Survival of extremely low-birth-weight infants improves, but lifelong challenges remain
In the United States, the anticipated mortality rate for infants weighing less than 500 g who were born in the 1980s was nearly 100%, according to researchers.
In the following decades, advances in science and medicine have dramatically improved the odds of survival for the smallest babies. For example, a retrospective multicenter cohort study published in April in JAMA Pediatrics showed that with active treatment, about 26% of infants weighing less than 400 g — or slightly less than 1 lb — survived to discharge.
These advances are due, in large part, to pharmacologic and technological interventions — some of which were in development as early as the 1970s — including the introduction of continuous positive airway pressure, mechanical ventilation and exogenous surfactant.
According to Ololade A. Okito, MD, attending physician in the division of neonatology in Children’s National Health System, many studies examine gestational age rather than birth weight. There is some overlap between the two measures, she said, but the distinction is important when looking at statistics.
“Extremely low-birth-weight (ELBW) refers to those babies who are born at less than 1,000 g,” Okito said in an interview. “Those babies who we consider extreme preterm babies are born at less than 28 weeks’ gestational age.”
In the U.S., the number of ELBW infants represents about 0.5% of all live births, Linda D. Wallen, MD, associate division chief of clinical operations at Seattle Children’s and clinical professor of pediatrics at the University of Washington, told Infectious Diseases in Children.
“It’s a pretty small number,” she said.
The number of these infants who are born every year may be small, but the problems they continue to face — despite technological and pharmacologic advances that have improved their chances for survival — are not. Infectious Diseases in Children spoke with experts in neonatology and pediatrics about the challenges these babies face immediately after birth and later on in life, the specific advances that have increased their survival and how those developments have changed the conversation physicians are having with parents.
Prematurity affects multiple body systems
The problems that affect ELBW infants can vary — from neurosensory (blindness and other visual problems, hearing loss and cerebral palsy), cognitive (speech and learning difficulties) and behavioral issues (such as autism spectrum disorder). That last category is relatively new, Wallen said, and there are not a great deal of data supporting the relationship yet. Other areas of concern include respiratory distress and difficulties with feeding and weight gain.
One significant concern is the risk for intraventricular hemorrhage, according to Hitesh Deshmukh, MD, PhD, attending neonatologist and assistant professor of pediatrics at Cincinnati Children’s Hospital Medical Center.
“This rupture allows blood in spaces of the brain where blood shouldn’t be,” he said. “This damages the neurons and results in neurological consequences, which can vary in spectrum from a mild learning disability to cerebral palsy. That’s why there’s such wide variation in how these infants do.”
According to findings published in Anesthesia & Analgesia, neurosensory impairment, such as deafness that requires assistance, blindness and persistent hypo- or hypertonia, has improved among premature children. However, neurodevelopmental abnormalities — as measured by the Mental Developmental Index and the Psychomotor Development Index — still remain a problem.
In addition, bronchopulmonary dysplasia in preterm infants has been correlated with poor neurodevelopmental outcomes, Owen and colleagues reported. The treatment for bronchopulmonary dysplasia — postnatal corticosteroids — is a balancing act, though, because early treatment can increase the risk for gastrointestinal perforation and cerebral palsy without decreasing the risk for mortality. Later treatment with corticosteroids appears to be more effective because it increases the chances of successful extubation and reduces the risk for bronchopulmonary dysplasia without increasing the combined outcome of cerebral palsy or death, Owens and colleagues found. Ultrasound is recommended for all high-risk infants, or those born at less than 30 weeks’ gestation, to identify intracranial conditions like an intraventricular hemorrhage, periventricular hemorrhagic infarction, ventriculomegaly, large cerebellar hemorrhages and cystic white matter injury.
“One of the most widely referenced studies was done by the NICHD Neonatal Research Network,” Okito said. “The study looked at neurodevelopmental outcomes of babies born from 22 to 26 weeks’ gestational age who received potentially lifesaving interventions initiated in the delivery room. For these infants, the overall rates of survival without severe impairment ranged from 3% for those born at 22 weeks to 75% for those born at 26 weeks.”
Combatting challenges related to feeding, infection
According to Harding and colleagues, extremely preterm infants have low stores of key nutrients such as iron, zinc, calcium and vitamins, with little or no subcutaneous fat or glycogen stores. They are also physiologically immature. These factors necessitate high energy and fluid requirements, all of which are compounded by other stressors. In addition, early ingestion of high amounts of fluid can increase the risk for adverse outcomes, such as bronchopulmonary dysplasia and necrotizing enterocolitis, and feeding is difficult because the infants’ ability to suck, swallow and breath is immature.
