Neonatal encephalopathy involves disturbed neurological function due to a lack of oxygen supply to the baby during birth, which may also cause hypoxic-ischemic encephalopathy (HIE) in newborns.

Neonatal Encephalopathy

Overview

<p>Neonatal encephalopathy (NE) is characterized by a neurological deficit in neonates, typically born after 35 weeks of pregnancy. It is characterized by neurological deficits in neonates, typically born after 35 weeks of pregnancy. Neonates are newborn babies who are younger than the first four weeks of life. The most definitive signs to call the suspected disease NE, include impaired consciousness, increased or diminished reflexes of the body, and compromised cardiac and respiratory systems.</p>

<p>However, it should be noted that if the condition is consequent to a diminished oxygen supply to the baby&rsquo;s nervous system in the mother&rsquo;s womb, the condition will be termed hypoxic-ischemic encephalopathy (HIE) and can serve as a cause of NE<sup><a href="#accordion">[1]</a></sup>.</p>

<p>NE is an extremely disturbing disease for newborns and can exhibit multi-organ complications. NE occurs in approximately 3 of 1000 live births. More horrifying statistics report that it can lead to 6-9% of neonatal deaths overall. Furthermore, it is seen that Intrapartum hypoxia-ischemia is a causative factor in 30% of cases of NE in developed countries and 60% in developing countries<sup><a href="#accordion">[2]</a></sup>.&nbsp;Intrapartum means the time period between when a baby is conceived, till the deliverance of the placenta.</p>

<p>A study carried out in 2010 reported that approximately 1.15 million babies acquired NE through intrapartum events. Around 96% of these cases found in low and middle-income countries. The mortality rate related to NE in the year 2010 was 287,000. The surviving 233,000 neonates, ended up developing neurodevelopmental issues later<sup><a href="#accordion">[3]</a></sup>.</p>

<div>&nbsp;</div>

<p>NE, in some cases can be replaced by the term HIE. This is because NE is the ultimate fate of HIE and it was only recently that scientists drew a fine line between them. HIE is an alarming condition in which oxygen deprivation can have malicious outcomes on the neonate&rsquo;s brain. Such patients exhibit the same clinical sign and symptoms as a patient with NE and are at an exclusive risk for cerebral palsy (CP). CP refers to one&rsquo;s state to be unable to control his movement, balance and posture<sup><a href="#accordion">[5].</a></sup></p>

<p>HIE can be divided into three stages and shows signs and symptoms according to the respective stage. As this disease cannot be taken lightly, it becomes crucial to diagnose it appropriately and initiate the required treatment. Following are the stages of hypoxic-ischemic encephalopathy (HIE):</p>

<p>&nbsp;</p>

<h5><strong>1. Stage I</strong></h5>

<p>Stage I is usually a mild version of the disease and its signs are seen to disappear within a day. However, it should not be taken lightly and monitored carefully. Signs and symptoms include<sup><a href="#accordion">[4]</a></sup>:</p>

<ul>
	<li>Increased reflexes of the patient</li>
	<li>Deep tendon reflexes</li>
	<li>Irritability</li>
	<li>Feeding problems</li>
	<li>Insomnia</li>
	<li>Occasional crying</li>
</ul>

<p>&nbsp;</p>

<h5><strong>2. Stage II</strong></h5>

<p>The second stage is when the intensity of the disease becomes moderate to moderately severe. The first few weeks after treatment is initiated mark the most crucial period as it is a decisive part of the prognosis. The clinical symptoms evident in this variety include<sup><a href="#accordion">[4]</a></sup>:</p>

<ul>
	<li>&nbsp;Extreme tiredness</li>
	<li>&nbsp;Decreased tone of the body</li>
	<li>&nbsp;Less reactive to induced stimulus to the body</li>
	<li>&nbsp;A phenomenon called the Moro reflex is seen, in which a baby tries to prevent falling by extending his arms.</li>
	<li>&nbsp;A brief pause in breathing</li>
	<li>&nbsp;Seizures</li>
	<li>&nbsp;Avoiding breastfeedings</li>
</ul>

