From survival to a vision of lifelong health

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The last 40 years have seen major advances in neonatal care - what could only be dreamed of in the 1970s is now routine, which has resulted in a dramatic increase in the survival rate for premature babies. There are now as many as 100,000 under-18s in Sweden who were born prematurely, and the big question is: What happens next?

Less than a year after Annette and Dan Landgren had lost a daughter to a late miscarriage at 26 weeks, they were expecting a child again. And once again, something was amiss. The baby was due in mid-August but by the beginning of April something was wrong. Annette had already begun to dilate and was admitted to Helsingborg General Hospital for observation. However, nothing happened and everything seemed to be under control for a few weeks. But suddenly her waters broke one morning and she was rushed by ambulance down to Lund where doctors tried to stop the labour. Which they did& but only temporarily.

In the early hours of the following morning she gave birth to a little boy, three and a half months early. Born in week 24, he was just 28 cm long and weighed a meagre 670 grammes. The doctors in Lund had already explained that there were no guarantees that the baby would survive, and that he would have to show clear signs of life for them to go ahead with treatment. He did just that, and 11 years on Eliott Landgren is a lively lad at secondary school. He is one of the "new survivors" as Swedish doctors call them.

"Before 1970 over 90% of all babies under a kilo died, whereas today almost 90% survive," says Hugo Lagercrantz, professor of paediatrics at Karolinska Institutet and former head of neonatal care at the Astrid Lindgren Children's Hospital in Stockholm.

Every year 6% of all babies born in Sweden - around 6,000 in total - are delivered prematurely, and nearly all now survive. As such, there is a large number of premature babies who are living and growing up in Sweden.

"It's no longer rare," says Lagercrantz. "We now have around 100,000 under-18s in Sweden who were born prematurely."

Genetic factors one explanation

It is often difficult to pinpoint exactly why a baby is born prematurely in individual cases, though researchers have identified a number of risk factors at group level. The most important of these factors is genetic - 20-30% of all premature births can be attributed to genetics. Others include socioeconomic background, smoking during pregnancy, infection, overweight, twins, and maternal age, be it very old or very young.

"Ideally mothers would be 24 when they give birth, but it's not that common these days in Sweden," says Lagercrantz.

"Apart from among immigrants, who frequently have babies at this age, and also have fewer problems in this respect."

Although many of the risk factors for premature birth have changed over the last few decades - smoking, for example - the proportion of babies born prematurely in Sweden has, strangely enough, held steady at around 6% since the Swedish Medical Birth Register was set up in 1973. It may well be that improvements in some areas have been offset by a deterioration in others, but this is something that researchers do not currently have answers to.

Annette Landgren has yet to be given an explanation as to why Eliott came as early as he did.

"They did loads of tests on both Eliott and me, but they didn't pick up on anything unusual," she says. "And the fact that we lost our first child had nothing to do with Eliott's early arrival, according to the doctors."

Premature babies are not fully developed and are not ready to come into the world.

"It's a huge leap from being a foetus on the life-support system that is the placenta to coming out and making it on their own," says Mats Blennow, adjunct professor of perinatal brain research at Karolinska Institutet and paediatrician at Karolinska University Hospital, Huddinge. "It's remarkable that it works out as often as it does."

Blennow researches how the newborn brain can be protected from conditions such as hypoxia, which is often down to how the lungs and the brain work together. In extremely premature babies - those born between 22 and 27 weeks - the lungs are still immature. The majority, even among the tiniest of babies, can actually breathe themselves immediately after birth, but their lungs are unstable and the alveoli collapse after every breath. Unassisted, their breathing is often unable to oxygenate the brain and the body, and these babies develop respiratory distress syndrome (RDS), which can be fatal.

Damage to the retina

It has long been standard practice to pump oxygen into incubators. However, it is difficult to control oxygen levels in babies and many sustain damage to the retina known as retinopathy of prematurity (ROP), which results in impaired vision or total blindness.

Respirators were introduced in the 1970s to help babies breathe, a move that produced mixed results. They were then supplemented with an oxygen tube with continuous positive airway pressure (CPAP) to keep the lungs inflated. This produced better results, though some children were still affected by ROP on account of excess oxygen.

The alveoli collapse in immature lungs because they have yet to start production of a surfactant that normally coats each alveolus and supports it during exhalation.

Following several significant breakthroughs by various researchers around the world, Swedish doctors Bengt Robertson and Tore Curstedt, both from Karolinska Institutet, managed to produce a surfactant from pig lungs in the mid-1980s. This was approved as the medicine Curosurf (Curstedt-Robertson surfactant) in 1993.

This halved the number of deaths in extremely premature babies and was a huge step forwards for neonatal care. When it was then discovered that it was also possible to shock-start babies' own production of surfactant by giving mothers a high dose of cortisone immediately before birth, the effect was even better. But practitioners were still stuck in the traditional approach when it came to using the treatment.

