by D. F. Swaab
Aspecific Effects
The functional teratological impact of medication sometimes comes to light by chance. Majid Mirmiran, a PhD student working at our institute in the 1980s, studied the question of whether the high level of REM sleep in fetuses—REM being the phase in which you dream the most—is important for normal brain development. During this stage of sleep, the brain is strongly activated, a pattern that starts already in the womb. Mirmiran carried out an experiment that inhibited REM sleep in rats by giving the rats either chlorimipramine (an antidepressant) or clonidine (a medicine used to combat high blood pressure and migraine). The experiment was conducted on two- to three-week-old rats at a stage at which the rats’ brain development was comparable to fetal brain development in the second half of human pregnancy. After a short course of this treatment during their development, the adult animals had less REM and were more fearful. Moreover, the sex drive in the grown male rats diminished, and they became hyperactive. In other words, a mere two weeks of exposure to these substances during their development caused permanent alterations in the brains and behavior of rats. A subsequent study in Groningen looked at children whose mothers had been prescribed clonidine eight years previously during their pregnancy as a “safe” medication for high blood pressure and migraine. The children proved to have severe sleep disorders; some were even sleepwalkers. One of the problems of functional teratological disorders, in other words, is that doctors must be able to determine, on the basis of animal studies, what disorders they need to look for in humans. What’s more, the effects of the substances in question are aspecific. You can’t tell from a condition that manifests itself long after birth, such as a sleep disorder, exactly what substance taken during pregnancy caused the brain damage in question. Other examples of aspecific symptoms of functional teratology are learning disorders (caused by alcohol, cocaine, smoking, lead, marijuana, DDT, antiepileptic drugs), depression, phobias and other psychiatric problems (diethylstilbestrol, smoking), transsexuality (phenobarbital, diphantoin), aggression (progestogens, smoking), impaired motor skills, and social and emotional problems.
Additionally, chemical substances are thought to contribute to developmental disorders in which diverse factors play a role, like schizophrenia, autism, SIDS, and ADHD. Depending on her baby’s genetic background, a woman who smokes during pregnancy can increase the chances of her child developing ADHD by a factor of nine. The risk of ADHD is also increased when adrenal cortex hormones are administered during pregnancy to promote lung development in babies at risk of being born prematurely. This procedure has been found to impair brain development, potentially causing not only ADHD but also a smaller brain, impaired motor skills, and a lower IQ. These hormones are now administered much more sparingly.
Dilemma
One of the dilemmas confronted by doctors is that patients with schizophrenia, depression, or epilepsy often continue to need treatment during pregnancy, because the mother’s condition is potentially harmful to her child. Unfortunately, taking antipsychotics like chlorpromazine during pregnancy has been shown to cause motor disorders in children, and some antiepileptics increase the risk of spina bifida or transsexuality. It’s best to treat epilepsy during pregnancy with a single drug (rather than a combination) together with folic acid. Some antiepileptics are more harmful than others: Valproic acid has been shown to impair verbal IQ more than other epilepsy medications. Around 2 percent of pregnant women take antidepressants even when they have only mild depression. Such drugs don’t appear to increase the risk of serious birth defects, though the children born to these mothers are somewhat underweight and slightly premature, score somewhat less well on the post-birth Apgar test, and have subtle motor disorders. However, these disadvantages must be weighed against the problems that can result from a mother being stressed and depressed during pregnancy, such as impaired cognitive performance, attention, and language development. When a mother is fearful during pregnancy, she can permanently activate her baby’s stress axis, thus increasing the risk of phobia, impulsiveness, ADHD, and depression later in life. If at all possible, it’s worth considering treating depression in pregnant women with alternative therapies, like light therapy, transcranial magnetic stimulation, massage, acupuncture, or online therapy. Clearly, doctors treating such patients need to do a lot of careful thinking.
