Resuscitation of Infants With Congenital Diaphragmatic Hernia With an Intact Umbilical Cord

CDH is a severe birth defect, with a prevalence of 1:2000 to 1:3000 live births where a
defect in the diaphragm results in, herniation of the abdominal contents into the chest with
subsequent compression of the intrathoracic structures. Compression of the intrathoracic
structures results in pulmonary and left ventricular (LV) hypoplasia and abnormal development
of the pulmonary vasculature in utero. These abnormalities in the development of the heart
and lungs in utero, result in persistent pulmonary hypertension of the newborn (PPHN) and
respiratory insufficiency after birth. Respiratory insufficiency is managed with intubation
and mechanical ventilation. In addition to managing respiratory insufficiency, intubation
prevents entrainment of air into the intestines and further compression of the lungs and
heart. As part of routine resuscitation in infants with CDH intubation is performed after the
delivery personnel separates the baby from the placenta by cutting the umbilical cord.
Resuscitation of infants with CDH also involves placement of a nasogastric tube (NG) into the
stomach for removal of entrained air and secretions as well as placement of catheters in the
umbilical artery and vein for administration of medications (vein) and continuous blood
pressure monitoring and sampling of blood (artery). As part of routine practice at our
institution, these initial steps of resuscitation are all performed in parallel such that
while one team is intubating and initiating ventilation as well as placing the NG tube,
another team is placing umbilical lines. This approach has allowed the investigators to
obtain arterial blood gas samples in 20 infants with CDH at a median of 4 minutes of life
(range 2-9 minutes). When compared to cord blood arterial samples, pCO2 increases by a median
of 35mmHg (range 11-77mmHg) from a median cord ABG pCO2 of 55mmHg (range 28-78 mmHg) to
88mmHg (range 65-123 mmHg). In addition to these changes in pCO2 median base deficit changed
from -2 ± 0.5350 in the arterial cord blood sample to -7.994 ± 0.8547 in the umbilical
arterial blood sample. The resultant respiratory and metabolic acidosis decreased the pH from
7.289 ± 0.01946 in the arterial cord blood sample to 7.036 ± 0.02051 after birth. In addition
to the above measures, as part of routine resuscitation, the investigators routinely obtain
echocardiographic studies in the first hour of life, to guide pulmonary hypertension
management. These studies demonstrate left ventricular (LV) dysfunction and right to left
shunting at the ductus arteriosus about 50% of the time. The investigators speculate that the
LV dysfunction and increased pulmonary vascular resistance are at least in part due to the
acidemia described above. In addition, decreased preload to the LV from right to left
shunting at the ductus arteriosus also likely contributes to LV dysfunction. Standard of care
for infants with marked abnormalities in gas exchange and LV dysfunction is ECMO rescue early
on in the delivery room.

Clamping of the umbilical cord is one of the first interventions that occurs after birth.
This separates the infant from the placenta, signifying a landmark period during which the
newborn transforms into an independent entity. The transition from a fetus to a neonate at
birth represents a critical phase in our life. Early or immediate cord clamping is standard
practice where delivery of the fetus is followed by immediate clamping of the umbilical cord
(<15 seconds). In 2010, the International Liaison Committee on Resuscitation (ILCOR)
recommended that cord clamping could be delayed for at least 1 min. Since then for low risk
infants, delayed cord clamping has become routine with the delivering providers delaying
clamping of the cord for 1 minute prior to initiating routine newborn care. In these low risk
infants there have been many published reports demonstrating benefit with delayed cord
clamping. The benefits are primarily attributed to an increase in neonatal blood volume,
secondary to placenta-fetal transfusion. More recently the benefits of delayed cord clamping
have been demonstrated in higher risk infants. In preterm infants, delayed cord clamping
decreased the need for inotropic support after birth, decreased the need for blood
transfusions and reduced the incidence of necrotizing enterocolitis and intraventricular
hemorrhage. These improvements appear more in line with improvements in cardiac function,
which may or may not be associated with an increase in blood volume. More recently, in
infants with congenital heart disease delayed cord clamping has been shown to be feasible and
decreased the need for packed red blood cell transfusions after birth. Despite the benefits
of delayed cord clamping on both the cardiopulmonary transition as well as postnatal
outcomes, delayed cord clamping has never been employed in infants with congenital
diaphragmatic hernia. This is due to the need for immediate resuscitation after birth and the
risk of adverse outcomes by delaying the initiation of postnatal care.