"The surfactant was given only where CPAP and respiratory care weren't sufficient," says Blennow. "Then someone realised that if the problem was that the babies didn't have surfactant, why not give it to them immediately?"

He recalls very clearly the first time he used the method after reading about it in a scientific journal. It was New Year's night, 1998.

"It went amazingly well - the baby picked up immediately, and then I went out into the magnificent night and the entire hospital was enveloped in frost. It was just beautiful," he says.

As with the lungs, the brains of extremely premature babies are very immature. Instead of the traditionally crumpled walnut-like cerebral cortex, the brain in these children is still completely smooth, the signals travel slowly and the networks are not yet particularly well developed.

"The difference between the brain of an extremely premature baby and that of a full-term baby is greater than the difference between the brain of a full-term baby and that of an elderly person with dementia," says Blennow. "So there are enormous changes taking place while they're in our care."

This is why many neonatal wards try to do as much as possible to replicate the womb - the optimal environment for the brain's development, as Blennow likes to call it. This involves being warm and snug, dark and fairly quiet. Doctors and other staff try to take samples and do tests when the babies are awake and can cope with them.

The premature brain does not yet have a system for protecting itself against major swings in blood pressure, which means that very high blood pressure can lead to cerebral haemorrhages, and very low blood pressure to brain damage caused by lack of oxygen.

One in three extremely premature babies suffers at least one cerebral haemorrhage while in hospital, but fortunately the bleeding tends to be in a part of the brain where it does not result in any lasting problems. Two out of three babies who suffer a haemorrhage at an early stage generally come through without any problems whatsoever.

Monitoring the babies' development

Ulrika Ådén is a docent at Karolinska Institutet and paediatrician at Karolinska University Hospital, Solna. She researches factors that have a negative impact on the premature brain's development during the early stages, the consequences as the children get older, and what can be done to reduce the risk of this negative impact. Ådén and her research group therefore monitor children as they go through school to see how they develop and how well they get on.

"We have, for example, discovered that those children who need an operation for an open ductus - the blood vessel that links the pulmonary artery to the aorta as a foetus, but should then be shut off - are several times more likely to be affected by brain damage," she says. "Now we're going back to see whether we can improve the ductus operation to minimise the risk."

Her research group is also part of a major national study where all babies born extremely prematurely in Sweden between 1 April 2004 and 31 March 2007 are monitored as they grow up.

"We're currently looking at them aged six and a half," says Ådén. "The results aren't ready yet, but most of them seem to live a good life without any obvious physical problems."

"But when we do neuropsychological tests we can see that many of them have problems with their working memory, for example. Attention-deficit problems similar to ADHD or autism are also more common in this group than in other children. But even though these conditions are more common in this group, most of the children develop well."

Children who are born prematurely and have their brain develop outside the womb do not necessarily have some form of brain damage. When slightly older children who were born prematurely do IQ tests they fall on a normal distribution curve, just as with other children, albeit shifted a little downwards.

"This means that the group as a whole has a slightly lower IQ than other children, but also that some of the children in the group have a normal IQ and some have a high IQ," says Ådén.

In the case of Eliott Landgren, things have gone both well and not so well. His time on a respirator resulted in damage to his retinas, which means that his vision is now very impaired. He has an assistant who acts as an extra pair of eyes at school, as well as cameras that magnify the whiteboard and text in books onto screens where he sits. However, he goes to a normal school and follows a normal curriculum.

"Eliott's school friends have been fantastic. It's amazing how they rally round and help him," says his father Dan Landgren. The way they make life easier by describing things to him is completely natural."

Eliott did not have any cerebral haemorrhages while in hospital and avoided infections during his first three weeks. But he did have a ductus operation when he was three weeks old, albeit without complications. School is going well and he has no problems keeping up in most subjects.

"He's struggling a bit with English at the moment, and handwriting too," says Landgren. "But they do group-work in class and everyone wants to work with Eliott as he's by far and away the fastest at typing on the computer."

The care of premature babies has made enormous progress over the last 40 years. Had Eliott been born just 20-30 years earlier it is unlikely that he would have survived. It was simply not possible to save such small premature babies.

"When I was training at St Göran's Hospital in the late 1970s the doctors said that we just weren't interested in babies weighing less than a kilo," says Mats Blennow.

Sweden has long been among the frontrunners in neonatal care and currently has one of the highest survival rates in the world for extremely premature babies.

"This is partly because we enjoy a good standard of living and partly because we have good neonatal care that is well organised," says Mikael Norman, professor of paediatrics with a special focus on neonatology at Karolinska Institutet, and operational head of neonatal care on the wards of Karolinska University Hospital.

Recent figures show that 85% of live births in week 26 in Sweden survive. They weigh, on average, one kilo. The earlier a baby is born, the lower the chances of survival, but no fewer than 82% survive in week 25, 67% in week 24 and just over 50% in week 23. There is then a gap as barely 10% of live births in week 22 survived between 2004 and 2007. And this appears to be where the line is drawn - there is no reliable evidence that babies born in week 21 have survived, be it in Sweden or anywhere else in the world.