Mechanisms
Brain cells are created with incredible rapidity in the womb and shortly after birth, and this process continues, somewhat more slowly, until around the fourth year of life. Brain maturation goes on much longer; in the case of the prefrontal cortex, it continues right up to the age of twenty-five. Every facet of brain cell development can be disrupted by chemical substances during pregnancy. Disturbances to the migration of brain cells can lead to heterotopias, a condition in which groups of cells making their way to the cerebral cortex end up in the wrong part of the brain. They get trapped in the white matter, the fiber connections, as they journey to the cerebral cortex (fig. 20), a location where they can’t function properly. Substances that are regularly taken by pregnant women, such as benzodiazepines, can induce this condition. Drinking during pregnancy also causes malformations and malfunctions of nerve cell fibers. Smoking and drinking during pregnancy alter the receptors for nicotine, and smoking cannabis can alter the dopamine receptors in the fetal brain.
Conclusions
Addictive substances, medication, and environmental substances can permanently disrupt fetal brain development, leading to learning and behavioral disorders in later life. Congenital defects of this kind are known as functional or behavioral-teratological defects.
Tracing the connection between these disorders and the effects of chemical substances is difficult due to the length of time between the child’s exposure to such substances in the womb and their effects, which may only be manifested when the child goes to school or—in the case of reproductive problems—perhaps twenty or thirty years later. Moreover, the conditions caused by these substances, like learning and sleep disorders, are so aspecific that they can’t be used to identify the substance that caused the brain damage during pregnancy. On top of that, a single substance can produce different symptoms depending on the stage of development at which the child was exposed to it. All of this is complicated by the fact that doctors, especially in the absence of reliable animal studies, don’t know what disorders they should be looking for. With women who may require drug treatment during pregnancy, it’s essential to discuss potential problems at an early stage so that if a pregnancy is planned, the safest drug or alternative therapy can be prescribed.
THE SHORT-TERM OUTLOOK OF THE UNBORN CHILD
We’re programmed in the womb for life after birth. We acquire our feeling of being male or female, our sexual orientation, and our level of aggression while still in the womb (see chapters 3 and 8). Later, our sex hormones activate the brain systems that are programmed before birth, and our sexuality and aggression are manifested. This intrauterine programming is influenced by the hereditary information passed on by our parents. As a result, a significant part of our character is determined from the moment of conception, as is our risk of brain disorders like schizophrenia, autism, depression, and addiction (see chapters 5 and 10). But the information in our DNA is much too limited to program our brains fully in advance. The brain has solved this problem by overproducing cells and synapses. As cells develop, they compete for the best contacts. From these they obtain growth substances that make them more active, enabling them to make more and better connections. Cells that fail to do so die off, and surplus connections are pruned off.
Besides our genetic determination, our developing brains are influenced by all kinds of other factors that affect brain cell activity, like fetal and maternal hormones and nutrients and environmental chemicals passing through the placenta. For instance, sex hormones program us along male or female lines. Our levels of aggression and stress are set before birth for the rest of our lives. Extreme signals from the outside world also le
ad to fetal brain systems being permanently modified. In this way, the unborn child prepares itself for a hard life outside the womb. In the short term the fetal brain’s plasticity promotes survival, but it also makes it more vulnerable to harmful substances like nicotine. In the long term, fetal programming can also contribute to chronic diseases, as a study at Amsterdam’s Academic Medical Center shows. Toward the end of the Second World War, the Nazi occupiers of the Netherlands robbed the country of its food supply, leading to the famine of 1944–45. Babies were not only underweight at birth (fig. 9) but also more likely to develop antisocial behavior and obesity in later life. They turned out to prefer fatty foods and to exercise less. They were also more likely to develop high blood pressure, schizophrenia, and depression. The implications are far-reaching because the same mechanisms still come into play when fetuses are malnourished because of placental malfunction, causing babies to be born underweight.
