In the 50s, two new drugs appeared that helped to cope with common problems during pregnancy: thalidomide and diethylstilbestrol (DES). They were considered safe for pregnant women and had real (or apparent) positive effects. The history of both drugs should warn many about the danger of treating healthy pregnant women with potent drugs.

The first story is about the infamous thalidomide. It was opened in East Germany in the mid-50s and entered the market as a cure for insomnia and anxiety; it was soon discovered that it also helps against morning sickness. The women were very happy. Almost no one doubted its benefits, because most scientists and doctors believed that drugs do not penetrate the placenta; if the mother feels good, then the child is all right.

Unfortunately, what happened next is known. In 1957-1961, the thalidomide was prescribed to thousands of women. In 1960, it was sold over-the-counter in Germany. Even today it is not known exactly how many women fell under its action. But we know that between ten and twenty thousand children were born with serious birth defects, mainly related to the development of limbs: short or missing legs and arms, as well as pelvic, ear and eye anomalies. Many cases were fatal. As soon as it became clear what was going on, the thalidomide was immediately banned.

Fortunately, Frances Kelsey, the then Commissioner of the Department for control over products and medicines of the USA has postponed the approval of thalidomide until proven its safety. The toxicity was evident in the first tests, which were taken from born children. Nevertheless, it took a few more years of discussions and questions, whether the defects, for example, tests of atomic bombs or some other reasons, to finally ban the medicine. During all this time the sad list of children all grew.

The second edifying story is related to the form of estrogen, DES, which was developed at Oxford University in 1938 under a grant from the Medical research Council of England. It was not patented because of the law prohibiting profit from medicines developed with state money. So it was available to any company interested in its production. And interested in many. In 1941, the food and drug Administration allowed it to be used to treat a variety of symptoms of menopause, cessation of lactation after birth, and stagnation of milk in the breast. DES had no obvious or important side effects, so in the 1940s, on a wave of enthusiasm, doctors began to use it to treat various pregnancy-related problems, including preventing recurrent miscarriages and alleviating morning sickness.

DES appeared in an era when the General public believed in the power of medical science and trusted the opinion of doctors. Advertisements in medical journals portrayed or kiddies with blooming guise of, attentive and smiling. It was meant that they are healthy thanks to the fact that mothers took DES. It was very difficult for doctors to swim against the current: many prescribed it, and large companies with a reputation were engaged in advertising. The drug received not less than 3 million pregnant women in the United States and in other developed countries. Unfortunately, the belief in this medicine was not supported by any scientific data. Its popularity is purely a merit of marketing.

In 1953, an elaborate clinical trial was published in the American Journal of Obstetrics and Gynecology, showing that DES has no positive effect on the course of pregnancy. Gradually in all textbooks of medicine began to say that it is ineffective. Nevertheless, the medicine was prescribed for many years. There was a noticeable gap between the recommendations of medical literature and the actions of doctors. The decisive action was exerted by inertia, customs and pressure of colleagues. The drug was ineffective, but no one thought it was also unsafe.

The first problems were discovered only in 1971, when doctors from Boston published a study on a very rare cancer called “clear-cell vaginal adenocarcinoma”. Most vaginal cancers develop in older women, but all cases of this type have been observed in adolescent girls and young women. It was found that the mother of seven of the eight patients involved in the study, once took DES. Patients received a dose of the drug while still in the womb, but the consequences were manifested only 14-22 years later. They were followed by other cases. Now we know that inside the womb exposure to the drug increased the risk of developing this cancer by forty times.

Rare tumors, unfortunately, were only the tip of the iceberg. The 2011 study, led by Dr. Robert Hoover of the National cancer Institute, compared the cumulative risks of women exposed to DES in utero and not exposed. It turned out that the percentage of infertility among the first is more than twice (33.3 against 15.5 %). The “daughters of DES” was less likely to give birth to their own children. In addition, there was a high risk of miscarriage in the second trimester of pregnancy (16.4 against 1.7%), an increased risk of premature birth and all related problems, as well as a greater number of cases of early breast cancer.

