A Fateful First Act

I prided myself on being low-key about my pregnancy. I didn't read What to Expect When You're Expecting—OK, so I bought a copy, but I only used it as a reference. I traveled, I socialized, and I worked full-time until five days before giving birth, even though I was carrying twins. I did not want to believe that anything essential about me had changed. That is, until the night I shook my husband from sleep, sobbing hysterically, convinced that by eating a few pieces of feta cheese I had irreversibly damaged our babies.

I had read that some cheeses could harbor a bacterium called Listeria that causes birth defects. But I rebelled. All these prohibitions directed at my most innocent pleasures! I'd already cut out wine, coffee, sushi, bike riding, and countless other things I enjoyed. When I was six months pregnant, I got sick after gorging on a cheese plate at an office party. In the midst of my ensuing panic—would my children suffer their whole lives for one dumb, piggy move of mine?—something clicked: These fetuses weren't veteran humans. They were different, and painfully vulnerable.

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Everyone knows by now that it's bad for women to smoke or drink while pregnant, but a large body of research is revealing that much more subtle influences, such as being anemic, feeling perpetually stressed, or simply getting the flu, can also harm a developing baby. "It's a new understanding of what causes vulnerability to disease," says Vivette Glover, a perinatal psychobiologist at Imperial College London.

Until recently, doctors believed that the journey from fertilized egg to baby followed unwavering genetic instructions. But a flood of new studies reveals that fetal development is a complicated duet between the baby's genes and the messages it receives from its mother. Based on those signals, the fetus chooses one path over another, often resulting in long-term changes—to the structure of its kidneys, say, or how sensitive its brain will be to the chemical dopamine, which plays a role in mood, motivation, and reward.

This new science of fetal programming, which investigates how in utero influences cause physiological changes that can linger into later life, is producing clues to mysterious disorders such as autism and schizophrenia, as well as evidence of the very early effects of stress and toxins. Scientists still don't know all the hows and whys of these fetal cues, but the when is very clear: earlier than we ever thought.

A Delicate Project

Our first nine months resonate for the next 70 or 80 years because the fetal enterprise is so enormously ambitious. In just 270 days, a single cell becomes trillions of diverse and specialized cells—that's more cells than there are galaxies in the universe. As in any construction project, events unfold in a highly coordinated sequence. Each cell not only has its own job to do, it spurs other cells to action—sending out chemical signals that tell its neighbors to divide like crazy or to self-destruct. So when something goes wrong it can set off a domino effect. Cells might not travel to their intended destination, or they might stop multiplying too soon, or, in the case of brain cells, they might fail to establish the right interconnections.

"We pass more biological milestones before we're born than at any other time in our lives," says Peter Nathanielsz, director of the Center for Pregnancy and Newborn Research at the University of Texas Health Science Center at San Antonio. "If we do not pass them correctly, there is a price to pay."

Pregnancy is a dynamic process; the fetus is attuned to its mother in many ways. It learns about the day-night cycle from her rhythm of sleep and activity. It knows her voice: A classic 1980 study showed that immediately after birth, infants prefer a recording of their own mother reading a book over that of another woman reading the same story. The fetus even comes to appreciate its mother's taste in food after swallowing gallons of amniotic fluid tinged with those flavors. "The fetus is already a learning organism," says Christopher Coe, a psychologist at the University of Wisconsin-Madison.

By the same token, if its mother fails to provide vital nutrients, the fetus prepares for a world of scarcity, adjusting its metabolism so that it can wring the most out of every calorie. Such a baby might be born with a liver and pancreas that have less capacity to process fats and sugars, predisposing the adult to high cholesterol levels and diabetes. If the mom's stress hormones are high, her baby prepares to enter a harsh world—recalibrating its brain and nervous system to be on high alert for potential threats. As the years pass, the alterations that took place in the womb—especially when coupled with an unlucky genetic inheritance, a troubled upbringing, or an unhealthy lifestyle—may lead to problems: Heart attack. Diabetes. Osteoporosis. Depression. Schizophrenia.

