What We Have Learned From The ELGAN Study So Far
The name of the study
We named our study the ELGAN Study because all the babies were Extremely Low Gestational Age Newborns (ELGANs), defined as born more than 3 months before the expected date of birth.
The purpose of the study
We designed the ELGAN Study to learn more about the causes of medical problems and developmental difficulties that are common in babies born very early.
An observational study
The ELGAN Study is an observational study, which means that no treatments or medications are being tested. Rather, we collect information from an interview with the mother and from the babies' medical charts. We also collected blood (as a drop on filter paper) that was leftover from other blood tests ordered by the babies' doctors. Because babies born very early need blood tests often, we were able to collect a drop of blood (called blood spots) from each baby almost weekly.
Making sense of all the things we are learning
Just like other kinds of detectives, we are looking for the many clues that might help us understand what happens to babies who are born very early.
The first clue: Inflammation
Inflammation happens when we are hurt or have an infection. The hurt or infected area becomes red, warm and swollen. Although inflammation is one of the body's ways to protect us against danger, and to help us heal, too much inflammation can harm the lungs, intestines, eyes, and brain.
The ELGAN Study measured 25 different proteins in the blood spots. Each is a signal, or marker of inflammation. From this we have learned more about the inflammation and how long it stayed in the blood.
Adult bodies can clear up the inflammation as soon as the danger has passed. We do not know when the danger passed for each baby in the ELGAN Study. However, we found that the earlier the baby was born, the more the inflammation continued or reappeared. In addition, the longer the inflammation seemed to stay in the blood, the more risk of damage to the lungs, intestines, and brain. This is probably one of the most important things the ELGAN study has taught us so far.
A second clue: especially low birth weight
Babies who weigh much less at birth than the average baby born at their gestational age were more likely to have developmental difficulties than those whose birth weight was closer to the expected weight. We are working to understand why this happens.
We did not design the ELGAN Study to identify the causes of preterm delivery. Nevertheless, the ELGAN Study is teaching us things that might help towards that goal.
High rate of organism recovery from the placenta
When the ELGAN Study began, most obstetricians thought that bacteria did not live in the healthy uterus. Whether you are pregnant or not, the uterus was supposed to be free of bacteria.
We found that there were bacteria in most placentas, especially in the earliest born babies. When bacteria were present, the placentas were more likely to be inflamed. We think that the bacteria inside the placenta during pregnancy may be related to the inflammation we saw in the first weeks of life.
Classification of pregnancy disorders
Based on how often we found bacteria in the placenta and how inflamed the placenta was, we divided the pregnancy disorders that lead to very preterm delivery into two groups:
1) The inflammation group includes labor, rupture of membranes, vaginal bleeding, and cervical insufficiency.
2) The non-inflammation group includes preeclampsia, very slow fetal weight gain, and what is called "fetal distress."
Children born in the inflammation group have higher rates of brain ultrasound abnormalities than in the non-inflammation group. We think they may also be different in their learning abilities when we look at how they do at school age in the continuation of the ELGAN Study.
Preterm labor is not like labor at full term
A woman goes into labor at term because her fetus sends a signal it is physically ready to face the outside world. The mechanism for this involves development of the adrenal glands. This usually happens close to 40 weeks of gestation.
The ELGAN Study found that this mechanism does not apply to the onset of premature labor. Rather, inflammation in the uterus is connected with very preterm labor. As a result, very early labor and term labor are probably caused by different processes.
The major lung disorder among babies in this research study is sometimes called "bronchopulmonary dysplasia" (BPD) or "chronic lung disease" (CLD). These terms are used when the baby regularly needs extra oxygen for months after birth.
Because children with the worst BPD were at greater risk of developmental problems at age 2, one of our goals was to find out what added to the risk of BPD. Babies who needed a ventilator for breathing assistance every day during the first few weeks after birth were highly likely to develop BPD. Some aspect of needing or receiving mechanical ventilation probably contributes to BPD. We have learned that, among the babies at highest risk of this lung disorder, were those who had the most inflammation in their blood two weeks after birth. This leads us to wonder whether the inflammation caused by the lung disease or by the irritation of the ventilator might also add to later learning difficulties, something that we hope to learn more about in the continuation of the ELGAN research study.
There are two bowel problems that extremely low gestational age newborns are at greater risk of developing than term newborns. One is called necrotizing enterocolitis and is caused by inflammation of the intestinal wall. The other is called isolated intestinal perforation. Both of these disorders appear to go together with inflammation in the blood, but it is not clear if the inflammation starts before or after the bowel disease.
Too many blood vessels in the back of the eye cause the disorder now known as retinopathy of prematurity. More than 50 years ago, doctors realized that high oxygen levels could lead to this disorder. While the emphasis continues to be oxygen, the ELGAN study found that inflammation might also add to the occurrence or seriousness of retinopathy of prematurity.
The National Institutes of Neurological Disorders and Stroke continues to support the ELGAN Study. One of the missions of this branch of the National Institutes of Health (NIH) is to find ways to prevent brain damage in children and adults. As a result, the major focus of the ELGAN Study has been the brain. That is why the continuation of the study includes evaluations of brain functions (attention, integrating information, solving puzzles, social skills).
Ultrasound scans in the NICU
When the children were in the NICU, ultrasound scans of the brain were done several times as part of routine care. These scans can show areas of bleeding and areas of damage.
For the most part, the babies who had inflammation in the blood on at least 2 separate days a week apart were at higher risk to have smaller volumes of brain tissue than those without inflammation. Just looking at brain size, however, does not tell us how well a child will do, which is why we asked the children to come back for an assessment at age 2, and now again at close to age 10.
At age 2
Two other findings at age 2 years were also connected with inflammation in the blood seen over a week's time. These include lower scores on a development test and a smaller head measurement at age 2 years. Children who were particularly small for their gestational age at birth also had lower scores on development testing at 2 years. However, neither development testing at 2 years nor head size accurately tells us how a child will do at school age, which is one of the goals we have in the continuation of the ELGAN Study.
At age 10
The current phase of the ELGAN Study will try to answer some important questions:
Does early inflammation add to learning problems years later?
Will the findings on the brain MRI be related to measures of learning and thinking at 10 years?
Do findings on the brain MRI tell us something about how inflammation in the blood near the time of birth might lead to learning difficulties?
Is limited weight gain before birth connected with specific learning problems? If so, how might this happen?
Answers to these questions have the potential to improve medical care given in the NICU and to identify treatments to protect the brain of babies born at extremely low gestational ages.
In closing, we thank all ELGAN children and their families for what they have done to help us learn more so that future generations of very preterm babies might be less likely to have learning problems.