The sons of women who took DES also have increased health risks – in particular, problems with male sexual organs, for example, cysts or omission of testicles from the abdominal cavity into the scrotum. According to some evidence, even the grandchildren of women who took DES experience similar problems.

These terrible problems could not be detected before, because unlike the case of thalidomide, the effect was only decades later. In addition, female infertility has different causes. Someone had to put forward a hypothesis and conduct a thorough study to make sure that the cumulative risk of such health problems is higher in the “daughters of DES”. But now all this is known.

One conclusion from these stories is quite obvious to me. Many have learned a lesson in childhood from their parents: even if everyone else is doing something, it does not mean the safety of the action. Half a century ago for pregnant women was considered normal reception of DES and thalidomide. Today, caesarean sections, or antibiotics. These practices are unprecedented.

Throughout the animal world, mothers transmit germs to their children at birth. Different types of tadpoles get specific skin bacteria from frog mothers, although all live in the same pond with the same bacterial composition. Chicken eggs are sown microbes from the pouch next to the rectum of the mother chicken. And the children of mammals for millennia get the first microbial populations, passing through the mother’s vagina. This transmission is a critical aspect of infant and human health. But now he’s in great danger.

Over the past one hundred and fifty years, childbearing has changed dramatically. Yes, childbirth has become much safer than ever before. The equipment of maternity hospitals helps to cope with many problems, from which countless babies and mothers died in the old days. But along with this incredible progress came the silent threat that we have only now come to understand. The spread of caesarean sections and the excessive use of antibiotics to treat women and newborns alter the composition of the microbiome that mothers transmit to children.

During any pregnancy microbes do play a secret role. For example, have you ever wondered why women gain more weight than can be explained by the size of the fetus and placenta? The answer is bacteria.

The mother’s blood carries nutrients, oxygen and certain antibodies to the fetus through the placenta. Back through the blood returned waste of the fetus and carbon dioxide, which are excreted by the mother. As far as we know, there are usually no bacteria in the uterus. It is considered to be completely sterile environment, but now even the medical dogma questioned. However, we know that at such an early stage of life, some infections, such as rubella and syphilis, can do things.

With the growth of the fetus in women grow Breasts and uterus. At the same time, imperceptibly for us, starts the movement of microbes in the digestive tract. During the first trimester of some species of bacteria is in excess, and others-much less. In the third trimester, shortly before delivery, there are even more significant changes. All processes involving tens and hundreds of species of bacteria are not accidental. Dozens of women, which explored, bacterial composition varied equally. So, microbes are preparing for something important, as if they are part of an adaptive property that helps to survive pregnancy and prepare for childbirth.

A few years ago, Dr. Ruth Ley, a young woman scientist at Cornell University who had just given birth to a child, decided to study this process in the laboratory. One of the main biological problems of pregnancy – the mother has to feed two at the same time. She needs to look for ways to accumulate and mobilize energy and the optimal division between her and the child. Ruth hypothesized that the woman may be helped by intestinal microbes, reorganizing the metabolism so that it benefits the fetus.

The Ruth team used microbial-free mice born and raised under sterile conditions to investigate the role of intestinal bacteria during pregnancy. Animals are free from any bacteria and, as far as it is possible to make sure, from viruses and other microorganisms, so they help scientists to start each experiment from scratch. Mice live in plastic balls. But scientists can at any time interrupt the antimicrobial state, sowing any necessary microbes – one species, several or a whole community from the body of another mouse or even a person. Numerous studies have shown that human microbes can settle in a new medium, and mice will survive such a “transplant”. Such rodents become peculiar hybrids: mouse body and genes, but a huge number of human microbes.

Ruth wanted to know what would happen if you took microbes from the intestines of pregnant women and injected them into the intestines of microbial mice. Her team compared two types of transplants: fecal microbes obtained during the first and third trimesters. After sowing, Ruth began to observe how the animals will grow. Just two weeks later, the difference was obvious. Mice that received the third trimester microbes gained more weight, they had higher blood sugar levels compared to those that received the first trimester microbes.

If we extend the results to humans, it turns out that many of the physiological and pathological properties of pregnancy are controlled, at least in part, by microbes that live in the mother and evolve to help her and themselves. When during pregnancy there is a lack of food – as in the history of mankind has often happened – microbes change the metabolism of women, so she received from food more calories. And in this way increase the likelihood of the next generation, which will be their new home.

