Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (13 page)

Modern agriculture, with the intensive production of everything from livestock to fruit, is bringing antibiotic-resistant bacteria and the antibiotics themselves directly to humans. Later, we will discuss the possible consequences. But in terms of my work, the most important aspect is growth promotion. If receiving antibiotics at a young age fattens up our farm animals, changing their development, then might that be analogous to what happens when we give our children antibiotics? Are we inadvertently fattening them up, when our intention is to treat their illnesses?

8.

MOTHER AND CHILD

In the 1950s two new drugs became available to treat common problems in pregnancy. One was thalidomide and the other was diethylstilbestrol, otherwise known as DES. These were drugs that were considered safe for pregnant women and had actual or purported benefits. Each provides a strong cautionary tale of the dangers of treating millions of healthy pregnant women with potent drugs.

First is the now infamous story of thalidomide. Discovered in East Germany in the mid-1950s and released in 1957 as a treatment for insomnia and anxiety, the drug was soon found effective in alleviating morning sickness. Women were thrilled. Essentially no one questioned its use because most scientists and doctors believed that drugs did not pass through the placenta; so if the mother was okay, the baby would be too.

Sadly, most of us know what happened. Between 1957 and 1961, thousands of women were prescribed thalidomide. In 1960 it could be purchased over the counter in Germany without a prescription. Even today, we don’t know how many women were exposed. What we do know is that at least ten thousand to twenty thousand babies were born with serious birth defects, mostly involving limb development, with shortened or missing arms and legs, as well as anomalies of the pelvis, eyes, and ears. Many defects were lethal. Once it became clear what was going on, thalidomide was immediately banned.

Luckily, Francis Kelsey, the commissioner of the U.S. Food and Drug Administration, withheld approval of thalidomide until it could be shown to be safe. Thus women in America were largely spared the tragedy of those birth defects in their babies, unless they happened to get thalidomide in another country. The toxicity of thalidomide was obvious at birth, so after multiple cases appeared, it was not so difficult to understand what had happened. Still, it took a few years, amid discussions and questions of whether the birth defects were due to nuclear bomb testing and other causes, to ban the drug. During those years, the toll of misery mounted relentlessly.

A second cautionary tale concerns a form of estrogen, DES, that was developed at Oxford University in 1938 under a grant from the Medical Research Council in England. It was never patented because of a policy against making profits on drugs discovered using public funds. As a result, DES was available to any company that wanted it, and many did. In 1941 the Food and Drug Administration permitted its use for treating a variety of menopausal symptoms, for stopping lactation after birth, and for reducing breast engorgement. DES had no obvious or important side effects, and in the 1940s, amid a great wave of enthusiasm, doctors began using it to treat pregnant women for a wide variety of problems, including the prevention of recurrent miscarriage and alleviating morning sickness.

DES came along at a time when the public believed in the power of medical science and trusted doctors’ authority. Medical journal advertisements showed beautiful babies with great complexions, alert and smiling, implying that their robust health was due to DES. It was difficult for many physicians to resist the tide, since so many of their colleagues were using it, and large, reputable companies were promoting it. Probably more than 3 million pregnant women received DES, mostly in the United States but in other developed countries as well. Unfortunately, there was no real science backing up this faith in the drug. Its popularity was an exercise in pure marketing.

In 1953 a carefully conducted clinical trial was published in the
American Journal of Obstetrics and Gynecology
showing that DES did not improve pregnancy outcomes in the least. Gradually medical textbooks all came to say that it was not effective. Still, DES continued to be used in pregnancy for years afterward. There was a disconnect between what the medical literature was advising and what doctors were doing. Inertia, custom, and peer pressure prevailed. Even though it was ineffective, no one thought that it wasn’t safe.

The first indication of trouble came in 1971, when doctors in Boston published a study concerning a very rare cancer called clear-cell adenocarcinoma of the vagina. Most vaginal cancers occur in older women, but these all occurred in adolescents or young adults. An investigation revealed that the mothers of seven of the eight patients in the study took DES in pregnancy. These girls and young women had been exposed to DES when they were in their mother’s womb, but the consequences did not manifest until fourteen to twenty-two years later. More cases followed. We now know that having been exposed to DES in utero increased the risk of these cancers fortyfold.

