species having been identified to date, with unknown numbers yet to be discovered.

How do all those bacteria get there? The fetal intestine, in the absence of congenital infection, is sterile in utero. The bacteria that come to colonize the bowel are acquired during birth and shortly afterwards, a process that is very much influenced by how a baby is born.

The gut microbiota and mode of delivery

In vaginally-born babies the colonizing bacteria originate primarily in the maternal birth canal and rectum. Once swallowed by the newborn during birth, these bacteria pass through the stomach and upper intestine and colonize the lower intestine, a complicated initial process that takes about a week.

Infants born by cesarean section—particularly cesareans performed before labor begins—don’t encounter the bacteria of the birth canal and maternal rectum. (If a cesarean is performed during labor the infant may be exposed to these bacteria, but to a lesser degree than in vaginal birth.) Instead, bacteria from the skin and hospital environment quickly populate the bowel. As a result, the bacteria inhabiting the lower intestine following a cesarean—the gut microbiota—can differ significantly from those found in the vaginally-born baby.

Whatever the mode of delivery, a core gut microbiota is well established within a few weeks of life and persists largely intact into adulthood. A less stable peripheral microbiota—one that is more sensitive to changes in diet and environmental factors, like antibiotics—is created as well. Between one and two years of age, when weaning from breast milk typically leads to a diet lower in fat and higher in carbohydrates, the gut microbiota takes on its final, mature profile.

Development of the newborn immune system

The dramatic first steps in immune system development take place at the same time the core microbiota is being formed, and the gut bacteria play a key role in that process.

In the hours and days following birth, the newly-arrived bacteria of the gut microbiota stimulate the newborn’s production of white blood

A t-lymphocyte

cells and other immune system components, as well as antibodies directed at unwelcome, disease-causing microorganisms. The bacteria of the microbiota also “teach” the newborn’s immune system to tolerate their own advantageous presence—to differentiate bacterial friend from foe, in other words.

In a cesarean birth the fledgling immune system is confronted with unfamiliar, often hostile bacteria—including Clostridium difficile, a particularly troublesome hospital-acquired bug. In addition, the healthy probiotic bacteria associated with vaginal birth that the newborn’s immune system expects to see arrive later and in lower numbers. These changes in the composition of the normal gut microbiota occur during a critical time in immune system development.

The cesarean-asthma theory (in a nutshell)

Here’s how cesareans and asthma are likely connected:

Humans evolved right along with the gut microbiota normally acquired during vaginal birth. When the composition of that microbiota is imbalanced, or unusual germs like Clostridium difficile appear, the immune system doesn’t like it. A low-grade, long-lasting inflammatory response directed at these intruders begins at birth, leading to a kind of “leakiness” of the intestinal lining. Proteins and carbohydrates that normally would not be absorbed from the intestinal contents—including large food molecules—make their way into the infant’s bloodstream.

To make a very long story short, that inflammation and the abnormal digestion and absorption of food that results appears to increase the risk of asthma and eczema—and diabetes, obesity, and other chronic illnesses—later in life.

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Normalizing the post-cesarean gut microbiota

Reducing the cesarean rate is an obvious best practice in promoting a healthy gut microbiota. But there will always be a need for cesarean section, and so researchers are now beginning to focus on “normalization” of the gut microbiota of cesarean-born babies. Although there are as yet no proven therapies, here are some possibilities:

  • Probiotics. Though administering healthful probiotic bacteria to correct an imbalanced microbiota makes intuitive sense, studies to date have been disappointing. However, research into “good” bacteria and how they become established in the intestine is active and ongoing.
  • Direct transfer of maternal secretions. Placing maternal vaginal and rectal material into the newborn’s mouth has been proposed—more or less mimicking natural colonization—but to date there are no published studies to support the practice.
  • Fecal transplantation. Direct transfer of fecal material from healthy adults into the gastrointestinal tract of people suffering from Clostridium difficile infections has shown promise. Using healthy parents as “donors” for their babies has been proposed, but applying such technology to otherwise healthy newborns is highly impractical at present, to say the least.

Conclusion

A cesarean section doesn’t automatically doom a child to a lifetime of asthma or eczema, just as a vaginal birth isn’t an absolute guarantee of perfect health. But cesarean birth, by altering normal gut microbiota development, does appear to moderately increase the risk of these and other chronic health conditions. A woman who has the option of choosing her mode of delivery should consider this along with the many other factors she must weigh in deciding how her baby will be born.

Mark Sloan M.D.