It turns out, changes in microbial composition can partly explain the extra pounds, high sugar or glucose in the blood. Everything is logical: mothers store more energy to optimize their children’s chances of a successful life.

One of the consequences of this process is the development of some so – called diabetes mellitus in pregnant women: they can not cope with excess weight without harm to the body. For the most part, the disease passes in a mild form and disappears by itself a few weeks after birth. Some are not so lucky, and diabetes is more severe. But for them, the Ruth experiment is good news: someday, perhaps, we will learn to manipulate the intestinal microbes of pregnant women to optimize the process of energy storage and cope with diabetes. For example, restore your own microflora from the first trimester or maybe transplant microbes from women who did not have such diabetes at all. Or give mothers prebiotics-food specially selected for feeding the microbes that live in the body. These studies open up a whole world of new opportunities to ensure slightly greater pregnancy safety.

While the microbes in the mother’s intestine store energy, another population of microbes – in the vagina-also begins to change. Everyone’s getting ready for the baby. As mentioned earlier, women of childbearing age carry bacteria, mainly lactobacilli, which make the environment acidic. It protects the body from dangerous bacteria that are afraid of acid. In addition, lactobacilli have a powerful Arsenal of molecules that inhibit or kill other bacteria.

During pregnancy, they thrive and dominate, displacing other inhabitants and uninvited guests. And all because they are preparing for the main event – childbirth, which for the most part occur on the 38th or 39th week. It is not yet known what exactly triggers this process: why one woman can give birth two weeks “earlier”, and the other – a week “later”. I personally suspect that microbes were involved here as well.

When the water leaves, a stream of fluid sweeps through the vagina, picking up bacteria and washing them on the woman’s hips. Lactobacilli rapidly colonize the skin. The child is still in the womb and preparing to leave. In the course of labor, contractions intensify, causing the cervix to fully open. And in childbirth, and the baby released a lot of hormones, including adrenaline and oxytocin.

Whatever the delivery, fast or slow, a sterile baby soon comes into contact with lactobacilli from the vagina. Elastic like a glove, the vagina touches all the covers of the newborn, covering the soft skin. At this time, and there is a transfer of microbes. Children’s skin plays the role of a sponge, absorbing them. The head lies face down and is turned to the back of the mother to clearly fit into the birth canal. The first liquid that the child sucks up contains the mother’s microbes, including a small part of the fecal mass. Childbirth is not an antiseptic process, but it has been like this for 70 million years, since the first mammals appeared.

Born, the child instinctively stretches his mouth full of lactobacilli, to the mother’s breast and begins to suck milk. The interaction is perfectly organized: lactobacilli and other bacteria that produce lactic acid decompose lactose, the main milk sugar, and produce energy from it. The first food of the child becomes colostrum containing protective antibodies. A carefully thought-out sequence of actions, including the vagina, baby, mouth, breast and milk, ensures that among the first bacteria in the intestines of the newborn will be species capable of digesting milk. They are armed with their own antibiotics, which prevent competing, possibly dangerous bacteria to colonize the intestines of the newly-born. Lactobacilli that dominate the mother’s vagina shortly before delivery become the “Foundation” for microbial populations that come after them. Now the child has everything to start an independent life.

Breast milk, which appears a few days later, brings even greater benefit to the newborn. It contains carbohydrates-oligosaccharides, which the child can not digest. Why does milk contain energy-rich compounds that do not directly benefit the child? They’re germs. Oligosaccharides are food for some bacteria, particularly Bifi dobacterium infantis, another foundational species found in healthy children. In addition, breast milk contains urea, one of the main components of urine, which is poisonous to infants. It is again designed to feed the beneficial bacteria – giving them a source of nitrogen to produce their own proteins so that they do not have to compete for nitrogen with the child himself. How clever nature: created a system where the mother’s waste is used to stimulate the growth of bacteria useful to the child.