<p>&nbsp;</p>

<h5><strong>3. Stage III</strong></h5>

<p>While stages I and II are less severe, stage III is a full-fledged alarming state with complications such as death and irreversible neurological damage accredited to its name. Signs and symptoms include<sup><a href="#accordion">[4]</a></sup>:</p>

<ul>
	<li>&nbsp; Coma</li>
	<li>&nbsp; Unresponsiveness to external stimuli</li>
	<li>&nbsp; Greater floppiness of the muscular structure, compared to the earlier stages</li>
	<li>&nbsp; Neonatal reflexes are absent for example sucking, Moro reflex, and grasping</li>
	<li>&nbsp; Treatment-resistant seizures</li>
	<li>&nbsp; Irregular heartbeat and blood pressure<br />
	&nbsp;</li>
</ul>

Causes

<p>Causes of neonatal encephalopathy can be grouped into an event-wise manner. Pre-labor, during labor and post-labor time frames will have different causes and are scrutinized as follows<sup><a href="#accordion">[8]</a></sup>:</p>

<p>&nbsp;</p>

<h5><strong>1. Pre-Labor</strong></h5>

<ul>
	<li>An infection that has been transmitted from mother to baby in the womb</li>
	<li>Preeclampsia of the mother, which refers to high blood pressure in pregnancy</li>
	<li>Diabetic mother</li>
	<li>Improper blood supply to the placenta</li>
</ul>

<p>&nbsp;</p>

<h5><strong>2. At The Time Of Labor</strong></h5>

<ul>
	<li>Excessive bleeding from the placental site</li>
	<li>Diseases related to the umbilical cord</li>
	<li>Extremely low blood pressure found in mothers</li>
	<li>Baby presented in a breech fetal position at the time of delivery</li>
	<li>Uterine rupture</li>
</ul>

<p>&nbsp;</p>

<h5><strong>3. After Being Delivered</strong></h5>

<ul>
	<li>Neonate being severely premature</li>
	<li>Trauma during labor to the neonate&rsquo;s brain</li>
	<li>Cardiopulmonary failure</li>
	<li>A serious infection</li>
	<li>Extremely low blood pressure found in the neonate</li>
</ul>

<div>&nbsp;</div>

<p>Although there are no specific tests to screen a newborn for neonatal Encephalopathy, a detailed history of the parents along with the relevant signs and symptoms presented by the newborn can warrant for diagnostic tests to be carried out. Points that raise suspicion of the disease in history are<sup><a href="#accordion">[1]</a></sup>:</p>

<ul>
	<li>Infection with group B Streptococcus bacteria</li>
	<li>Eventful labor i.e. cord prolapse</li>
	<li>Eclampsia or preeclampsia</li>
	<li>Drugs used by the mother during pregnancy, e.g. selective serotonin reuptake inhibitors (SSRIs)</li>
	<li>Family history of cerebral palsy</li>
	<li>Cataract signifies inborn errors of metabolism</li>
	<li>History of neuropathies (minimal strength) and myopathies (weakness in the muscles)</li>
	<li>History of miscarriages or other troubled pregnancies</li>
</ul>

<div>&nbsp;</div>

Diagnosis

<p>As discussed earlier, Neonatal Encephalopathy can predispose malicious outcomes, hence it becomes necessary to efficiently reach a diagnosis. After detailed history and examination is completed, tests can be run in a systematic fashion<sup><a href="#accordion">[1].</a></sup>&nbsp;</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>First Line Investigations</strong></h5>
	</li>
</ul>

<p>These include:</p>

<ol>
	<li>&nbsp;pH</li>
	<li>&nbsp;Markers that signify inflammation</li>
	<li>&nbsp;Glucose</li>
	<li>&nbsp;Liver function test</li>
	<li>&nbsp;Clotting profile</li>
	<li>&nbsp;Urea and electrolytes</li>
</ol>

<p>&nbsp;</p>

<p>These investigations are necessary for every patient suspected of neonatal encephalopathy. It gives a basic outlook of the body&rsquo;s metabolic processes and any evidence of an infection.</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Analysis Of Seizures (If Exists)</strong></h5>
	</li>
</ul>

