CDH Trial moderate lung hypoplasia

 

Patients are currently invited to participate in a clinical trial that looks into the potential added value of treating babies with isolated CDH and moderate lung hypoplasia prior to birth.  These babies have an estimated chance of survival around 50%, and a 30 % risk to require oxygen therapy for at least one month after birth with expectant intrauterine management

 

We hope that treatment before birth makes the lung grow enough to decrease this risk of postnatal demise and prolonged oxygen needs. The study is based on previous experience with babies with severe diaphragmatic hernia, in which postnatal outcome seems to improve by the prenatal placement of a balloon in the wind-pipe (trachea). This balloon stops lung fluid from flowing from the lung towards the amniotic cavity and produces in this way an increase in pulmonary pressure leading to lung growth. In babies with severe CDH, the prenatal therapy increased postnatal survival and decreased the need for prolonged oxygen administration as compared to a group of historical controls of babies with severe CDH that didn’t undergo fetal surgery.

 

Whether prenatal tracheal occlusion with a balloon truly improves outcomes in babies with moderate pulmonary hypoplasia remains uncertain as FETO was so far only proposed to babies with severe pulmonary hypoplasia.

 

The study is officially called “RANDOMIZED TRIAL OF FETOSCOPIC ENDOLUMINAL TRACHEAL OCCLUSION (FETO) VERSUS EXPECTANT MANAGEMENT DURING PREGNANCY IN FETUSES WITH LEFT SIDED AND ISOLATED CONGENITAL DIAPHRAGMATIC HERNIA AND MODERATE PULMONARY HYPOPLASIA”. The acronym used is ‘TOTAL’ (Tracheal Occlusion To Accelerate Lung growth)

 

 

Study conditions.

 

Who can participate?

Who can’t participate?

Mother 18 years or older

Not willing to be undergoing “randomization”

Singleton pregnancy

Twins or more

Written consent

Not able to consent in full

Left sided diaphragmatic hernia

Right sided or bilateral diaphragmatic hernia

No associated anomalies and normal chromosomes

Additional problems

Gestation no more than 31 wks and 5 days at randomization

Balloon cannot be placed prior to 31 weeks and 6 days

Moderate hypoplasia defined as observed over expected lung area to head circumference

25 – 34.9 % (position of liver not relevant) OR

35 – 44.9 with liver in the chest

measured at the latest at 32 weeks and 5 days

Severe hypoplasia

Mild hypoplasia

Acceptance of responsibility to come to FETO center for balloon removal

Maternal diseases or technical limitations making prenatal surgery hazardous or impossible

Cervix longer than 15 mm

Short cervix (<15mm) at randomization

 

Provided their patient consents, doctors can enter individual patient information on this website. This information will then be screened against the above checklist and an individual prognosis for the patient will be calculated. We will also determine whether the patient is potentially eligible for the trial. Doctors or patients may contact the FETO centers if there is any doubt about eligibility.

 

Evaluation and enrolment process

 

Patients who are open to study participation are brought in contact with one of the FETO centers.

 

The mothers will be asked to consent to be scanned again, mainly to check for the criteria listed above. When these are not met, they will be advised on how the case presents.

 

When the criteria are met, they will be counseled in length about study participation. This will be done by a team of fetal medicine specialists, and if the patient has not seen a neonatologist and surgeon at her local center yet, or in case of questions, she will have the opportunity to consult with those specialists as well. 

 

In the counseling process, the consequences of CDH, as described elsewhere, will be highlighted (or repeated). The pro's and the con’s of participation to this clinical study as well as the (logistic) consequences of prenatal intervention will be discussed. The place where the mother is planned to give birth is a very important part of the prenatal counseling.

 

If study participation seems a reasonable choice, the mother will be asked to consent for inclusion in the trial. After that, the FETO center will log in onto the study website, where a checklist will be filled out. Only with consent and when all criteria are met, the patient will be officially entered into the study. The mother and fetus will be allocated either to FETO prior to birth, or expectant management prior to birth, both followed by intensive neonatal care following recommended internationally agreed guidelines. In case of therapy prior to birth, a date for balloon insertion and removal will be fixed.