While these are rare tumors, it turns out they were the tip of the iceberg. A 2011 study headed up by Dr. Robert Hoover at the National Cancer Institute compared the cumulative risks in women exposed to DES in utero with those not exposed and found a doubling of their infertility rate (33.3 percent vs. 15.5 percent). The DES babies had less of a chance to have their own babies. Exposure also had significant effects on their loss of second-trimester pregnancies (16.4 vs. 1.7 percent), higher rates of preterm deliveries with all of their attendant problems, and more cases of early breast cancer.

Sons of women who took DES also had heightened disease risks, including problems in their male genital tracts, such as cysts and failure of the testes to descend properly from the abdomen. A wisp of evidence suggests there may be similar effects in the grandchildren of women who took DES.

These dreadful health problems were not detected earlier because, unlike with thalidomide, the effects were delayed by decades. Also there are multiple reasons a woman can be infertile. Someone had to have a hypothesis and look carefully to see that cumulative risks for such problems were higher in DES babies. And now we know.

One takeaway from these stories shouts out to me. It’s a lesson many of us learned earlier from our parents: just because everyone else is doing something doesn’t mean that it is safe. Back then it was normal for pregnant women to receive DES and thalidomide. Today it is normal for women to have Cesarian sections and to take antibiotics during pregnancy. These practices are occurring on an unprecedented scale.

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Throughout the animal kingdom, mothers transfer microbes to their young while giving birth. Different species of tadpoles acquire specific skin bacteria from mother frogs even though they all live in the same pond with the same bacterial background. Emerging chicken eggs get inoculated with microbes from a bacteria-filled pouch near the mother hen’s rectum. And for millennia, mammalian babies have acquired founding populations of microbes by passing through their mother’s vagina. This microbial handoff is also a critical aspect of infant health in humans. Today it is in peril.

In the past one hundred and fifty years, birth practices have changed dramatically. To be sure, the act of childbirth is safer than ever. Hospitals are equipped to handle the kinds of emergencies that killed countless women and infants in the past. But with this incredible progress has come a silent hazard that we are just beginning to understand. High rates of Cesarian sections and the overuse of antibiotics in mothers and newborns are altering the types of microbial species that mothers have always passed on to their newborns.

Microbes play a hidden role in the course of every pregnancy. For example, have you ever wondered why pregnant women gain more weight than can be accounted for by the size of their fetus and placenta? Bacteria are an answer.

The mother’s blood carries nutrients, oxygen, and certain antibodies to the fetus via the permeable placenta. Fetal waste products and carbon dioxide are returned through the blood, and the mother’s organs eliminate them. As far as we know, there are no bacteria normally present in the womb. It is believed to be a totally sterile environment, although this tenet of medicine is coming under question. However, we do know that particular infections, like rubella or syphilis, at such an early stage of life wreak havoc.

As the fetus grows, the mother’s breasts and uterus start to enlarge. Simultaneously, and invisibly, the microbes in her intestinal tract begin to stir. During the first trimester, certain species of bacteria become overrepresented while others become less common. By the third trimester, just before the baby is born, even greater shifts occur. These changes, involving scores of species, are not random. The compositions change in the same direction across the dozens of women who have been studied. The pattern suggests that these microbes are up to something important, as if they are part of an adaptive trait designed to promote the pregnancy and prepare for birth.

A few years ago, Dr. Ruth Ley, a young scientist from Cornell who had just given birth, decided to study this process in her laboratory. One of the central biological problems of pregnancy is that the mother is responsible for feeding two people. She must find a way to shore up and mobilize energy and optimally divide it between her and her baby. Ruth hypothesized that the mother’s gut microbes might help by reorganizing her metabolism in ways that benefit the fetus.