<p>Electroencephalogram (EEG) is recorded of the patient to ensure whether the seizures are a sign of neonatal encephalopathy or an epileptic disorder. Treatment is given appropriately, however, if they still persist, investigations like magnetic resonance imaging are done to rule out any brain structure abnormality.</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>&nbsp;Second Line Investigations</strong></h5>
	</li>
</ul>

<p>These include:</p>

<p>&nbsp;</p>

<p>1.&nbsp; Ammonia and urinary ketones are checked first, due to the fast processing of these products of metabolism. These are investigated because of increased metabolic functions in NE patients.</p>

<p>&nbsp;</p>

<p>2. Other investigations, such as</p>

<p>a. Neuroimaging</p>

<p>b. Echocardiogram</p>

<p>c. Amino acids concentration in the plasma</p>

<p>d. Urinary amino acids</p>

<p>&nbsp;e. Acylcarnitine screen</p>

<p>&nbsp;</p>

<p>All of these investigations are relevant to the fact that neonatal encephalopathy can show up on MRI or other neuro-images suggestive of brain damage, and increased metabolites tested in these investigations signify the presence of neonatal encephalopathy.</p>

<p>&nbsp;</p>

<p><strong>Note: </strong>It should be noted that while all the investigations are necessary, a strong history and examination does half of the job, and relevant to the stage being hypothesized, necessary investigations can be carried out.</p>

<div>&nbsp;</div>

Treatment

<p>As neonatal encephalopathy affects the brain, it is crucial to protect this vital organ as vigorously as possible. The following are the treatment modalities that have shown success in curing encephalopathy<sup><a href="#accordion">[8]</a></sup>:</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Cooling Down The Brain</strong></h5>
	</li>
</ul>

<p>Hypothermia refers to a drop in the temperature and is considered to be an effective method in the treatment of neonatal encephalopathy. This cooling time period is of almost three days, and during this duration, the baby is kept in cooling blankets. Moreover, during this therapeutic hypothermia period, the baby&rsquo;s heart rate is decreased and the baby seems calmer than usual. However, it should not be a subject of worry, as the baby is provided with necessary nutrition through intravenous supply.</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Seizure Treatment</strong></h5>
	</li>
</ul>

<p>If the newborn has seizures as well, they should be treated exclusively with anti-seizure medications. Moreover, the surroundings of the baby must be kept safe as well to prevent any indirect injury due to seizures.</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Supportive Treatment</strong></h5>
	</li>
</ul>

<p>As the newborn is already fighting against a complicated disease, it is necessary to take off unnecessary load on the other vital systems. Your healthcare provider may use approaches to ensure stabilized blood pressure and&nbsp;kidney function and even consider the possibility of passing a breathing tube if the neonate is having difficulties in breathing.&nbsp;&nbsp;</p>

<div>&nbsp;</div>

<p>Studies reveal that neonatal encephalopathy can not only cause complications in the neurological system but is capable of causing damage to multiple organs as well. Following are the complications, neonatal encephalopathy can cause<sup><a href="#accordion">[9]</a></sup>:</p>

<p>&nbsp;</p>

<p><strong>1. Coagulopathy</strong>: It refers to a state in which clotting is disturbed, which can cause increased bleeding or excessive clotting. Studies prove that coagulopathy is the most dominant complication of neonatal encephalopathy. Oxygen deprivation does not only affect the brain leading to encephalopathy but also affects the bone marrow and liver, resulting in impaired production and functioning of platelets and clotting factors.</p>

<p><strong>2. Kidney Dysfunction:</strong> Kidneys are also severely affected if neonatal encephalopathy is not treated efficiently. Associated with kidney damage, cardiac signs and symptoms can also present.</p>

<p><strong>3. Cardiac Abnormalities</strong>: Cardiac abnormalities don&rsquo;t have an independent precedent but are the third most common complication seen in patients with neonatal encephalopathy consequent to kidney dysfunction.</p>