In a recent study doppler ultrasound was used to measure arterial and venous umbilical blood
flow during delayed cord clamping in term vaginal deliveries. After birth, the probe was
placed in the middle of the umbilical cord and pattern and duration of flow in vein and
arteries were evaluated until cord clamping. In 90% of infants, umbilical venous flow was
still present at 4 minutes and 36 seconds. In 83% of infants, umbilical arterial flow was
still present at 4 minutes and 22 seconds and in 72% of infants bidirectional arterial flow
was observed. Bidirectional arterial flow appeared at 45 seconds after birth and persisted
for a median duration of 2 minutes and 24 seconds (01:37- 03:52). This study implies that
placental gas exchange may remain active for at least 4-5 minutes after birth and suggests
that delaying cord clamping for 4-5 minutes while initiating resuscitation may be feasible.

In fetal sheep, the effect of initiation of ventilation with an intact umbilical cord was
studied by placing flow probes around the ductus arteriosus, carotid and pulmonary arteries
and catheters in the carotid and pulmonary arteries for direct pressure measurements. With
clamping of the umbilical cord prior to initiation of ventilation, carotid artery and
pulmonary artery pressure increased, carotid artery blood flow increased initially and then
decreased and pulmonary artery blood flow and right ventricular output decreased. These
changes in carotid and pulmonary pressure and flow were accompanied by a decrease in heart
rate. With just 30 seconds of ventilation prior to clamping of the umbilical cord, the
fluctuations in heart rate, carotid and pulmonary artery pressure and flow were prevented and
the cardiopulmonary transition was much more stable.

The first published report of resuscitation with an intact umbilical cord compared 24 hour
hematocrit in premature infants (23 0/7-31 6/7 weeks' GA) randomized to 60 seconds of V
(initial continuous positive airway pressure) with addition of positive pressure ventilation
if needed - delayed cord clamping (DCC), V-DCC or DCC-only where infants were dried and
stimulated by gently rubbing the back if apneic. In this study no differences were seen in
the peak hematocrit in the first 24 hours, delivery room interventions, early hemodynamics
(cerebral oxygenation by near-infrared spectroscopy, cardiac output and stroke volume by
electrical cardiometry, or superior vena cava flow by functional echocardiography), or
neonatal outcomes. The onset of breathing was similar between both groups however infants
receiving DCC received a greater duration of stimulation than V-DCC. While no benefit was
seen with V-DCC, no adverse effects were seen and this study demonstrated the feasibility of
resuscitation with the cord intact. In addition the primary outcome measure differed from our
question of interest as the infants enrolled in this study were low risk for abnormalities in
the cardiopulmonary transition.

In this protocol, the investigators propose initiation of resuscitation during the period of
delayed cord clamping in infants with congenital diaphragmatic hernia. This is a feasibility
study that will assess tolerance of the participants (pregnant mother and their high-risk
infants) to this method of resuscitation as well as the optimal setup and approach to
resuscitation. Tolerance to this approach would provide these infants the benefits of delayed
cord clamping while allowing for simultaneous resuscitation. The first aim of this study is
to assess maternal and fetal tolerance to the procedure and determine the optimal approach to
resuscitation. In addition to this the investigators will assess if initiation of
resuscitation during the period of delayed cord clamping can stabilize gas exchange and
prevent the hypercarbia and acidosis that ensues after birth. Due to the physiologic effects
of initiation of ventilation prior to clamping of the umbilical cord the investigators
hypothesize that initiation of resuscitation prior to umbilical cord clamping will stabilize
the cardiopulmonary transition and will decrease the prevalence of LV dysfunction in this
population. The results of this study will lay the foundation for a future multi-center
randomized trial and are likely to impact the manner in which newborns with CDH are
resuscitated after birth

Inclusion Criteria:

• Pregnant women 18 years of age and older with a fetus with the diagnosis of left and
right sided congenital diaphragmatic hernia who consent to the protocol.

Exclusion Criteria:

- Patients with Morgagni type defects.

- Infants that have undergone fetal endoscopic tracheal occlusion (FETO)

- Infants with CDH with chromosomal anomalies trisomy 18 and 13

- Infants with bilateral congenital diaphragmatic hernia