The improvement in survival rates for increasingly premature babies, combined with Swedish abortion legislation, does however highlight the question of when a foetus becomes an individual, a person. Under Swedish law, a woman may, with permission from the Swedish National Board of Health and Welfare, abort a foetus up until week 22. However, babies born in week 22 do actually survive on the neonatal wards. This is an ethical dilemma that the doctors approach in slightly different ways.

"The ultrasound dating scans for babies are often accurate to within one or a few days, but can also be up to a week out, which is why I think that it's strange that we have these regulations," says Mikael Norman. "On one floor of the hospital we're aborting foetuses and on another we're looking after them in intensive care, and both are legal here in Sweden."

"I personally think that it is problematic that the limits are so close to each other, especially when survival rates for babies born at 22 weeks have increased over the last two to three years."

"Yes, it is an ethical dilemma, but abortions after week 18 are done in tragic, complicated circumstances that always require special dispensation," says Mats Blennow.

"Juxtaposing them with the fact that some babies survive at week 22 is over-simplifying the problem."

Ulrika Ådén objects to the notion that there can be a set time for when a foetus becomes a person.

"I view all my patients as individuals," she says. "It's more about giving it everything we've got if we can see that things might work out. In which case, we view the baby as an individual, of course we do."

Hugo Lagercrantz feels much the same way and thinks that the issue is more an artificial journalistic construct than an actual medical dilemma, at least for him.

"Not until birth does a baby awaken from its foetal slumber and develop human consciousness. A foetus is not conscious or a person in that way. Which is why setting the abortion limit at 22 weeks is quite appropriate, as it isn't possible to survive outside the womb before then."

All four do, however, agree that the limit has now been reached and that it is neither possible nor desirable to save babies who are born more prematurely than this.

Taking the long view

Instead, the future is about taking the long view when it comes to these children and their health. To date everything has been so focused on the initial period after the birth that it has almost been forgotten that these babies then grow up. Together with ophthalmologist Lena Jacobson, Lagercrantz wrote an article last autumn for Swedish national newspaper Dagens Nyheter emphasising that premature babies often fall between two stools as they can develop problems that are too great for normal schools to cope with, but not sufficiently bad to warrant special schooling.

"People talk about miracle babies and are so happy, but when they hit school age there can be a whole host of problems - problems that are often different to normal disabilities, says Lagercrantz. They can have problems with their vision and dyscalculia, where they find it hard to work with numbers. They can have special disabilities that make it hard to find their way to the classroom, or to recognise teachers and classmates. Children with cerebral palsy, or who are blind or deaf, are catered for, but that's just not the case for these children."

However, studies show that most premature babies who survive to school age have a fairly positive outlook. Although they have some disabilities they are often quite content with their life. And if they grow up in a secure environment with good support from home, they cope almost as well with school as their full-term friends.

"So it's not a case of saving loads of children only to condemn them to a life of misery. No, that's not the case at all," says Lagercrantz.

Researchers are now also looking at how these children get on after they leave school.

"As a group they're slightly worse off than their full-term peers: they earn a lower average wage, a lower percentage are university-educated, and psychological disorders are slightly more common, but most live entirely independent lives," says Mikael Norman.

"They're also at greater risk of cardiovascular disease, high blood pressure and diabetes as adults, though we don't yet know what's on the cards when they reach middle age or old age. They're a new type of survivor and we haven't got many generations to draw on in our research, so we just dont have that knowledge at the moment."

Furthermore, the premature babies now entering middle age were born in the 1960s and 1970s. Given that neonatal care has made such enormous advances since then, it is far from certain that the knowledge gained from this cohort about the increased risk of health problems and will actually apply to premature babies born today.

The researchers' primary focus now is to develop neonatal care to minimise the health risks of starting life prematurely. Norman pinpoints three clear areas for improvement

"It's partly about giving babies a better supply of nutrition - even though we think we're doing our best, it isn't good enough. It's also about staying clear of infection. It's not OK for some babies to get septicaemia and die. Which is why Karolinska University Hospital has set up a five-year plan that aims to ensure that nobody gets care-related infections.

"Finally, we have to improve care and reduce stress during the new-born period. We think that much of the stress that these children frequently feel is because they were very stressed while in care, and this leads to a kind of over-sensitivity that they can't get rid of.

"Once we've made improvements in these three areas, I think we'll see a reduction in the long-term health problems of children born prematurely."

In the meantime, Eliott Landgren is taking one day at a time. He is playing games on the computer and might go out with his father on the tandem a bit later. But what the future holds for him when he grows up is not something that he dwells on.

"He won't be able to drive, we know that," says mum Annette. "When we're in Lund for an eye appointment he usually says that he'd like to be a scientist or an eye doctor."

"But right now he quite fancies being a baker," says dad Dan. "He doesn't really have any special aspirations like I did as a kid - he lives very much in the here and now."

Text: Fredrik Hedlund. Published in the magazine Medicinsk Vetenskap nr 2 2012.