<p><strong>4. Multiorgan Dysfunction</strong>: Studies prove that neonatal encephalopathy causes multi-organ dysfunction and this unfortunately results in death.&nbsp;</p>

<div>&nbsp;</div>

<p>Although neonatal encephalopathy may come across a dangerous condition, which it certainly is, there are certain factors that are high risk and suitable prevention should be enforced as soon as possible. Risk factors include<sup><a href="#accordion">[7]</a></sup>:</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Maternal Health</strong></h5>
	</li>
</ul>

<p>Studies show that maternal hypertension plays a major role in the development of neonatal encephalopathy. Apart from this, maternal risk factors include maternal thyroid disease, bleeding during pregnancy, viral illness, preeclampsia, an abnormal placenta, and intrauterine growth restriction. Hence, to screen a newborn for Neonatal Encephalopathy, detailed history of the mother during pregnancy becomes vital as well.&nbsp;</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Hypoxia</strong></h5>
	</li>
</ul>

<p><strong>​​​​​​​</strong>Hypoxia refers to the loss of oxygen supply. Current research indicates that in 29% of cases of neonatal encephalopathy, hypoxia is a contributing factor, and in 4% of cases, hypoxia alone was enough to cause the disease. Hypoxia can cause an increase in erythropoiesis (production of red blood cells) and the release of immature nucleated red cells (nRBCs) into circulation. Hence neonates suspected with NE test positive for cord blood nRBCs.</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Infection</strong></h5>
	</li>
</ul>

<p><strong>​​​​​​​</strong>Interleukin-6, a marker of infection was studied to be predominant in patients with encephalopathy right after birth. This was confirmed when a polymerase chain reaction (PCR) was carried out and it detected 11 cases of bacteremia (bacteria present in the blood) in encephalopathic neonates in Africa who had a negative blood culture.</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Metabolic Disorders</strong></h5>
	</li>
</ul>

<p><strong>​​​​​​​</strong>Researchers have found that newborns with an inborn error of metabolism were at a higher risk of neonatal encephalopathy. EEG was the most crucial investigation to support the study, as it positively identified 27 cases with seizures being the dominant clinical sign. Inborn errors of metabolism are genetic disorders in which food is not converted into energy by the body. Examples include urea cycle disorders and fatty acid oxidation defects.</p>

<p>&nbsp;</p>

<ul>
	<li>
	<h5><strong>Disorders Of The Placenta</strong></h5>
	</li>
</ul>

<p><strong>​​​​​​​</strong>Studies show neonates who were positive for neonatal encephalopathy had certain umbilical cord diseases as well. These diseases included inflammation of the fetal vasculature (fetal vasculitis), a bacterial infection of the surrounding layers of the fetus (chorioamnionitis), and umbilical cord lesions. The presence of more than one of these diseases, simultaneously, increases the newborn&rsquo;s chances to get Neonatal Encephalopathy.</p>

<div>&nbsp;</div>

<p>Advances in science have now allowed us to not only treat patients of such a delicate age (neonatal period) but also prevent malicious disease while the fetus is developing. The following are the preventive measures that can be taken against neonatal encephalopathy<sup><a href="#accordion">[7]</a></sup>:</p>

<p>&nbsp;</p>

<p><strong>1. Giving Adequate Antenatal And Postnatal Care</strong>: High-risk pregnancies should be identified timely and given required care. While it may not always prevent NE directly, this can help prevent a lot of diseases that can lead to neonatal encephalopathy.</p>

<p><strong>2. Completing The Term:</strong> It becomes immensely important for your healthcare provider to make sure that the baby is born at term. The earlier the delivery, the more susceptible the premature baby is to a number of diseases including immature lungs, infections, and neonatal encephalopathy. However, if for any reason premature delivery cannot be prevented, the outcomes can be controlled by injecting betamethasone. This is a corticosteroid that essentially matures the baby&rsquo;s body enough to survive in the prematurity stage.</p>

<p><strong>3. Use Of Magnesium Sulphate:</strong> Magnesium sulfate is acclaimed for its ability to not only prevent premature delivery but also has neuroprotective effects on the fetus&rsquo;s brain.</p>