It seems that even before birth, a child registers a shortage of food in its surroundings. What evolutionary advantage might this have? In such cases, all the brain systems that regulate metabolism are programmed in the womb so as to retain every calorie. Later in life, these individuals feel less satiated when they eat. Since they’re smaller at birth, they also need less food. So even at this early stage, children adapt their brains and behavior to a life of scarcity outside the womb. Their tendency to antisocial behavior equips them to defend their own interests, giving them an advantage in situations where there isn’t enough to go around. Their activated stress axis will also contribute to this survival strategy. But if they are then born into surroundings where there’s an abundance of food, this adaptive strategy becomes a handicap. Their inability to feel satiated means they are more likely to be obese and to develop hypertension. They also run a greater risk of addiction. And the fact that their stress axis is constantly switched on heightens their risk of depression and schizophrenia. So the diseases that are more likely to arise after prenatal malnutrition could be regarded as the side effects of an adaptive strategy that improves the fetus’s chance of survival in the short term.
Disruption to the sexual differentiation of an unborn child’s brain when its mother is severely stressed during pregnancy (see chapter 3) could be regarded in a similar light. When a pregnant woman experiences stress, the brain of a female fetus will become more male and vice versa. This also appears to be an adaptive response. A girl will be able to cope better in later life if she’s robust and competitive, while a boy who isn’t macho is less likely to get into conflict with alpha males in that stressful environment. This is also an excellent survival strategy in the short term, but in the long term it can impair reproduction and increase the likelihood of developmental disabilities and schizophrenia.
In sum, the fetus appears only to think of survival in the short term, adapting to the difficult circumstances that it anticipates immediately after birth. It’s of course wrong to speak of a fetus “thinking.” Over a period of millions of years, unborn children have been exposed to threats of this kind. Occasionally, a baby possessed a mutation that enabled it to adapt better to the problems facing it, and this favorable mutation then spread through the population. And you can’t blame a child for opting for short-term adaptations without taking account of the long-term consequences, because longevity is only a very recent human accomplishment.
FIGURE 9. A child born in Amsterdam’s Wilhelmina Gasthuis hospital during the famine (the “Hunger Winter”) of 1944–45. Not only did these babies have low birth weight, in adulthood they were more prone to antisocial behavior and obesity. They showed a preference for fatty foods and were less likely to exercise. They also had greater risk of developing high blood pressure, schizophrenia, depression, and addiction. Photograph: NIOD Institute for War, Genocide and Holocaust Studies.
Up to now, doctors have been able to treat only the later consequences of fetal programming. Now, armed with knowledge about such programming, doctors can encourage targeted prevention by providing advice on nutrition during pregnancy, for instance.
DOES A FETUS FEEL PAIN?
When George W. Bush was president, impressive footage of a fetus in the womb being touched by a needle and responding with violent movements made the rounds. Pro-life advocates used the video to suggest that fetuses feel pain and will attempt to protect themselves from instruments of abortion. The federal government considered making it mandatory for doctors to inform women that there was “substantial evidence” that an abortion would inflict pain on a fetus. In the case of pregnancies of over twenty-two weeks, it was proposed that anesthesia must be administered to fetuses before an abortion. Doctors who failed to comply would be fined $100,000 and lose their jobs. These proposals met with approval from the pro-life movement, but how much actual evidence is there to show that fetuses truly feel pain?
In a mature state of development, painful stimuli are transported by nerve fibers from the skin via the spinal cord to the center of the brain, the thalamus (fig. 2). From there, the stimuli go to two areas: the primary sensory cortex, where one becomes aware of pain, and the cingulate cortex, the brain’s alarm center (fig. 27), which interprets pain and directs the emotional and autonomic responses: emotion, contorted face, stress response, rapid breathing, higher blood pressure, and increased heart rate.