Selected references:

1)    Effects of mode of delivery on gut microbiota composition

Biasucci G, Rubini M, Riboni S, et al (2010). Mode of delivery affects the bacterial community in the newborn gut. Early Human Development 86:S13-S15

Penders J, Tjhijs C, Vink C, et al (2006). Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118(2):511-521.

Salimen S, Gibson GR, McCartney AL (2004). Influence of mode of delivery on gut microbiota in seven year old children. Gut 53:1388-1389.

2)    Development of the newborn immune system

Huurre A, et al (2008). Mode of delivery: Effects on gut microbiota and humoral immunity. Neonatology 93:236-240.

Johnson C, Versalovic J (2012). The human microbiome and its potential importance to pediatrics.  Pediatrics (published online April 2, 2012; DOI: 10.1542/peds2011-2736).

Vael C, Desager, K (2009). The importance of the development of the intestinal microbiota in infancy. Current Opinion in Pediatrics 21(6):794-800

3)    Cesarean birth, gut microbiota, and asthma/atopic disease

Azad M, Korzyrkyj A (2012). Perinatal programming of asthma: The role of the gut microbiota. Clinical and Developmental Immunology Volume 2012; Article ID 932072; doi:10.1155/2012/932072

Thanvagnanam S, Fleming J, Bromley A, et al (2008). A meta-analysis of the association between caesarean section and childhood asthma. Clinical & Experimental Allergy 38(4): 629-633.

van Nimwegen F, Penders J, Stobberingh E, et al (2011). Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. Journal of Allergy and Clinical Immunology 128(5):948-955.e3

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Filed under Asthma, Cesareans, Maternal-child health, Natural childbirth, Obesity, Science

Science & Sensibility, part 2

Science & Sensibility, Lamaze International’s “Research Blog About Healthy Pregnancy, Birth & Beyond,” just posted an essay of mine titled “Unintended Consequences: Cesarean Section, the Gut Microbiota, and Child Health.” It’s an explanation of the probable link between cesareans and childhood asthma, eczema, and other chronic health problems. Stop by and have a read!


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Filed under Asthma, Cesareans, Maternal-child health, Obesity, Science

Why ‘Obamacare’ is important for American children

Good news for kids.

“You cannot educate an unhealthy child, and you cannot keep an uneducated child healthy.” Jocelyn Elders M.D., former U.S. Surgeon General

I was one of millions of happy people following Thursday’s Supreme Court ruling that upheld the Affordable Care Act. The ACA greatly expands access to care, benefits, and coverage for millions of children, and if there’s any hope for the future of this country it has to start with healthy children.

It’s difficult for people with health insurance to truly understand what it’s like for those who don’t have it. Or for those who had it and then lost it in the recent economic downturn. And it’s easy to overlook the toll this can take on a child’s chances of success in life.

Here’s one example from my practice:

I took care of a family I’ll call the Swensons for several years. Greg and Connie have three kids, ages 6, 7,and 10. Greg is a welder and his wife Connie was a receptionist at the construction firm where Greg worked. Both lost their jobs about a year ago, and with it went their health insurance. They moved to a neighboring state to live with family and search for work in a more construction-friendly region.

Stephen, their ten year-old, is a very bright boy who suffers from asthma. When they had health insurance and jobs, Greg and Connie were able to keep Stephen healthy, but not without inhalers, allergy medications, and clinic visits.

When Greg and Connie lost their incomes and insurance, though, medications and regular doctor visits quickly ate up what money the Swensons had saved. Stephen got sicker. He wound up in  emergency rooms three times, and then was hospitalized for a few days when his asthma got out of control. He missed about three weeks of school due to his illness, and he was fatigued for a few weeks after that.  It took him the rest of the school year to catch up to his new classmates on the work he’d missed when he was sick.

None of that had to happen. In most other industrialized countries Greg and Connie could have simply taken Stephen to a pediatrician or family doctor in their new home town and stayed on top of his asthma care. Money would still have been tight, but they wouldn’t have had to go deep into debt to keep Stephen healthy and doing well in school.

The American Academy of Pediatrics has a nice summary the ACA’s benefits for children  (see the fact sheets for more details). Take a look–it’ll give you some hope for the future. How anyone can equate that to the second coming of 9/11 is beyond my powers of comprehension.

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Another reason to breast feed (as if you needed one)

(Painting by Tamara de Lempicka)

A new study from Great Britain has found that breast fed babies have better lung function at age 12 than those who are formula fed.  This was particularly noticeable in the children of mothers who have asthma, a finding that contradicted some earlier research.

I’ll check on this, but I assume the improvement is attributed to better immune system function in breast fed children. As more research looks at the link between vaginal birth, breast feeding and immune system health, we’ll likely be seeing more studies like these.

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