Like a Virgin

by Prasad, Aarathi

  Underdeveloped lungs are a major battle front in sustaining the very premature; indeed, newborns’ deaths because of respiratory failure have been recognized since ancient times. In the third millennium BCE, the legendary Chinese emperor and philosopher Huangdi reportedly noticed that this fatal syndrome occurred more often among infants born prematurely. Techniques for artificially reviving breathing in newborns date back to Soranus of Ephesus, who lived in the first century CE. Soranus even criticized ‘the majority of barbarians’ for the evidently common practice of immersing an infant in cold water to encourage them to breathe. And in the fourth century BCE, the father of medicine, Hippocrates, appears to have been the first to describe an intervention that is still in use to this day – inserting a tube into the trachea to support ventilation.

  Even into the early eighteenth century, divine intervention was mostly given the credit for successful resuscitation. From the mid-1600s, midwives were trained to use mouth-to-mouth resuscitation as an attempt to awaken stillborn infants – with little luck. The technique seemed so clearly destined for failure that the Royal Society, dedicated to the discussion and promotion of scientific topics, branded it nonsense, stating in no uncertain terms that ‘life ends when breathing ceases’.

  Others were more scientific in their approaches, though some of their solutions were often bizarre, and certainly amusing. In 1752, for example, the Scottish obstetrician William Smellie outlined the standard repertoire for treating apparently lifeless newborns: ‘the head, temples and breast rubbed with spirits; garlic, onion or mustard applied to the mouth and nose’. (Smellie also advocated a form of artificial respiration, and also the application of a straight endotracheal tube for resuscitation, much as is still used today.) Doctors have pried bellows up the nostrils; wafted brandy mist under the nose; shaken the body or swung it upside down; rhythmically pulled the tongue in and out; tickled the chest; tickled the mouth; tickled the throat; yelled. They have also tried dilating the rectum using a raven’s beak or a corncob, and blown tobacco smoke up the rectum with a clay pipe.

  Fortunately, corncobs have fallen out of fashion, and artificial respiration using a ventilator – a mechanical device that fills the lungs with air – is now the accepted course. Unfortunately, the ventilator has not overcome one of the problems in resuscitating very premature babies: odds are that the life-saving device will irrevocably damage the delicate lungs, with serious side effects. If the lungs are damaged, that means less oxygen gets to the brain, increasing the likelihood of mental impairment.

  So doctors and scientists started looking for a method that more closely simulates how air enters the foetus’s lungs in a mother’s womb. There, the foetus receives oxygen through the umbilical cord via the placenta, but the lungs are filled not with air but with fluid. This amniotic fluid is the ‘water’ that ‘breaks’ at the beginning of labour. At around six months, the foetus can use its own lungs to absorb oxygen, much as adults do, but it still continues to absorb oxygen from the amniotic fluid in which it lives.

  Naturally, when scientists came up with a gentler alternative to forced ventilation, the method they chose involved delivering liquid oxygen directly into a premature baby’s lungs. The result is the ECMO (extra-corporeal membrane oxygenation) machine, which is essentially an artificial lung. For the ECMO to work, surgeons must attach the machine’s pump to the blood vessels in the baby’s neck or groin. But this is not free of risk either. Using ECMO can trigger bleeding, blood clot formation, and infections, and lead to transfusion problems, so although the chances of survival are much higher, doctors are still searching for an even cleverer technology that can circumvent the threats that arise when a mother’s womb is no longer the foetus’s home.

  Of course, the fragile state of the lungs is not the lone concern for the parent of a premature baby; the very thing that defines us as human – the brain – also needs a great deal of medical attention. It is only at thirty-seven to forty weeks of gestation – full term – that the brain passes certain key milestones that allow it to provide support for life outside the womb. These include greater myelination, where brain cells become coated with myelin, a substance that helps them to transmit signals faster and more efficiently – including processing sensory information and sending directions for responses, the sort of activity that permits us to pull our hand away from a flame, and thus survive threats to life. Because the brain develops over a more protracted timespan than the other organs, it is only in the third trimester of pregnancy, about twenty-eight to forty weeks after conception, that the striking growth and refinement of the brain’s wiring takes place. And because the brain is relatively immature at birth, it is more susceptible to injury from premature arrival in the outside world.