A normal pregnancy lasts for forty weeks. The wiring to conduct pain stimuli from the fetus’s cerebral cortex is in place by the twenty-sixth week. Only then can such stimuli travel from the skin to the child’s cerebral cortex, but whether they are then consciously received has yet to be established. It seems unlikely that premature babies can consciously feel pain before the twenty-ninth or thirtieth week. The pain sensors in the skin and the nerve pathways that convey pain signals are in place as early as the seventh week, enabling the fetus to respond to touch from a needle. But, contrary to the claims of fanatical pro-lifers, that certainly doesn’t constitute proof that the fetus can feel pain. For that to happen, the stimulus must first reach the cerebral cortex, and the cortex must be mature enough to process stimuli meaningfully. Before the cortex is fully mature, the fetal response to pain stimuli is purely based on spinal-cord reflexes. Anencephalic babies, who are born with most of the brain missing, respond in exactly the same way. In their case, the response to pain stimuli is just as violent and generalized—the whole body seems to be involved—as in intact fetuses in the first trimester of pregnancy, precisely because the cerebral cortex hasn’t matured and can’t keep the spinal-cord reflex in proportion.
Contacts between the thalamus and the cortical plate under the cerebral cortex are established from twelve to sixteen weeks. The cortical plate is a waiting room for fibers that will grow into the cerebral cortex (between twenty-three and thirty weeks). EEG measurements, which determine electrical activity in the brain, and blood circulation in the cerebral cortex of premature babies show a response to pain stimuli from twenty-five to twenty-nine weeks. So at that stage, pain stimuli are arriving in the cerebral cortex. The question is whether the cerebral cortex is already mature enough to receive the pain consciously. Conscious perception is also necessary for pain to be perceived emotionally. EEG measurements in newborns show a difference between the response to touch and the response to the pain of a heel prick only as of thirty-five to thirty-seven weeks.
Nowadays, when treating premature babies in incubators, it’s generally thought to be safer to assume that they feel and experience pain. They respond to invasive treatment and the taking of blood through movement and alterations in heart rate, breathing, blood pressure, oxygen pressure, and stress hormone levels. The same applies to operations like circumcision. That doesn’t prove, however, that pain is perceived consciously, because these autonomic responses come from regions below the cerebral cortex and therefore might be based on unconscious processes. The same applies to the movements that premature babies make in response to pain stimuli, because these can still be spinal-cord reflexes that don’t penetrate through to the c
erebral cortex. Not only do anencephalic babies respond to physical stimulus by recoiling, but brain-dead adults in vegetative comas whose cerebral cortex is entirely destroyed also respond in the same way.
So premature babies are seen to respond to pain stimuli in the cerebral cortex as of twenty-five to twenty-nine weeks, but even then we can’t be certain that this response is conscious. It’s even harder to establish whether a fetus possesses consciousness. The “waking stage” in a fetus’s wake and sleep cycles is sometimes regarded as a surrogate for consciousness. But during the late stage of pregnancy, fetuses spend around 95 percent of the time asleep, that is, unconscious, due to the immaturity of their brains and the effects of placental hormones. During the remaining 5 percent of the time, they are “awake,” but that period is more like a transitional phase between REM and non-REM sleep than a period of genuine wakefulness or consciousness.
Unpleasant stimuli have been shown to cause changes in cerebral cortex activity in premature babies aged twenty-five to twenty-nine weeks, but there are great differences between a premature baby and a fetus of the same age. Stimuli that prompt a waking response after birth (like a shortage of oxygen) have the completely opposite effect on a fetus: They suppress the waking stage. This allows a fetus to conserve energy in difficult circumstances that it’s powerless to escape anyway. Even a potentially “painful” or “annoying” stimulus, like a strong vibration or a loud noise, elicits only a subcortical response in a fetus. Moreover, that a twenty-eight-week-old fetus can “learn” to respond to the stimulus doesn’t mean that a conscious memory process is involved. Again, primitive “learning behavior” of this type can also be seen in anencephalic babies. So it’s an unconscious form of learning for which the cerebral cortex isn’t needed.