 

After randomization

 

Those assigned to FETO procedure, will have this operation between 30 and 32 weeks. Hospital stay will vary from less than a day to a few days depending on recovery or the occurrence of unexpected events. The balloon must be removed ideally before birth, or if birth comes earlier, during labor or immediately after the baby is born. It is advisable that the patient stays close to the center where the balloon was placed because of the high experience for safe balloon removal in those hospitals. In the absence of problems, balloon removal will be scheduled beyond 34 weeks.

 

Those assigned not to undergo an operation during your pregnancy will be followed in the referring hospital for the remainder of pregnancy. They or their doctors will be requested to provide further outcome of the pregnancy. This includes information on lung growth as well as on the postnatal course of the baby. This information will be gathered via the neonatologist or surgeon, or in case of problems, via the patient.

 

Birth is ideally planned in the regional referring hospital with the best facilities for intensive neonatal care and expertise in treating babies with diaphragmatic hernia. The baby will be resuscitated and operated when the time is appropriate. General recommendations on how such babies are best managed were edited by a team of international experts and are there to guide the postnatal management.

 

What are the side effects of FETO?

 

Independent of a prenatal operation, one has to remember the baby has a CDH. This is a disease with its own prognosis and its known side effects for the baby before and after birth. Some of these remain present, even if FETO is undertaken prior to birth.

 

The most common and important complication of FETO is early rupture of the membranes with vaginal loss of amniotic fluid. In the experience with severe hypoplasia (where the balloon is put in place around 26 weeks of gestation), this occurs in 5% within one week from FETO, and in 20% within six weeks from the initial operation. We do not dispose of numbers on operations done at a later stage of pregnancy as proposed in the actual trial because until now such ‘late’ interventions were only rarely done.

The importance of rupture of the membranes is that amniotic fluid leakage may lead to premature contractions and preterm birth. The consequences of preterm delivery are dependent on the gestational age at birth. Since FETO is only offered at 30-32 weeks in the actual trial, it is hoped that such consequences will be limited.

 

Another concern is that the balloon could damage the trachea. This has not been seen in animal experiments nor in our experience with the majority of babies born after FETO for severe CDH. In a few babies however, the balloon seemed to cause a local widening of the trachea, again typically without serious problems. But in some babies it may have caused temporary coughing problems. However it is not entirely clear whether other factors such as the presence of a ventilation tube (which also haves a balloon) or other reasons, including the diaphragmatic defect itself did not play a role in causing these problems.

 

Despite the extensive experience by the FETO centers, the prenatal intervention can cause localized bleeding or wound infection at the entry site of the instruments.

 

 

What if there is a problem?

 

Both the prenatal balloon procedure and intensive treatment after birth are well described therapies. The study comparing these is conducted under the general liability insurance of the hospitals where the care will be offered. If problems arise or complications occur, appropriate and expeditious medical treatment will be instituted by those doctors.

 

Any complaint about the way patients are dealt with during the study or any possible harm can be discussed with the researchers at the FETO centers or the doctors caring locally. They will do their best to answer those questions. There is also the possibility, as for any patient outside a study, to complain formally, through the local hospital representative in charge of patient’s rights. When any harm happened due to negligence legal action may be undertaken.

 

What will be measured during the study

 

During pregnancy:

 

  • Lung growth
  • Balloon position (if operated)

 

After birth:

 

  • Oxygen dependency
  • Need for medication for lung hypertension
  • Need for heart-lung machine, days requiring a ventilator, until normal feeding and in the hospital
  • Day of the surgery and requirement of a patch to close the defect
  • Occurrence of brain problems, infections, prematurity problems, reflux

 

Later in life patients will be called back:

 

  • Lung function at one year
  • Neurologic development at one and two years

 

In case of non-survival the time point at which it occurs will be noted and the cause will be asked.

In non-surviving CDH babies, a so called autopsy is always recommended. Results of such examination would also be requested.