The First Ache
By ANNIE MURPHY PAUL
Published: February 10, 2008 in the New York TImes.
http://www.nytimes.com/2008/02/10/magaz ... elbias%3As
Twenty-five years ago, when Kanwaljeet Anand was a medical resident in a neonatal intensive care unit, his tiny patients, many of them preterm infants, were often wheeled out of the ward and into an operating room. He soon learned what to expect on their return. The babies came back in terrible shape: their skin was gray, their breathing shallow, their pulses weak. Anand spent hours stabilizing their vital signs, increasing their oxygen supply and administering insulin to balance their blood sugar.
“What’s going on in there to make these babies so stressed?” Anand wondered. Breaking with hospital practice, he wrangled permission to follow his patients into the O.R. “That’s when I discovered that the babies were not getting anesthesia,” he recalled recently. Infants undergoing major surgery were receiving only a paralytic to keep them still. Anand’s encounter with this practice occurred at John Radcliffe Hospital in Oxford, England, but it was common almost everywhere. Doctors were convinced that newborns’ nervous systems were too immature to sense pain, and that the dangers of anesthesia exceeded any potential benefits.
Anand resolved to find out if this was true. In a series of clinical trials, he demonstrated that operations performed under minimal or no anesthesia produced a “massive stress response” in newborn babies, releasing a flood of fight-or-flight hormones like adrenaline and cortisol. Potent anesthesia, he found, could significantly reduce this reaction. Babies who were put under during an operation had lower stress-hormone levels, more stable breathing and blood-sugar readings and fewer postoperative complications. Anesthesia even made them more likely to survive. Anand showed that when pain relief was provided during and after heart operations on newborns, the mortality rate dropped from around 25 percent to less than 10 percent. These were extraordinary results, and they helped change the way medicine is practiced. Today, adequate pain relief for even the youngest infants is the standard of care, and the treatment that so concerned Anand two decades ago would now be considered a violation of medical ethics.
But Anand was not through with making observations. As NICU technology improved, the preterm infants he cared for grew younger and younger — with gestational ages of 24 weeks, 23, 22 — and he noticed that even the most premature babies grimaced when pricked by a needle. “So I said to myself, Could it be that this pain system is developed and functional before the baby is born?” he told me in the fall. It was not an abstract question: fetuses as well as newborns may now go under the knife. Once highly experimental, fetal surgery — to remove lung tumors, clear blocked urinary tracts, repair malformed diaphragms — is a frequent occurrence at a half-dozen fetal treatment centers around the country, and could soon become standard care for some conditions diagnosed prenatally like spina bifida. Whether the fetus feels pain is a question that matters to the doctor wielding the scalpel.
And it matters, of course, for the practice of abortion. Over the past four years, anti-abortion groups have turned fetal pain into a new front in their battle to restrict or ban abortion. Anti-abortion politicians have drafted laws requiring doctors to tell patients seeking abortions that a fetus can feel pain and to offer the fetus anesthesia; such legislation has already passed in five states. Anand says he does not oppose abortion in all circumstances but says decisions should be made on a case-by-case basis. Nonetheless, much of the activists’ and lawmakers’ most powerful rhetoric on fetal pain is borrowed from Anand himself.
Known to all as Sunny, Anand is a soft-spoken man who wears the turban and beard of his Sikh faith. Now a professor at the University of Arkansas for Medical Sciences and a pediatrician at the Arkansas Children’s Hospital in Little Rock, he emphasizes that he approaches the question of fetal pain as a scientist: “I eat my best hypotheses for breakfast,” he says, referring to the promising leads he has discarded when research failed to bear them out. New evidence, however, has persuaded him that fetuses can feel pain by 20 weeks gestation (that is, halfway through a full-term pregnancy) and possibly earlier. As Anand raised awareness about pain in infants, he is now bringing attention to what he calls “signals from the beginnings of pain.”