Ruth’s team used germ-free mice to investigate the role of gut bacteria in pregnancy. Born and raised in sterile conditions, germ-free mice allow researchers to begin each experiment with a clean slate; the mice are free of all bacteria and, as far as we can determine, free of viruses and other microorganisms. They live in a plastic bubble. But scientists can end the germ-free state by introducing whichever microbes they want, one bug at a time, a few different ones, or entire communities from the contents of another mouse or even from a human. Prior work by many researchers has shown that human microbes will “take” in their new host and that these mice will accept this “graft.” Such recipient mice are a kind of hybrid, mouse body and genes with a huge number of human microbes.

Ruth wanted to know what would happen if she took microbes from the intestines of pregnant women and put them into the intestines of germ-free mice. Her team compared two varieties of transplant: fecal microbes obtained from women during the first trimester of pregnancy and then from the third trimester. After inoculating the animals, she waited to see how they were growing. After just two weeks, the differences were substantial. The mice that received microbes from the third-trimester women gained more weight and had higher blood-sugar levels compared to the mice that received microbes from the first-trimester women.

If extended to humans, the experiment implies that many physiological and pathological features of pregnancy are controlled, at least in part, by the mother’s resident microbes, which evolved to help her and themselves. When food is in short supply during pregnancy, as has often occurred in human history, the mother’s microbes will shift their net metabolism so that more calories flow from food to her body. In this way, her microbes increase the odds that there will be a next generation, one that will provide a new home for them.

Thus shifts in microbial composition may be partially responsible for those extra pounds as well as for the increased sugar or glucose levels that commonly occur during pregnancy. It makes sense; mothers store more energy to optimize the success of their newborns.

One consequence of this process is that some women develop gestational diabetes; they can’t handle the extra weight without stressing their systems. Most of the time, the problem is mild and resolves within weeks after delivery. Or, for an unfortunate few, the diabetes is severe. The good news stemming from Ruth’s experiment is that one day we might be able to manipulate gut microbes in pregnant women to optimize their energy storage and tone down the diabetes. We might do this by restoring microbes harvested from the mother’s first trimester, or maybe introduce microbes from women who don’t develop diabetes. Or maybe give mothers prebiotics, foods tailored to nourish the composition of each woman’s resident microbes. These studies open a world of new possibilities to make pregnancy a little safer.

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As microbes in the mother’s intestinal tract store up energy, another population of microbes—this time in her vagina—begins shifting as well. They, too, are preparing for the baby’s birth. As noted earlier, women of reproductive age carry bacteria, primarily lactobacilli, which make the vaginal canal more acidic. This environment provides a hardy defense against dangerous bacteria that are sensitive to acid. Lactobacilli also have evolved a potent arsenal of molecules that inhibit or kill other bacteria.

During pregnancy, these tiger-mother lactobacilli flourish and predominate, crowding out other resident species and potential invaders. They are gearing up for the main event—birth—which occurs around the thirty-eighth or thirty-ninth week of most pregnancies. We don’t know what initiates the process, why one woman is two weeks “early” while another is one week “late.” My suspicion is that microbes are involved in this too.

When the mother’s water breaks, a rush of fluid is unleashed into her vagina, sweeping up bacteria as it flows out of her body onto her thighs. This splash, now dominated by lactobacilli, rapidly colonizes the mother’s skin. Meanwhile the baby is still in the womb preparing to exit. As labor progresses, contractions strengthen, forcing the cervix to fully dilate so the baby can emerge. A rush of hormones, including adrenaline and oxytocin, surge through mother and infant.

Whether the birth is fast or slow, the formerly germ-free baby soon comes into contact with the lactobacilli in the vagina. Very flexible, rather like a glove, the vagina covers the newborn’s every surface, hugging its soft skin as it passes through. And with that hugging a transfer occurs. The baby’s skin is a sponge, taking up the vaginal microbes rubbing against it. The baby’s head faces down and is turned toward the mother’s back to fit snugly in the birth canal. The first fluids the baby sucks in contain mom’s microbes, including some fecal matter. Labor is not an antiseptic process, but it has been going on like this for a long time—at least 70 million years since our earliest mammalian ancestors.