  Babies born before full term will fare very differently, depending on when they are born. At thirty-six weeks, a premature baby will probably be slow to feed. Before thirty-three weeks, however, a baby will need to negotiate more serious problems, including those immature lungs. And at twenty-eight weeks or younger, a baby will face some very significant problems – though he or she will still have a remarkable survival rate of up to eighty percent, thanks to modern medicine.

  One of the most common issues among the very premature is bleeding in the brain. Although doctors do not know exactly why this happens, it increases the risk that a child born prematurely will sustain a cognitive or neuromotor disability, such as cerebral palsy (including the inability to walk), blindness, profound deafness or mental retardation. Forty-one percent will be diagnosed with such an impairment by the time they reach school age, meaning that within the current bounds of care, most will face a lifetime of disability. This is compared to only two percent of classmates born at full term.

  Around five percent to nine percent of all babies in developing countries, and twelve percent of babies in the US, will be born prematurely. In some places, the increase in pre-term births is related to an increase in the number of multiple births of babies, often conceived through assisted reproductive technologies such as IVF and ICSI. But there are socio-economic factors involved too. For example, the average birth weight of a baby should be between three and four kilograms – from six pounds eight ounces to just shy of nine pounds. Though seven percent of babies in the UK weigh less than 2.5 kilograms, or five pounds eight ounces, at birth, this percentage rises to ten percent in deprived areas, such as Hackney, a poorer borough in east London.

  In Hackney, I visited the intensive care unit of a neonatal ward at a large hospital. The ward contained several rooms for the care of the very premature, and all were furnished with incubators that contained babies of different ages. Above the clear plastic boxes (the material of choice, rather than glass and wood) were monitors, fitted with flashing lights and steady electronic beeps that announced every heartbeat, breath, and deviation in blood pressure. Every so often, a clutch of staff clad in blue gowns would wheel in a new incubator with an even newer baby, tubes threaded gingerly to the nose and veins to deliver essential oxygen and food. A new red-eyed parent or set of red-eyed parents would stand by, asking questions. A neonatal nurse would be assigned to stand sentry over the box – checking, measuring, tending. The nurse would work to make the incubator cosy, humid, and homely, like the environment the baby had left behind too soon. In the smallest of the ward’s rooms, the babies were so young that many still looked like foetuses. One in particular was mesmerizing, a perfectly formed tiny doll with translucent skin, his delicate hands and miniature feet wriggling occasionally. It was only twenty-four weeks since he had been conceived. It felt voyeuristic – like looking inside his mother’s womb, at a being no one should normally see for another three months. Intimate, remarkable, beautiful. And a revelation.

  For the survival of babies born prematurely, the incubator is a triumph of bioengineering. Yet what can be achieved with incubators is still very limited. One of the paediatric consultants on the Hackney ward described how, although modern incubators look sleek and efficient,
the way they function and what they can provide has essentially not changed in decades. While the incubators can provide warmth and humidity, they still cannot give any of the nutrients necessary for growth. Instead, a premature baby must have all those tubes inserted into his or her body to deliver ‘parenteral nutrition’, that is, the complete nutrition provided intravenously, via needle-like catheters inserted directly into the veins and bypassing the digestive system altogether. Yet more tubes passed through the nose and threaded to the stomach will give the child milk, if tests show its digestive system is able to take it. This care is incredibly challenging due to the extreme immaturity of the baby’s gut. In a mother’s womb, the stomach and gut will not digest food at such an early stage of gestation, but once out of the womb, a small amount of the mother’s breast milk will be used to acclimatize the baby’s stomach to its new environment. The baby will also be sedated, at least some of the time, to stop him or her from pulling the tubes out, and to decrease or prevent any discomfort or pain. Moreover, infection around the tubes is a serious threat, and can lead to severe problems for the child’s future health, should he or she survive. However you look at it, the incubators we have today are still a poor substitute for the relative security provided by the mother’s womb.