Meanwhile, skin bacteria constantly colonize the mother of the child, and with every kiss, it gets more and microorganisms from her mouth. Once upon a time, mothers used to lick their babies dry; many animals still do that, passing their microbes on to the next generation. But now, when a child is born from the vagina, it is immediately cleaned and removed the shell that covered him in the womb. This material, a cheese-like lubricant produced by the skin of the fetus, has hundreds of useful components, including proteins that suppress certain dangerous bacteria. Since the hospital staff are in a hurry to take a clean child to her mother for photography, the shell is often washed off. Do they do this service to the child? No one has yet conducted detailed studies, but intuition suggests that the cheese-like lubricant is used to attract beneficial bacteria and get rid of potential pathogens.

Children come to a world in which there is a huge variety of bacteria. But the species that colonize them directly, are not accidental. Continuing the work of the script, debugged thousands of years, nature selects the “good guys” that do that for a child is an important metabolic functions, helping to develop cells of the intestinal walls and expel “evildoers.”

The first microbes that colonize a newborn start a dynamic process, creating conditions for the emergence of a new microbiota, similar to the “adult”. They activate genes and build “niches” for the future microbial population. Their very presence stimulates the intestine to help in the development of immunity. In General, we are born with innate immunity, a collection of proteins, cells, detergents and compounds that protect our integuments by recognizing structures characteristic of many species of microorganisms. Then develop adaptive immunity, which learns to distinguish “their”from” strangers.” Our children’s microbes are the first teachers to tell the developing defense system what is dangerous and what is not.

In the following months and years of life, children receive new microbes from more complex foods and from the people around them: parents, grandparents, brothers and sisters, other relatives, then from neighbors, classmates, friends and other people. Eventually, the process becomes ” random.” Different children have different germs, the immune system also develops differently. As mentioned earlier, to three years each has its own unique microbial “base”. This is a very important thing for me. In just three years, a large and diverse set of microbes self-organizes into a life-support system equal in complexity to an adult microbiota. It happens to everyone.

So, three years, in which the most activity develop the first microbes do-inhabitants of, – time metabolic, immunological and neurological development child. During this critical period, the Foundation is laid for all biological processes that unfold during life – unless, of course, there is something that will break the slender algorithm.

Caesarean section is basically an unrecognized threat to mother-to-child transmission of microbes. Instead of birth through the birth canal, which is accompanied by a set of lactobacilli, the child is removed surgically through an incision of the abdominal cavity. The procedure was invented In ancient Rome to save the lives of children. Mothers always died.

Among the common reasons for the operation-prolonged or not started properly childbirth, fetal stress, rupture of the amnion or collapse of the umbilical cord, high blood pressure in the mother, pelvic presentation of the child, too large a child who will not pass through the birth canal. In some populations, the number of such emergency caesarean sections reaches 20%, in countries like Sweden, on the contrary, – only 4%.

Today it is a safe procedure, because it is almost always carried out by experienced obstetricians in hospitals. This happens when the life of the mother or child is in danger, sometimes almost immediately after receiving the information.

Caesarean section is so safe that in some cases, many women themselves prefer it. One of the reasons is the desire to reduce or avoid pain. This is not a trivial question. For personal or cultural views some are afraid to give birth. Millions choose an affordable and safe alternative. Some working women do so to fit childbirth into a busy work schedule. Others-not to miss someone’s wedding or prom. Third-to be sure that the birth will take exactly the doctor who they are observed.

Doctors also influence the choice of birth. Some are very conservative and prescribe this procedure, only noticing the stress of the fetus or suspecting the mother’s problems. For example, when there is a threat of pelvic presentation, natural childbirth can be dangerous. However, most fruits shortly before childbirth still turn the head. Thinking cynically, this process takes less time and fuss than a regular birth. In addition, most doctors and hospitals earn more money on operations than on natural childbirth.

For all these reasons, the number of caesarean sections in the United States increased from every fifth delivery in 1996 to every third – in 2011, that is, by almost 50 %. If the trend continues, by 2020, half of America’s children (2 million a year) will be born surgically.

In different countries, the number of caesarean sections varies dramatically. In Brazil, 46% of children “Caesar”. In Italy-38 %, but in Rome, where, as is considered, this operation invented, – 80 %. In the Scandinavian countries, proud of medical conservatism-less than 17%, in the Netherlands – 13%.

