Brazilian research published in the journal Scientific Reports sheds light on the rapid and often fatal deterioration in the health of newborns with congenital diaphragmatic hernia (CDH). In addition to uncovering the biological mechanism behind this sudden deterioration, the study raises concerns about the treatments currently used in neonatal intensive care units.
Congenital diaphragmatic hernia is considered a rare condition that occurs when the diaphragm (the muscle that separates the chest from the abdomen) does not form completely during embryonic development, leaving an opening. Through this "hole," abdominal organs – such as the stomach, intestines, and liver – can move into the chest cavity and occupy the space normally reserved for the lungs. This compresses the lungs and prevents them from developing normally. The causes are still unknown.
Babies are born with breathing difficulties and low blood oxygen levels. They may also have high blood pressure in the lungs, which puts a strain on the heart. For this reason, they require intensive care to stabilize their condition. Surgery can correct mild cases and improve survival rates in severe cases.
While studying this condition, researchers discovered that "non-functional" capillaries – small blood vessels that do not participate in oxygen exchange – proliferate in the compressed lungs of these newborns. The study reveals that pulmonary hypertension, previously viewed solely as a problem, actually acts as a temporary shield to prevent blood from flooding and overloading this network of non-functional vessels. This finding indicates that medical teams must exercise extreme caution when using vasodilator medications, as these drugs can nullify this protective mechanism and lead to fatal pulmonary congestion.
Funded by FAPESP, the research sheds light on the biological factors that lead to the end of the so-called "honeymoon" period – a brief phase of initial stability in infants with CDH that is usually followed by rapid clinical deterioration. The findings challenge the long-held belief in medical literature that this respiratory reprieve ends precisely because pressure in the lungs rises excessively.
Based on animal and human models, the results suggest that pulmonary hypertension is present during the "honeymoon" period and reflects the proliferation of non-functional capillaries rather than being the primary cause. Thus, the period ends when changes occur in the outermost layers of the lung's blood vessel network, resulting in loss of elasticity and dilation of the pulmonary arteries.
This process can result in congestion (accumulation of blood) and impaired lung oxygenation, leading to the loss of large amounts of blood, plasma, and body fluids, and a consequent reduction in the heart's ability to pump blood to the tissues (refractory hypovolemic shock). The outcome is potentially fatal.
"The most important aspect of this study is that it provides new insights into the pathophysiology beyond what was previously believed: that the lung, compressed by other organs, caused pulmonary hypertension, hindering blood flow. As a result, the organ's function would be impaired. In addition to pulmonary hypertension, we detected the proliferation of non-functional capillaries. We also demonstrated that the increase in pressure may be a protective mechanism to prevent the lung from filling with blood," Alexandre Todorovic Fabro tells Agência FAPESP. Fabro is a medical pathologist and the corresponding author of the article alongside Lourenço Sbragia Neto . Both Fabro and Neto are from the Ribeirão Preto Medical School at the University of São Paulo (FMRP-USP).
"With these results, we've become pioneers in quantifying those capillaries. We still don't know how to treat the condition, but we've opened an important door to understanding the mechanisms involved," adds Sbragia Neto, who is considered one of Brazil's leading researchers in fetal surgery and congenital diaphragmatic hernia.
A study led by Sbragia Neto and published in 2022 is still used today to contextualize the prevalence of CDH cases in São Paulo, with one recorded case of the malformation for every 6,000 births. This figure can be extrapolated to Brazil and is similar to that of developed countries such as Canada, the United States, and European Union member states, ranging from one case per 3,000 to 6,000 live births.
However, the physician emphasizes that Brazil's healthcare infrastructure varies by region. Congenital diaphragmatic hernia is diagnosed during prenatal care through ultrasound examinations. In some cases, treatment can be performed before birth using the FETO (fetoscopic endoluminal tracheal occlusion) technique. This technique involves inserting a balloon into the fetal trachea. The balloon blocks the outflow of fluid, creating pressure and stimulating lung growth during pregnancy.
After birth, the child may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO), a procedure that is rarely performed in Brazil due to its high cost. ECMO uses a machine to "filter" the blood, allowing the heart and lungs to rest and recover.
The role of blood vessels
Contrary to what the name suggests, non-functional capillaries are not damaged; they are called this because they do not perform their primary biological function of exchanging oxygen for carbon dioxide.
In healthy lungs, air travels through the airways until it reaches the alveoli, which are small sacs surrounded by a network of fine blood vessels. This is where gas exchange occurs: oxygen passes into the blood while carbon dioxide, produced by the body, is expelled during exhalation.
Meanwhile, the functional pulmonary vessels remain dilated, allowing the blood to circulate with little resistance and become oxygenated. The blood then returns to the heart for redistribution throughout the body. In this case, the non-functional capillaries form a sort of "reserve pool," if needed. They normally receive little or no blood, but when blood flow increases, they can be "recruited," which expands the area for gas exchange and aids blood circulation without significantly raising pulmonary pressure.
In contrast, babies with CDH have one or both lungs that are underdeveloped, with fewer alveoli and blood vessels, which reduces the surface area available for oxygen to enter the blood. Furthermore, the pulmonary vessels are narrower, which impairs blood flow to the alveoli and compromises oxygenation, overburdening the heart.
A little-studied topic
Sbragia Neto explains that his group began investigating the role of non-functional capillaries in cases of congenital diaphragmatic hernia after Fabro noticed this connection in pathological analyses – a virtually unaddressed topic in the scientific literature.
"When I arrived in Ribeirão Preto, lung biopsies were rarely performed. Later, over time, we began to see an increase. Lung morphology must be considered in the context of radiology and the patient's clinical presentation. Brazil had no tradition in pulmonary pathology," says Fabro, who is currently a professor at São Paulo State University (UNESP) in Botucatu.
Using rat and rabbit models with induced malformations and human samples from autopsies, the researchers conducted morphometric analyses involving the measurement of capillaries and arteries for comparison with control groups.
They discovered that, in addition to playing an important role in the development of CDH, the proliferation of non-functional capillaries is associated with mortality at a later stage. At the same time, abnormal vascular remodeling is linked to the persistence of pulmonary hypertension during the "honeymoon" period.
According to the findings of the study, pulmonary arteries progressively lose their elastic recoil and become dilated. This change impairs blood flow control in the lungs, leading to a gradual worsening of oxygenation. Blood then accumulates, causing pulmonary congestion. Once compensatory mechanisms are exhausted, oxygen deprivation that does not respond to treatment develops, increasing the risk of death, even when vasoactive medications are used.
The researchers intend to continue their work investigating the mechanisms involved in vascular dilation. To accomplish this, they plan to use a mouse model that replicates the pulmonary changes characteristic of CDH. The article describing the model lists Sbragia Neto among its authors and can be found in the Journal of Surgical Research .
The CDH research received funding from FAPESP through five projects: 22/02821-0 , 23/10186-6 , 23/04199-8 , 21/09024-6 , and 22/12021-1 .
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