  Over those same decades, doctors have been attempting to secure the viability of ever-more premature babies. To succeed, they will have to invent an incubator that is more womblike – something almost like the womb itself. One unlikely source of data into how a womblike incubator might work has come from studies of miscarriages that have occurred at the very earliest stages of pregnancy. By looking at pregnancies that have failed, researchers have been better able to understand how embryos implant into the womb. Some day, with this information, embryos might not only be created in the laboratory, through in vitro fertilization, but even be attached to an artificial placenta in an artificial womb and gestate there until they are ready to be born. Still, it’s one thing to cultivate sharks successfully in a man-made environment; it’s another to nurture humans in one.

  Scientists in Japan and the United States are experimenting to find out if an artificial womb for humans might be feasible, using cells both in Petri dishes and in living animals to copy the inner workings of mammals. With all mammals, it is vital that newborns are able to discard the placenta when they leave the natural womb. The placenta, after all, is the life-support mechanism that allows a fertilized egg to develop into an embryo; it is also the frontline of development in protecting the foetus from infection and in providing nourishment. For this reason, when in the 1960s researchers first began to toil towards creating a machine that would stand in for the essential placenta, they faced many of the problems that intensive care doctors face when human babies are born prematurely. These problems proved especially challenging with their chosen subjects – goat foetuses.

  During a further series of experiments in the 1980s, a team led by the late Professor Yoshinori Kuwabara encountered several serious setbacks. In particular, the goat foetuses moved, as all babies in the womb do – and some quite vigorously. During incubation, and especially once their condition was stable, the goat foetuses showed a variety of movements that would have been absolutely normal behaviour had they been in their mothers’ wombs. They rolled their eyes, moved their mouths, swallowed, breathed, twitched, wriggled, rolled, stretched, and moved their limbs. One even tried to stand up and run!

  Although these movements were a positive sign, demonstrating that the foetuses in those primitive systems were active and seemingly stable, they caused malfunctions in the system; tubes got pulled out with all that wriggling. In fact, for the foetus that tried to stand up and run, the movements cost it its life. The animal sustained massive blood loss through the umbilical blood vessels, from which it had inadvertently pulled out its tubes. Other foetuses perished in the same way.

  Swallowing also proved a problem. The foetuses did not drink out of thirst, but rather to help train the muscles of the throat and the digestive system during development – movements that are crucial for survival after birth. (Indeed, swallowing fluid inside the womb is the definition of redundant: a foetus’s body-water balance is maintained by the placenta.) In the environment of the artificial womb – a clear plastic tank about the size of a home aquarium filled with yellow liquid – the goat foetuses drank up their surroundings without any care for how much they ingested – and they ingested a lot. Several days after their incubation began, they had accumulated enough excessive fluids that their lungs became swollen. The fluid load also affected their developing cardiovascular system. The scientists were only able to continue the experiment by delivering sedatives and muscle relaxants to the goats, something that most human parents would be reluctant to see prescribed for their own child in an artificial womb, given the potential for life-long addiction.

  In the 1980s, researchers in Tokyo were garnering the first promising results in experiments with goats and artificial placentas. Then in 2002, Kuwabara’s group developed an incubator consisting of a plastic tank filled with artificial amniotic fluid and a complete artificial placental system to provide oxygen into the blood directly, instead of via tubes into the veins. Unlike previous attempts, which only kept goat foetuses alive for about two days, the scientists reported that the foetuses placed in their fluid-filled plastic boxes stayed alive for three weeks. Like the wobbegongs, they too survived a trial birth. The artificial womb was becoming a reality.