<div>&nbsp;</div>

Key Points

<ul>
	<li>Neonatal Encephalopathy (NE) refers to the condition seen in neonates characterized by neurological deficit.</li>
	<li>Most definitive signs include impaired consciousness, increased or diminished reflexes of the body, and compromised cardiac and respiratory systems.</li>
	<li>NE occurs in approximately in 3 out of 1000 live births and can lead to 6-9% of neonatal deaths overall.</li>
	<li>Intrapartum hypoxia-ischemia is a causative factor in 30% of cases of NE in developed countries and 60% in developing countries.</li>
	<li>A study carried out in 2010 reported that approximately 1.15 million babies contracted NE through intrapartum events.</li>
	<li>The mortality rate related to NE in the year 2010 was 287,000.</li>
	<li>NE, in some cases can be replaced by the term HIE and has three stages.</li>
	<li>Stage I is usually a mild version of the disease and its signs are seen to disappear within a day.</li>
	<li>The second stage is when the intensity of the disease becomes moderate to moderately severe.</li>
	<li>Stage III is a full-fledged alarming state with complications such as death and irreversible neurological damage.</li>
	<li>Causes of neonatal encephalopathy can be grouped into pre-labor, during labor, and post-labor time frames.</li>
	<li>Although there are no specific tests to screen a newborn for neonatal encephalopathy, a detailed history of the parents along with the relevant signs and symptoms presented by the newborn can warrant diagnostic tests to be carried out.</li>
	<li>First and second-line investigations along with detailed history can be carried out. The first line investigations include liver function tests while the second line may include neuroimaging and ammonia assessment.</li>
	<li>EEG is also an important investigation to get a better insight into seizures (if present).</li>
	<li>Treatment of neonatal encephalopathy includes therapeutic hypothermia, supportive treatment, and anti-seizure medications.</li>
	<li>Complications of neonatal encephalopathy include kidney dysfunction, cardiac anomalies, multi-organ dysfunction, and coagulopathy.</li>
	<li>Risk factors include placental abnormalities, umbilical cord problems, maternal hypertension, and infection.</li>
	<li>Whereas preventive measures include optimum antenatal and postnatal care along with the prevention of premature delivery.</li>
</ul>

[1] Martinello K, Hart AR, Yap S, et al Management and investigation of neonatal encephalopathy: 2017 update Archives of Disease in Childhood - Fetal and Neonatal Edition 2017;102:F346-F358.

[2] Aslam S, Strickland T, Molloy EJ. Neonatal encephalopathy: Need for recognition of multiple etiologies for optimal management. Frontiers.

[3] Lee AC, Kozuki N, Blencowe H, Vos T, Bahalim A, Darmstadt GL, Niermeyer S, Ellis M, Robertson NJ, Cousens S, Lawn JE. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. Pediatr Res. 2013 Dec;74 Suppl 1(Suppl 1):50-72.

[4] Brown L. What are the stages of Hie? Brown Trial Firm.

[5] Suh ES. Recent studies are focus on the new treatments for hypoxicischemic encephalopathy (HIE) and long-term outcomes in later childhood and adolescence in children with a history on HIE. Clin Exp Pediatr. 2021 Dec;64(12):628-629.

[6] Aslam S, Strickland T, Molloy EJ. Neonatal Encephalopathy: Need for Recognition of Multiple Etiologies for Optimal Management. Front Pediatr. 2019 Apr 16;7:142.

[7] Preventing hypoxic-ischemic encephalopathy (HIE). HIE Help Center.

[8] Neonatal hypoxic ischemic encephalopathy. UCSF Benioff Children's Hospitals.

[9] Barbara Michniewicz, Salwan R. Al Saad, Lukasz M. Karbowski, Janusz Gadzinowski, Marta Szymankiewicz, and Dawid Szpecht. Organ Complications of Infants with Hypoxic Ischemic Encephalopathy Before Therapeutic Hypothermia. Therapeutic Hypothermia and Temperature Management. Mar 2021.58-63.