But these signals are more ambiguous than those he spotted in newborn babies and far more controversial in their implications. Even as some research suggests that fetuses can feel pain as preterm babies do, other evidence indicates that they are anatomically, biochemically and psychologically distinct from babies in ways that make the experience of pain unlikely. The truth about fetal pain can seem as murky as an image on an ultrasound screen, a glimpse of a creature at once recognizably human and uncomfortably strange.
If the notion that newborns are incapable of feeling pain was once widespread among doctors, a comparable assumption about fetuses was even more entrenched. Nicholas Fisk is a fetal-medicine specialist and director of the University of Queensland Center for Clinical Research in Australia. For years, he says, “I would be doing a procedure to a fetus, and the mother would ask me, ‘Does my baby feel pain?’ The traditional, knee-jerk reaction was, ‘No, of course not.’ ” But research in Fisk’s laboratory (then at Imperial College in London) was making him uneasy about that answer. It showed that fetuses as young as 18 weeks react to an invasive procedure with a spike in stress hormones and a shunting of blood flow toward the brain — a strategy, also seen in infants and adults, to protect a vital organ from threat. Then Fisk carried out a study that closely resembled Anand’s pioneering research, using fetuses rather than newborns as his subjects. He selected 45 fetuses that required a potentially painful blood transfusion, giving one-third of them an injection of the potent painkiller fentanyl. As with Anand’s experiments, the results were striking: in fetuses that received the analgesic, the production of stress hormones was halved, and the pattern of blood flow remained normal.
Fisk says he believes that his findings provide suggestive evidence of fetal pain — perhaps the best evidence we’ll get. Pain, he notes, is a subjective phenomenon; in adults and older children, doctors measure it by asking patients to describe what they feel. (“On a scale of 0 to 10, how would you rate your current level of pain?”) To be certain that his fetal patients feel pain, Fisk says, “I would need one of them to come up to me at the age of 6 or 7 and say, ‘Excuse me, Doctor, that bloody hurt, what you did to me!’ ” In the absence of such first-person testimony, he concludes, it’s “better to err on the safe side” and assume that the fetus can feel pain starting around 20 to 24 weeks.
Blood transfusions are actually among the least invasive medical procedures performed on fetuses. More intrusive is endoscopic fetal surgery, in which surgeons manipulate a joystick-like instrument while watching the fetus on an ultrasound screen. Most invasive of all is open fetal surgery, in which a pregnant woman’s uterus is cut open and the fetus exposed. Ray Paschall, an anesthesiologist at Vanderbilt Medical Center in Nashville, remembers one of the first times he provided anesthesia to the mother and minimally to the fetus in an open fetal operation, more than 10 years ago. When the surgeon lowered his scalpel to the 25-week-old fetus, Paschall saw the tiny figure recoil in what looked to him like pain. A few months later, he watched another fetus, this one 23 weeks old, flinch at the touch of the instrument. That was enough for Paschall. In consultation with the hospital’s pediatric pain specialist, “I tremendously upped the dose of anesthetic to make sure that wouldn’t happen again,” he says. In the more than 200 operations he has assisted in since then, not a single fetus has drawn back from the knife. “I don’t care how primitive the reaction is, it’s still a human reaction,” Paschall says. “And I don’t believe it’s right. I don’t want them to feel pain.”
But whether pain is being felt is open to question. Mark Rosen was the anesthesiologist at the very first open fetal operation, performed in 1981 at the University of California, San Francisco, Medical Center, and the fetal anesthesia protocols he pioneered are now followed by his peers all over the world. Indeed, Rosen may have done more to prevent fetal pain than anyone else alive — except that he doesn’t believe that fetal pain exists. Research has persuaded him that before a point relatively late in pregnancy, the fetus is unable to perceive pain.