  An aquatic environment, an artificial womb, a synthetic placenta: these can surely keep premature babies alive. But could they be used to craft the future of all pregnancies?

  Perhaps because of the ethical tangles involved, many scientists working in the field have not disseminated much of their research, or the possible applications of it. That includes scientists such as Hung-Ching Liu, an internationally respected researcher in reproductive biology who, at a conference in 2001, said that her ‘final goal is having a child in the laboratory’. And not through old-fashioned childbirth.

  By that time, though, Liu had already managed to grow the lining for a human womb, using a sort of scaffolding over which cells, cultured from a woman’s womb, could multiply. This ‘womb’ was only a few sheets of cells in a Petri dish, not an entire organ. But when it was tested using fertilized eggs left over from IVF cycles, the eggs implanted in it at six days, just as they would in a real womb. Liu believes that this approach would ensure that the whole package – embryo and womb – would not be rejected by the immune system when inserted into the woman’s body to continue the long process of development.

  In the lab, researchers currently are not allowed to grow human foetuses for more than fourteen days, because it is at this point that foetuses develop a neural tube – the precursor of the brain and nervous system. This meant that Liu’s experiment could not progress beyond eight days after implantation. Still, going ahead even for this scant time gave her an opportunity to study how the placenta grows, and to see whether she could develop a womb-like device that could remain viable outside of the mother. The device would need to be hooked up to a computer, which would regulate the delivery of liquid to nourish the foetus, the removal of waste products, and the control of the team of hormones that are so finely balanced in the real-life body of an expectant mother. If scientists could achieve this, a baby could conceivably be brought to full term in an artificial womb.

  Liu’s vision is not fanciful, in terms of motivation or practicality, when you consider two issues. Women – even young women – without wombs are no small minority. In fact, ‘absolute uterine infertility’, which is defined as a woman’s infertility resulting from defective or absent wombs, affects millions throughout the world. In the United States alone, around five thousand hysterectomies are performed in women under the age of twenty-four; nearly nine million women of reproductive age have had a hysterectomy due to conditions including cervical cancer, endometriosis (where uterine cells grow elsewhere in the body, often on the ova
ries), and Mayer-Rokitansky-Küster-Hauser syndrome (in which the uterus can be underdeveloped, shaped more like a cord than a sac, or even absent). Most women with uterine infertility have no chance of becoming a genetic mother, except by the use of another woman as a surrogate, and no prospect of ever carrying a pregnancy to term. Liu works with infertile women, many of whom have survived cancer but lost their wombs and reproductive potential to the disease. Her hope is to offer these patients the option of having their own children.

  Second, the idea of creating a blood circuit that can serve as a placenta and work alongside an artificial womb and amniotic fluid is complex, seemingly too complex and too dangerous to use in anything outside of the great works of science fiction. But for premature babies, especially those who have difficulty breathing, the ideal situation would be to maintain them in a warm liquid bath, like the womb, attached to an artificial placenta rather than a lung-damaging ventilator. If the conditions in that bath could be set to match the environment of a natural womb, the baby might develop normally, without damage to the lungs and the oxygen-deprived brain. Recently, too, there has been progress in making liquid breathing a reality, through the development of a fluorocarbon liquid with the capacity to carry a large amount of dissolved oxygen and carbon dioxide. The liquid could be inserted into the lung, so that the lung sacs can expand at a much lower pressure, creating an intermediate developmental stage between the womb and life in the open air.

  Liu and many other researchers in the field are confident that, despite the complications and difficulties, the technological perfection of an artificial womb is achievable. The French biologist Henri Atlan predicts that, within a hundred years, science will master the complete development of the human foetus from conception. In the meantime, Carlo Bulletti, a professor of reproductive biotechnology at the University of Bologna, says that partial ectogenesis – growing foetuses between fourteen and thirty-five weeks of pregnancy – is already within our reach if we were to use all of the knowledge and technology at our disposal.