Strategies that have been used to increase feedings and weight gain generally start with IV fluids right after birth, followed by parenteral nutrition until enteral feedings can be fully tolerated, Harding and colleagues reported. Enteral feedings are started at very small increments — 1 mL every 4 to 12 hours — via an orogastric or nasogastric tube, and the volume of the feeding increases gradually. The shift from primarily IV nutrition to full enteral feedings may be intermittent, reverting back to IV nutrition when enteral feeding is not tolerated, and may take 14 days or longer.
Feeding preterm infants breast milk has also contributed to improved outcomes regarding feeding and weight gain. This breast milk is different from that produced by mothers of full-term infants, with an increased protein concentration. It improves feeding and weight gain outcomes via enhanced immune defenses and gastrointestinal function, a decrease in the rate of necrotizing enterocolitis and improved long-term neurodevelopment outcomes, according to Harding and colleagues.
David A. Kaufman, MD, professor of pediatrics in the division of neonatology at the University of Virginia Children’s Hospital and an Infectious Diseases in Children Editorial Board member, described the benefits of breast milk as “something old that’s new again.” According to Kaufman, it makes a significant difference.
“The gut of these extremely low-birth-weight infants puts them at risk for necrotizing enterocolitis,” he said. “If mom can provide milk, that’s the first choice. If not, donor milk is now widely available. We’ve been able to lower the number of infants who develop necrotizing enterocolitis because of this uptick in feedings with breast milk, and if they do develop this disease, it’s much less severe, with very low mortality.”
ELBW infants are at high risk for infection because of the immaturity of their immune systems, according to Okito.
“This increased risk means different things at different points during these children’s lives,” she said. “In the NICU, the major risk factor for early-onset
One important way that neonatologists have reduced the rate of infections among ELBW infants is by cutting down on the time that the infants are connected to machinery, such as ventilators, or other equipment, like IV lines. Pharmacologic interventions have also helped.
“We really work to get ELBW babies off ventilators and off parenteral nutrition, get their lines out and feed them much more aggressively,” Wallen said. “The use of donor breast milk and the mother’s milk has also increased dramatically for our tiniest babies, which certainly contributes to better, healthier infants, in part because we don’t have to keep lines in, which are prone to infection and other complications. We use antenatal steroids and magnesium for neuroprotection and antibiotics to try to control maternal infection that could result in early delivery. All of those things have, I think, made an enormous difference, and they’re much simpler than the changes in technology.”
Many ELBW infants are at a greater risk for infection not just immediately after birth, but over the course of their lives, Wallen said. Lung function affects this risk.
“One of the major problems that our preterm babies have when they go home is that they all have measurable abnormalities of lung function, despite the fact that they look fine and seem to be breathing fine,” Wallen said. “They’re not so bad that they affect the child, and they improve over time, but every preterm infant who goes home is much more susceptible to getting pneumonia or bronchiolitis — routine viruses that would not affect a term infant as severely — as well as respiratory syncytial virus.”
The prevalence of these infections raises another important issue in caring for ELBW infants as they age: vaccinations.
“Later on in these children’s lives, it’s really the same thing — it’s the infections that really take advantage of the lungs that we worry about,” Kaufman said. “We can do passive immunization with Synagis [palivizumab, AstraZeneca] for RSV. The influenza vaccine is obviously important. We also see diphtheria as a very severe infection in these kids who don’t get vaccinated. These are the ones that, even after they develop a stronger immune system, they’re still highly susceptible.”
When facing vaccine-hesitant parents, Kaufman stresses the importance of immunizations against respiratory viruses.
“If we can’t get the parents to allow us to administer all the vaccines, we specifically address all the respiratory viruses first if they’re having some hesitancy,” he said.
A study recently published in Pediatrics showed that preterm infants completed the recommended seven-vaccine series at a lower rate compared with term/post-term infants by 19 months (47.5% vs. 54%; adjusted OR = 0.77 [95% CI, 0.65-0.9]) and 36 months (63.6% vs. 71.3%; aOR = 0.73 [95% CI, 0.61-0.87]). The findings demonstrate the need for strategies to improve vaccination among high-risk infants, the researchers said.
Advances in care
Two of the biggest advances that have helped to increase the survival of ELBW infants include the development of the NICU and improved prenatal care, according to Deshmukh.
“For a long time, the concept of structured care for these infants by specially trained caregivers did not exist,” he said. “That only changed in 1975, when they established the specialized neonatal intensive care unit. After the introduction of this unit, the outcomes for these infants started to improve.”