Why such difference? Give birth the same everywhere. The only explanation is the difference in local practices and customs. For example, women in Rome, who now rarely give birth to more than one child, often become pregnant at the age of thirty: they have made a career and are constantly busy at work. Caesarean section is twice as likely as the rest of Italy. This suggests that the procedure is clearly not related to anatomical reasons.

So … what? What is the significance of the number? Why not do a cesarean section, if the mother is more comfortable, the doctor-easier,and the only fee-the hospital bill?

In fact, there is another “account” – biological. It affects the child directly. A few years ago, my wife Gloria was stuck for a couple of weeks in Puerto Ayacucho, the capital of the Venezuelan state of Amazonas. She conducted dietary and microbiological research there for twenty years and obtained permission to collect microbiome samples from Indians who lived in the state. She was going to go into the jungle to collect germs in a newly discovered Indian village, but the helicopter flight was canceled. So if you decide to bring at least some benefit, went to the local hospital. Will there be a difference in the composition of microbes in children born naturally and as a result of cesarean section? No one has yet studied this issue.

The study involved nine women aged 21 to 33 years and ten newborn children. Four gave birth naturally, five-as a result of planned caesarean sections. Gloria took samples of microbes from the skin, mouth and vagina of each of the mothers an hour before birth. And by sequencing DNA, it showed that all women in three places have bacteria from the largest groups present in similar proportions.

Fifteen minutes after birth, the wife collected samples from the skin, mouth and nose of the children. Then, the next day, took samples of the first feces of infants, which is called meconium.

All mothers, of course, on the bodies and in them there were many different types of bacteria, but gave birth naturally remained characteristic spots of amniotic fluid, containing many lactobacilli. More importantly, the composition of infants was different depending on the method of birth. In the mouth, on the skin and in the first feces of those who were born through the vagina, lived vaginal microbes of mothers – Lactobacillus, Prevotella or Sneathia. But in those born by caesarean section bacteria from their skin dominated: Staphylococcus, Corynebacterium and Propionibacterium. In all places – in the mouth, on the skin, in the gut – microbial composition are more like those on human skin and in the air operating, including at the hands of doctors and nurses and freshly laundered sheets. They were not colonized by maternal lactobacilli. The unpronounceable names of these microorganisms are not as important as the knowledge that the first populations of microbes in infants born as a result of caesarean section are not those that were “selected” by hundreds of thousands of years of human evolution.

From other researchers, we know that after babies begin to interact with the outside world in the first months of life, the microbiomes “align” and gradually become more similar. The initial difference between them decreases. One of the reasons is that all people sooner or later meet with organisms that play similar roles in their bodies. But maybe this initial difference at birth is more important than we thought. What if these first microbes-inhabitants give signals that critically affect the cells in the rapidly developing body of the baby?

Another threat to the newly acquired baby microbes-inhabitants – antibiotics, which takes the mother. After the story with thalidomide, the medical community has become much more cautious about taking medication for pregnant women. Does this mean that the medicines they are recommended are safe? And for whom, the mother or the fetus?

Most doctors consider it safe to use penicillins, including ampicillin, amoxicillin and Augmentin to treat mild infections during pregnancy – cough, sore throat, urinary tract infections. Sometimes, when doctors believe that the expectant mother has a viral infection, they give her antibiotics “to be sure” (in case the infection still turns out to be bacterial). As we know, these drugs affect the microbes that live in the mother, inhibiting vulnerable bacteria and selecting them for resistance. The closer to birth the antibiotic intake, the greater the chance that the child will receive a distorted population of microbes.

Then comes the actual birth. At this time, women are often given antibiotics to prevent infection after cesarean section and infection streptococci of the group B. About 40% of women in the US get them during childbirth; this means that 40 % of infants are exposed to its influence.

Thirty years ago, 2% of women developed infections after cesarean section. This was unacceptable, so now 100% receive a prophylactic dose of drugs before the first incision.

In addition, they are used for the prevention of serious infections, which causes Streptococcus in the mother of the group of bacteria that lives in the mouth, on the skin, sometimes in the vagina and rarely causes problems. It is worth remembering that streptococci-one of the most common microbes in the human body. A quarter to a third of pregnant women in the United States are carriers.

