The First Ache

The babies came back in terrible shape: their skin was gray, their breathing shallow, their pulses weak. Anand spent hours stabilising 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?” he wondered. He wrangled permission to follow his patients into the operating room. “That’s when I discovered that the babies were not getting anaesthesia,” he recalled. 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. Doctors were convinced that newborns’ nervous systems were too immature to sense pain, and that the dangers of anaesthesia exceeded any potential benefits.

A BREAKTHROUGH

Anand resolved to find out if this was true. In a series of clinical trials, he demonstrated such operations produced a “massive stress response” in newborns, releasing a flood of fight-or-flight hormones like adrenaline and cortisol. Potent anaesthesia, he found, could significantly reduce this reaction.

Anesthesia even made babies more likely to survive. When pain relief was provided during and after heart operations on newborns, Anand found the mortality rate dropped from around 25 per cent to less than 10 per cent.

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 which 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 pre-term infants he cared for grew younger and younger — with gestational ages of 24 weeks, then 23 weeks and then 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?”

It was not an abstract question: foetuses as well as newborns may now go under the knife. Once highly experimental, foetal surgery — to remove lung tumors, clear blocked urinary tracts, repair malformed diaphragms — is now frequent at a half-dozen foetal treatment centers in the US and could soon become standard care for some conditions diagnosed pre-natally like spina bifida. Whether the foetus feels pain is a question that matters to the doctor wielding the scalpel.

Known to all as Sunny, Anand, now a professor at the University of Arkansas for Medical Sciences and a paediatrician at the Arkansas Children’s Hospital in Little Rock, emphasises that he approaches the question of foetal pain as a scientist.

New evidence has persuaded him that foetuses can feel pain by 20 weeks gestation (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 newborns and controversial in their implications. And while some research suggests that foetuses can feel pain like pre-term babies, other evidence indicates that they are anatomically, biochemically and psychologically distinct in ways that make the experience of pain unlikely.

FOETUSES FEEL PAIN?

If the notion that newborns are incapable of feeling pain was once widespread among doctors, a comparable assumption about foetuses was even more entrenched.

Nicholas Fisk is a foetal-medicine specialist and director of the University of Queensland Center for Clinical Research in Australia. For years, he says, “I will be doing a procedure to a foetus, 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 foetuses 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. Fisk carried out a study that closely resembled Anand’s pioneering research. He selected 45 foetuses that required a potentially painful blood transfusion, giving one-third of them an injection of the potent painkiller fentanyl.

The results were striking: in foetuses 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 foetal pain – perhaps the best evidence we’ll get.

MORE PROOF?

Blood transfusions are actually among the least invasive medical procedures performed on foetuses. More intrusive is endoscopic foetal surgery, and the most invasive of all is open foetal surgery, in which a pregnant woman’s uterus is cut open and the foetus exposed. Ray Paschall, anaesthesiologist at Vanderbilt Medical Center in Nashville, remembers one of his first open foetal operation more than 10 years ago. When the surgeon lowered his scalpel to the 25-week-old foetus, Paschall saw the tiny figure recoil. A few months later, he watched another foetus, 23 weeks old, flinch at the touch of the instrument. That was enough for Paschall. “I tremendously upped the dose of anaesthetic to make sure that wouldn’t happen again,” he says. In over 200 operations he has assisted since, not a single foetus 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 want them to feel pain.”

THE REBUTTAL

But still, whether pain is being felt is open to question. Mark Rosen was the anaesthesiologist at the very first open foetal operation, performed in 1981 at the University of California, San Francisco, Medical Center and the foetal anaesthesia protocols he pioneered are now followed across the world. Indeed, Rosen may have done more to prevent foetal pain than anyone else — except that he doesn’t believe that foetal pain exists. Research has persuaded him that before a point relatively late in pregnancy, the foetus is unable to perceive pain.

Rosen provides anaesthesia 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 labour. Another purpose is to immobilise the foetus during surgery.

Relief of foetal pain, however, is not among his objectives. “I have every reason to want to believe that the foetus feels pain, that I’ve been treating pain all these years,” says Rosen. “But if you look at the evidence, it’s hard to conclude it is true.”

Rosen’s own hard look at the evidence came a few years ago, when he and a handful of other doctors at UCSF pulled together more than 2,000 articles from medical journals, weighing the accumulated evidence for and against foetal 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 senior author. The capacity to feel pain, he proposed, emerges around 29 to 30 weeks gestational age. Before that, he asserted, the foetus’s higher pain pathways are not yet fully developed and functional. What about the foetus that draws back at the touch of a scalpel? Rosen says that, at least early on, this movement is a reflex. 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 travel from receptors 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. Before nerve fibres 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 until late in gestation. What is up and running, he points out, is a structure called the subplate zone operational by 17 weeks, which some scientists believe may be capable of processing pain signals.

WHAT IF CORTEX IS ABSENT?

A few years ago, Swedish neuroscientist Bjorn Merker captured five children on video on a trip to Disney World. The youngsters, aged 1 to 5, were smiling, laughing, fussing, crying; they appeared alert and aware of what is going on around them. Yet all of them were 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 included his observations of these children in an article, published last year in 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,’ may have been reached prematurely, and may in fact be seriously in error,” he wrote.

While Rosen is skeptical, Anand praises Merker’s work as a “missing link” that could complete the case for fetal pain.

WHAT OF CONSCIOUSNESS?

Anatomy, however, is not the whole story. In the foetus, especially, we can’t deduce the presence or absence of consciousness from anatomical development alone; we must also consider the peculiar environment in which foetuses live. In a review published in 2005, David Mellor, founding director of the Animal Welfare Science and Bioethics Center at Massey University in New Zealand, wrote that the biochemicals produced by the placenta have a sedating and even anaesthetising effect on a foetus. The cocktail includes adenosine, which suppresses brain activity; pregnanolone, which relieves pain and prostaglandin D2, which induces sleep. Combined with the warmth and buoyancy of the womb, this brew lulls the foetus into a slumber, rendering it effectively unconscious. Even birth may not inaugurate the ability to feel pain, according to Stuart Derbyshire, psychologist at the University of Birmingham in Britain. His theory is that the experience of pain has to be learned — and the foetus, lacking language or interactions with caregivers, has no chance of learning it.

In fact, “there may not be a single moment when consciousness, or the potential to experience pain, is turned on,” Nicholas Fisk wrote with Vivette Glover, a colleague at Imperial College, in a volume on early pain edited by Anand. “It may come on gradually, like a dimmer switch.”

It appears that this slow dawning begins in the womb and continues even after birth. So where do we draw the line?