Rosen provides anesthesia for a number of other important reasons, he explains, including rendering the pregnant woman unconscious and preventing her uterus from contracting and setting off dangerous bleeding or early labor. Another purpose of anesthesia is to immobilize the fetus during surgery, and indeed, the drugs Rosen supplies to the pregnant woman do cross the placenta to reach the fetus. Relief of fetal pain, however, is not among his objectives. “I have every reason to want to believe that the fetus feels pain, that I’ve been treating pain all these years,” says Rosen, who is intense and a bit prickly. “But if you look at the evidence, it’s hard to conclude that that’s true.”
Rosen’s own hard look at the evidence came a few years ago, when he and a handful of other doctors at U.C.S.F. pulled together more than 2,000 articles from medical journals, weighing the accumulated evidence for and against fetal pain. They published the results in The Journal of the American Medical Association in 2005. “Pain perception probably does not function before the third trimester,” concluded Rosen, the review’s senior author. The capacity to feel pain, he proposed, emerges around 29 to 30 weeks gestational age, or about two and a half months before a full-term baby is born. Before that time, he asserted, the fetus’s higher pain pathways are not yet fully developed and functional.
What about a fetus that draws back at the touch of a scalpel? Rosen says that, at least early on, this movement is a reflex, like a leg that jerks when tapped by a doctor’s rubber mallet. Likewise, the release of stress hormones doesn’t necessarily indicate the experience of pain; stress hormones are also elevated, for example, in the bodies of brain-dead patients during organ harvesting. In order for pain to be felt, he maintains, the pain signal must be able to travel from receptors located all over the body, to the spinal cord, up through the brain’s thalamus and finally into the cerebral cortex. The last leap to the cortex is crucial, because this wrinkly top layer of the brain is believed to be the organ of consciousness, the generator of awareness of ourselves and things not ourselves (like a surgeon’s knife). Before nerve fibers extending from the thalamus have penetrated the cortex — connections that are not made until the beginning of the third trimester — there can be no consciousness and therefore no experience of pain.
Sunny Anand reacted strongly, even angrily, to the article’s conclusions. Rosen and his colleagues have “stuck their hands into a hornet’s nest,” Anand said at the time. “This is going to inflame a lot of scientists who are very, very concerned and are far more knowledgeable in this area than the authors appear to be. This is not the last word — definitely not.” Anand acknowledges that the cerebral cortex is not fully developed in the fetus until late in gestation. What is up and running, he points out, is a structure called the subplate zone, which some scientists believe may be capable of processing pain signals. A kind of holding station for developing nerve cells, which eventually melds into the mature brain, the subplate zone becomes operational at about 17 weeks. The fetus’s undeveloped state, in other words, may not preclude it from feeling pain. In fact, its immature physiology may well make it more sensitive to pain, not less: the body’s mechanisms for inhibiting pain and making it more bearable do not become active until after birth.
The fetus is not a “little adult,” Anand says, and we shouldn’t expect it to look or act like one. Rather, it’s a singular being with a life of the senses that is different, but no less real, than our own.
The same might be said of the five children who were captured on video by a Swedish neuroscientist named Bjorn Merker on a trip to Disney World a few years ago. The youngsters, ages 1 to 5, are shown smiling, laughing, fussing, crying; they appear alert and aware of what is going on around them. Yet each of these children was born essentially without a cerebral cortex. The condition is called hydranencephaly, in which the brain stem is preserved but the upper hemispheres are largely missing and replaced by fluid.
Merker (who has held positions at universities in Sweden and the United States but is currently unaffiliated) became interested in these children as the living embodiment of a scientific puzzle: where consciousness originates. He joined an online self-help group for the parents of children with hydranencephaly and read through thousands of e-mail messages, saving many that described incidents in which the children seemed to demonstrate awareness. In October 2004, he accompanied the five on the trip to Disney World, part of an annual get-together for families affected by the condition. Merker included his observations of these children in an article, published last year in the journal Behavioral and Brain Sciences, proposing that the brain stem is capable of supporting a preliminary kind of awareness on its own. “The tacit consensus concerning the cerebral cortex as the ‘organ of consciousness,’ ” Merker wrote, may “have been reached prematurely, and may in fact be seriously in error.”