Frazzled Origins

The womb experience helps establish a child's emotional resilience and susceptibility to disease, and unfortunately, that experience is not always completely under the mother's control.

If a woman is anxious for months at a time—say she's in a troubled marriage or is financially strapped—high levels of the stress hormone cortisol may reach her fetus. Such a fetus doesn't need as many brain receptors to sense the hormone's presence, so it develops fewer. But having fewer cortisol receptors changes a person's ability to cope in later life. The cortisol system has its own shut-off valve; when cortisol levels in the bloodstream reach a certain point, the body stops making the hormone and everything returns to normal. But people with fewer receptors don't sense that it's time to stop making cortisol until they're practically swimming in it. Living with high levels of cortisol not only creates wear and tear on the body but also makes it tough to handle strong emotions without lashing out or withdrawing, and it may set people up for depression.

Infants whose pregnant mothers developed posttraumatic stress disorder after the September 11 attacks were found to be more easily upset by loud noises and unfamiliar people. "Temperament is not only genetically determined," says Catherine Monk, a Columbia University psychologist. "It is constructed throughout early development and, in part, in utero by exposure to the mother's mood." In a study of thousands of women in England, those who ranked in the top 15 percent for anxiety during pregnancy had children with double the rate of emotional and behavioral problems at 10 years old.

Stress may cause long-term cognitive deficiencies, too. Coe subjects pregnant monkeys to three loud car-horn bursts at unpredictable intervals over a 10-minute period, and he does it daily for one-quarter of their pregnancy. "Certainly women living in the Congo or in Iraq have a much more stressful pregnancy than anything I ever studied," he says. Yet even this moderate amount of stress results in infant monkeys that are less able to hold up their heads or scrutinize novel objects. At three years old, their hippocampus, a brain area responsible for learning and memory, is 10 percent smaller than normal, which likely translates into worse functioning.

Just as challenges can bring out the best in adults, prenatal stress seems to benefit children sometimes: Two-year-olds whose mothers were moderately anxious or depressed during pregnancy performed better than average on reasoning and coordination tasks such as solving puzzles, stacking blocks, and manipulating small objects. It may be that moderately emotionally "charged" women provided a more varied intrauterine environment, with stimulations that sped up brain development.

On the other hand, one of the scariest risks for stressed-out pregnant women is the greater chance that their child will one day be schizophrenic. Israeli girls who were in their second month in the womb during the 1967 Arab-Israeli war were 4.3 times more likely to become schizophrenic than girls born at other times, and boys were 1.2 times more likely to develop the disease. Another study found that children of women who experienced the death of a close relative during the first trimester of pregnancy were also more likely to later develop schizophrenia.

Researchers speculate that the placenta is very sensitive to stress hormones coursing through a severely stressed-out mother's body, and that those hormones cause alterations in the fetal brain that help unleash schizophrenia down the line.

The First Forty Days

If a woman gets the flu during her first trimester, her child is seven times as likely to develop schizophrenia as a teenager or young adult. It may not be the flu itself that causes the malfunction, but rather an immunological reaction. Cytokines—proteins the mother's body produces in response to the flu—get transmitted to the fetus and harm its brain.

What is really intriguing is that mice that were given a specific cytokine, interleukin-6, gave birth to offspring who not only displayed schizophrenic-like behaviors but also behaviors analogous to those seen in autistic humans.