But sometimes group B Streptococcus can be fatal to newborns whose immune system has not started. Such infections are rare, but professional groups recommend that all pregnant women be tested for this microbe before delivery. If the test is positive, they take a dose of penicillin or a similar effective antibiotic shortly before the baby enters the birth canal.

But the problem, of course, is that, as we know, antibiotics are broad – spectrum drugs, not targeted. Yes, it kills group B Streptococcus, but it also acts on other, often friendly bacteria, destroying the vulnerable and selecting resistant. This practice changes the mother’s microbiome in all parts of the body just before they are to be passed on to the next generation.

In addition to everything else, the child is exposed and unplanned impact. Any antibiotic that gets into the blood of the fetus or the mother’s milk will inevitably change the composition of microbes. It is logical that an infant born with penicillin in the blood or intestines is different from a child born without it. One of the likely scenarios is the cure is striking in some genera of bacteria and improves the lives of others. It is not known whether it is a transient effect or the first step of the cumulative process. I think this is an interesting topic for detailed study.

One way or another, every year in the United States, more than a million pregnant women receive a positive test for group B Streptococcus, after which all of them are intravenously injected with penicillin {99} during childbirth to prevent it in infants. But only 1 out of 200 children sick, having received from the mother the streptococci {100} of group B. to protect the one, we put an optional effects still 199. We need some other solution, a better one.

If penicillin has no noticeable drawbacks other than rare allergies, then large-scale over-treatment does not seem to be a problem. But what if a change in microbial composition affects a child’s metabolic, immune, and/or cognitive development? As we will see from the experiments conducted in my laboratory and by other scientists, such fears have a real basis.

Another important consideration: now, of course, fewer children are born with serious infections from group B Streptococcus, but the number of other diseases is increasing. By killing or inhibiting some bacteria, penicillin selects other, resistant. For example, certain virulent strains of E. coli can infect vulnerable infants themselves. It is possible that, in terms of avoiding serious infections in newborns, the overall positive effect of penicillin injections on a million newborns per year is not as great as expected. A lot scared me and a recent conversation with a colleague: he said that the analysis of his wife for Streptococcus was negative, but the doctor still insisted on treatment (in case if the analysis of something “looked”). Fortunately, she refused.

Many women receive another dose before episiotomy, surgical incision of the perineum to prevent rupture and excessive bleeding during the passage of the baby’s head. A generation ago, only half of American women gave birth. Now, because of the change of customs-only a third. But in Latin America it is done nine out of ten women {101}, for the first time giving birth naturally. The percentage, again, varies depending on local customs and doctor’s advice. But most mothers do not even know that they received antibiotics during childbirth: they either were not told, or it was not before.

Finally, babies are also directly affected. Most do not suspect that all newborns in the United States immediately after birth are given an antibiotic. The reason is that many years ago, even before the appearance of such drugs, women with gonorrhea (venereal disease) could not get rid of the bacteria that caused it, although there were no symptoms of the disease. The infection was detected only after the child developed severe eye disease. Passing through the birth canal, the children received the sowing of bacteria on the face. Sometimes this eye infection, which is called “gonococcal ophthalmia”, was so severe that children remained blind.

For more than a hundred years, infants were given drops to prevent the disease – first lapis, then antibiotics after their appearance. The antibacterial effect, of course, is mainly manifested locally, but broad-spectrum drugs still enter the bloodstream and circulate through the body of the newborn. The dose is low, but most likely still affects the composition of microbes-the inhabitants of the body during the formation of the first population. My laboratory plans to conduct a study soon to measure the magnitude of the impact.

So, 4 million children born in the United States each year are being treated for a disease that, although catastrophic, is very rare. We need to develop more effective screening methods to prevent only children at the highest risk-for example, several hundred out of millions of newborns. In Sweden, babies do not drip any lapis or antibiotics, and this does not affect the incidence, so there is even a precedent for a more thorough assessment of risk and benefit. But all of these health formulas to treat millions to protect several hundred really vulnerable are based on the idea that taking drugs has no biological cost. What if they actually exist?

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