According to Raju and colleagues, the advent of the NICU was followed by other advances that improved the odds of survival for ELBW infants, including the development of surfactant therapy — which had “a major impact,” according to Kaufman — and infant ventilators. Respiratory distress was the most common cause of death for ELBW babies until the 1970s, when assisted ventilation ushered in the era of modern neonatal pediatrics, according to Owen and colleagues. In particular, the use of the gentler infant ventilators — rather than the adult ventilators that had been used previously — helped to improve outcomes. Survival among infants weighing less than 1,000 g at birth went from less than 10% in the 1960s, before assisted ventilation, to approximately 35% in the mid-1970s, when ventilation was pervasive.
Improvements in prenatal care was another important development.
“Upfront awareness of extremely preterm birth as a possibility really speaks to good care for the mother while she’s pregnant,” Okito said. “A dedicated obstetrician, coupled with improvements in prenatal care, added to the survival of preterm infants, including extremely low-birth-weight infants.”
The role of prenatal care contributes to improved survival of ELBW infants in part because it allows for earlier intervention, according to Kaufman.
“Getting to the hospital if there’s preterm labor, so that we can administer prenatal steroids and maybe even stop labor, helps a lot in terms of improving outcomes,” he said.
The focus on prenatal care really comes down to giving infants more time to grow, according to Deshmukh.
“With every week that you spend inside your mother’s womb, your chance of going home without any deficits increases by about 10%,” he said. “Similarly, the risk of going home with one or two problems decreases by a third. At week 26, the risk of going home with a deficit decreases by two-thirds.”
Changing the conversation
The advances in medicine and technology that have increased the survival of ELBW infants have changed the conversations that neonatologists and other health care professionals are having with parents. Their survival has also reshaped the role that pediatricians play in caring for the infants.
“It’s still a complex conversation, but as outcomes have improved, we have more information to share with parents,” he said.
Ethics play a major role in the conversation, Kaufman continued, as parents face difficult decisions at the limits of viability at 22 to 23 weeks’ gestation — particularly regarding resuscitation.
“The conversation we have with the parents of these extremely low-birth-weight infants has gotten better. We have a lot of outcomes we can talk about,” he said. “We’ve also moved to the point where, if there is a devastating outcome, moving to comfort or palliative care can also be an option.”
The strides in survival have also meant that pediatricians are now part of the care team for ELBW children.
“General pediatricians play a major role in the continued improvement of long-term outcomes for infants who are born prematurely,” Okito said. “It is not uncommon for an extremely low-birth-weight infant to require multidisciplinary follow-up once they’re discharged from the NICU, including outpatient visits with surgeons and early intervention services such as physical therapy or occupational therapy. The general pediatrician plays a crucial role in serving as the home base to bring this all together, which not only helps to improve the outcomes of the infant — it’s also is a significant source of support for parents.”
Deshmukh made the point that more and more ELBW infants are surviving to adulthood, which adds another dimension to their care.
“Babies who are born prematurely are at risk of cardiovascular disease and increased high blood pressure that can persist into adulthood,” he said. “Having the knowledge that a patient is premature should cue the pediatrician to keep a closer watch on blood pressure and cardiovascular health. Survivors of extreme prematurity also have more airway obstruction and more airway trapping. This impairment, which results in increased risk of asthma, actually persists into adulthood as well. It’s important for a pediatrician and other physicians to be cognizant of these problems.”
Several studies have also demonstrated that premature infants may have mild neurodevelopmental delays, Deshmukh continued. That can lead to a slight reduction in their educational success and cognitive function. Both teachers and pediatricians should be aware of this, he said.
However, the increased rate of survival among ELBW infants — and the team approach to care that is being embraced as these children age — are all encouraging developments.
“I hope, as we increase the quality of our care, infant survival becomes the norm, not the exception, and that our babies have as normal a life as they can,” Deshmukh said. – by Julia Ernst, MS
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- Hofstetter AM, et al. Pediatrics. 2019;doi:10.1542/peds.2018-3520.
- Owen LS, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)30312-4.
- Raju TNK, et al. Acta Pædiatrica. 2017;doi:0.1111/apa.1388.
- Rysavy MA, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410689.
- UNICEF. Low birthweight. Available at: https://data.unicef.org/topic/nutrition/low-birthweight/. Accessed August 22, 2019.
- For more information:
- Hitesh Deshmukh, MD, PhD, can be reached at Hitesh.Deshmukh@cchmc.org.
- David A. Kaufman, MD, can be reached at firstname.lastname@example.org.
- Ololade A. Okito, MD, can be reached at email@example.com.
- Linda D. Wallen, MD, can be reached at firstname.lastname@example.org.
Disclosures: Deshmukh, Kaufman, Okito and Wallen report no relevant financial disclosures.