A 2008 study suggests that 12 to 15 percent of autism cases may occur because maternal autoantibodies—antibodies that a person makes against something in themselves—interfere with proteins in the fetal brain. After identifying unusual antibodies in women who had more than one autistic child, researchers injected the antibodies into four pregnant monkeys. They also gave antibodies taken from women with healthy children to another four pregnant monkeys. The offspring of the monkey mothers who received the regular antibodies were fine, but all four of those whose mothers got the unusual autoantibodies spontaneously developed bizarre tics, such as pacing and doing repeated backflips. "Repetition of motor behaviors is one of the three cardinal features of autism," says David Amaral, a neuroscientist at the M.I.N.D. Institute at the University of California, Davis, who headed the study. Scientists don't know under which conditions these autoantibodies form, nor why they do so.

They do know that a critical window for development is 20 to 40 days after fertilization. During that time, fetuses that eventually develop autism or schizophrenia often begin to display shared physical characteristics, such as protruding ears and unusual toes.

A groundbreaking idea could hold the answer to the puzzle of why some children are autistic while others become schizophrenic. Researchers Bernard Crespi and Christopher Badcock argue that a struggle between genes from Dad's sperm and Mom's eggs results in different expressions of the same genes. When a genetic region that plays a role in brain development is disrupted, the theory says, if the genes inherited from the father dominate, the disruption gives rise to autism, whereas if the genes inherited from the mother dominate, the interference will result in schizophrenia.

Quality of (In Utero) Life Issues

A fetus's only source of sustenance is the food and oxygen its mother takes in, and its access to those supplies can be precarious. The mom's meals nourish her first, then travel a winding path—through temporarily expanded uterine arteries to the greedy placenta, and finally along the rope-like umbilical cord.

If a mother eats a low-calorie or low-protein diet, or one deficient in essential fats or critical nutrients, such as folic acid, vitamin D, or iron, a fetus may lack the raw materials it needs to properly build its brain and other organs. (Iron-deficient infants are shyer, fussier, and less sociable.) Children born to women who are pregnant during a famine, for example, are more susceptible to heart disease and depression when they grow up. Starved fetuses build smaller organs with fewer blood vessels, which can lead to high blood pressure later on. Animal research suggests that not eating enough in the first days after conception can increase the potential for cardiovascular disease and diabetes, which is why women should eat well while trying to get pregnant.

But eating too much is also risky. When women gain more than the recommended weight during pregnancy (25 to 35 pounds for healthy women), their kids are 48 percent more likely to be overweight at the age of seven. A high-fat diet during pregnancy reshapes rat offspring's brains, making them crave fatty foods and putting them at risk for lifelong obesity.

The negative effects of drinking while pregnant are well-known: Alcohol can damage key areas of the fetal brain, including the prefrontal cortex—the region responsible for planning, decision-making, and emotional restraint. What's new and disturbing is research showing that imbibing just a couple of drinks a day during the first 50 days after conception, when a woman may not yet know she is pregnant, creates the strongest effects.

Chemicals that lurk invisibly in our clothes and furniture, in the food we eat, and in the air we breathe dominate today's world. Some, like bisphenol A, a compound in some plastic water and baby bottles, resemble hormones such as estrogen that are produced by our own bodies, which makes them potentially harmful even at very low levels because the body is primed to respond to them. There is concern that the increase in abnormalities of newborn boys' reproductive organs—the rate of hypospadias, a birth defect of the urethra, doubled in the U.S. between 1970 and 1993—results from maternal exposure to such chemicals.

Faith, Love, and Compensation

My sons were born free of Listeria, and in fact were healthy in every way. But I now realize that there could be hidden problems. Twins have a harder time in utero because a mother can supply only so much food and oxygen, and they must share it. On top of that, this was my first pregnancy and I was over 35—factors that limit the stretchiness of the blood vessels that shuttle oxygen and nutrients to the uterus. Let's just say my fetuses were getting their supplies through a coffee stirrer instead of a straw.

And yet I remind myself: Birth is a beginning, not an ending. Nurturing and mental stimulation can reverse the effects of a compromised pregnancy. Monk and colleagues found that 4-month-old infants had high levels of stress hormones in their saliva when their mothers were anxious or depressed before the birth and unresponsive afterward. But when moms were attuned to their babies, the infants' cortisol levels were normal, no matter what the pregnancy was like.

If children learn good exercise and eating habits, they are unlikely to become obese or get diabetes. If their parents and other caregivers engage and nurture them, it is less likely they will develop learning or conduct disorders. "You can look at it as though the system has been primed," says Marta Weinstock-Rosin, a psychopharmacologist at Hebrew University in Jerusalem. "But if nothing else bad happens and everything is calm, it may well be all right."

And with an enriched upbringing, a compromised prenatal environment might even be turned to advantage. When brain development has been altered because a pregnant woman was highly anxious, drank martinis, or ate too much mercury-tainted fish, the resulting baby may be high-strung and hard to soothe. But the same sensitivity that leads to moodiness can also confer empathy and awareness. "You might just be more able to take in what's around you and actually do even better than average," Monk says.

Still, there's no getting around the fact that a mother's experiences profoundly shape her developing baby. Now that I know this, would I live my pregnancy differently? Absolutely. I would have eaten organic as much as possible to reduce my fetuses' exposure to toxins. To ensure that they had all the essential building blocks to grow healthy brain tissue, I would have poured flaxseed oil over my cereal and served up kale and broccoli almost every night. I would have begun taking prenatal vitamins and iron before getting pregnant. And imagining those little guys depending on me for all their oxygen, I would have thrown myself into yoga and spent 10 minutes every morning and evening taking deep breaths.

But I also remind myself of what I did right—a fair amount, judging from the mischievous, affectionate 2-year-olds my boys have become. "To have a baby is a huge affirmation and commitment to life and love," Monk says. Besides doing their best to stay healthy, mothers have no choice but to take a big leap of faith. —Emily Laber-Warren

Timed Health Tips

Expecting mothers are bombarded with guidelines, but some do's and don'ts are particularly important during specific windows in a fetus's development. Here are a few time-sensitive hints for optimizing the prenatal environment.

Pre-Conception

  • Get regular exercise. The better your cardiovascular health going into pregnancy, the more oxygen and nutrients you'll pipe to the developing baby.
  • Drop that glass of wine with dinner. The offspring of pregnant monkeys who sipped just two drinks a day have subtle learning and emotional problems. The alcohol was most damaging during the first several weeks of pregnancy, when you may not yet realize you're pregnant.
  • Get a flu shot to reduce the chance of getting the virus. Make sure you've been vaccinated for chicken pox, rubella, and hepatitis B at least three months before trying to conceive.

First Trimester

  • Limit stress. Severe stress during this time could heighten the chance that a baby will later become schizophrenic. You can't prevent most traumatic events, but don't work in a hostile environment if you don't have to.
  • Avoid smog. Air pollutants like carbon monoxide and ozone have been linked to heart defects when the exposure coincided with the second month of pregnancy, when the heart is forming.
  • Make a date with folate. Folic acid deficiency in the first 28 days of pregnancy leads to brain and spinal cord defects, so stock up on lentils, asparagus, and fortified cereal.

Second Trimester

  • Be an iron woman. By the 20th week of pregnancy, your stored iron supply may be depleted, meaning you could get anemic. For the sake of your own energy and for your growing fetus, take a supplement and eat spinach.
  • Stay off caffeine. You're not off the hook, Starbucks addicts: A large British study concluded that caffeine consumption during pregnancy was associated with smaller babies. The association continued all the way through pregnancy.

Third Trimester

  • Don't forget choline. Your brain cell volume decreases during the third trimester, and you may be feeling a little spacey. Found in egg yolks, soybeans, and beef, choline can help boost your memory and aid in your baby's ongoing brain development.
  • Meditate, do prenatal yoga, and breathe deeply to promote relaxation and increase the amount of oxygen that reaches the fetus. Your life is about to change drastically; don't stress out about having everything perfectly put together but do make sure you have social support lined up.

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