Neonatal The options for treatment in infants born at

Neonatal
hypoglycemia affects up to 15% of newborns (Harding et al., 2015). Risk factors
include preterm delivery, infant born from a diabetic mother, and those of high
or low birth weight. Untreated neonatal hypoglycemia can cause brain damage and
even death. The options for treatment in infants born at risk of hypoglycemia
may involve interventions such as increasing feeds with breast milk, infant
formula, Neonatal Intensive Care Unit (NICU) admission and or administration of
intravenous dextrose therapy to avoid developmental delays later in life. This
course of action is not only expensive but can also reduce the mother’s vital
time spent bonding and breastfeeding (Harding et al., 2015). The purpose of this paper is to discuss the
definition of neonatal hypoglycemia, its causes, adverse effects, implications,
and possible effective treatment alternatives.

A consistent and accepted definition of hypoglycemia
does not exist for the first two days of life (Uettwiller et al., 2015); this
is because there is no consensus on a specific level or range of value that
define hypoglycemia in the first 48 hours, or when to treat and how much
treatment to provide. A number of methods have attempted to recognize the
threshold blood glucose concentration at which there is a substantial
likelihood of functional brain impairment. One approach is an epidemiological
method, which defines blood glucose concentrations in cohorts of healthy
infants and uses the mean or an empirically derived cutoff value, such as < 2 s.ds (standard deviation) below the mean. Any single value is unlikely to represent a threshold of abnormality, as the data represent a continuum from normal (Adamkin & Polin, 2015). It has long been known that plasma glucose concentrations are lower in the first one to three days of life in normal newborn infants than at later ages. In normal newborns immediately following birth, the mean plasma glucose concentrations drop by 25–30 mg/dL (1.4–1.7 mmol/L) to a nadir of about 55–60 mg/dL (3–3.3 mmol/L) by one to two hours of age; glucose levels then steadily rise over the first few days of life to return to the normal range for infants, children, and adults (70–100 mg/dL 3.9–5.6 mmol/L) (Stanley et  al., 2015). As for the causes of neonatal hypoglycemia, these vary, occurring in both very low birth weight (VLBW) babies and also affecting approximately 8-30% of babies born to mothers with diabetes (Alemu, Olayinka, Baydoun, Hoch, & Elci, 2017). VLBW neonates develop hypoglycemia more readily due to limited reserves of fat and glycogen, which is generally composed during the third quarter of pregnancy (Uetwiller et al., 2015); in comparison, infants born to mothers with diabetes have a higher risk than babies born to non-diabetic mothers. The full extent of the individual risk factors of hypoglycemia remains unclear, but clinical risk factors include infant-related and mother-related risk factors. The previously identified infant-related risk factors are varied, ranging from pondered index and male, to macrosomia, small for gestation age, prematurity and lower cord blood index. Risk factors relating to the mother include maternal diabetes and maternal HbA1c, hyperglycemia, ethnic origin, diabetes diagnosed prior to 28 weeks gestation, blood glucose and a pre-pregnancy BMI of ? 25 kg/m2 (Alemu et al., 2017). Adverse effects of neonatal hypoglycemia are serious, ranging from brain damage to neuro-developmental delay, visual impairment and behavioural problems. Between 5 and 15% of otherwise healthy babies become hypoglycemic (Harris et al., 2017), and the prevalence is rising due to the increasing occurrence of preterm birth and maternal diabetes. Screening is recommended for babies with known risk factors, as half are likely to become hypoglycemic. In relation to neuro-developmental delays, impairment is defined as mild (mild cerebral palsy or Bayley-III motor composite score one to two SD below the mean or mild developmental delay), moderate (moderate cerebral palsy or a Bayley-III motor composite score two to three SD below the mean or moderate developmental delay or deaf), or severe (severe cerebral palsy the child is not ambulant at two years and likely to remain so or Bayley-III motor composite score more than three SD (standard deviation) below the mean or severe developmental delays or blindness) (Harris et al., 2017). In terms of visual impairments, children are considered to have a vision problem if they have any one of the following: internal ocular health problem, external ocular health problem, strabismus, abnormal ocular motility, no measurable stereopsis, or binocular visual acuity > 0.5 LogMAR or immeasurable (Harris et al.,
2017).

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The American
Pediatric Endocrine Society (PES) recently published guidelines for evaluation
and management of hypoglycemia in neonates, infants and children, including the
provision of recommendations for recognizing neonates that require diagnosis
and treatment during the first days of life. This includes disorders causing
severe and persistent hypoglycemia. Developing accurate screening for newborns
is essential for the diagnosis of persistent or genetic hypoglycemia disorders to
prevent and reduce the risk of hypoglycemia-induced brain injury. PES suggests
that mean plasma glucose levels are initially maintained at approximately 55 to
65 mg dl (deciliters) but then increase to 470 mg dl by two
to three days of life (Adamkin & Polin, 2016). Using these initial mean
plasma glucose levels may lead to many more infants being evaluated and treated
for asymptomatic hypoglycemia. Over screening, over diagnosing and over
treating are matters of concern when a ‘lower limit threshold’ is set too high
(Adamkin & Polin, 2016).

Treatment of hypoglycemic episodes varies considerably
in infants. A randomized trial of dextrose gel massaged into the buccal mucosa
for treatment of neonatal hypoglycemia was the focus of “The Sugar Babies Study,”
conducted in New Zealand by Hegarty et al. (2016). This study determined that
babies who received dextrose gel instead of placebo were not only less likely
to remain hypoglycemic, but also less likely to be admitted to NICU for
hypoglycemia, and receive nourishment other than formula at two weeks of age.
Dextrose gel is considered safe, inexpensive, simple to administer, and can be
used in almost any setting. Dextrose gel is now being used in some areas as
first-line treatment for neonatal hypoglycemia; however, because neonatal
hypoglycemia is known to cause brain injury, it is also vital to determine
whether using dextrose gel is either beneficial or causes any adverse effects
later in life. Therefore, children who had participated in the Sugar Babies
Study were invited to participate in a follow-up study with the primary aim to
determine whether treatment of hypoglycemic babies with dextrose compared to
placebo gel altered the rate of neuro-sensory impairment or processing
difficulties at two years’ corrected age (Harris et al., 2016).

In another study
conducted by Uettwiller et al. (2015), the glucose level was monitored either
by real-time continuous glucose monitoring system (RT-CGMS), or by an
intermittent capillary glucose testing (IGM-group) associated with a blind
study to detect retrospectively missed hypoglycemia. Following a dose of oral
glucose (30% dextrose solution) and a local anesthesia of lidocaine, the two
devices, both made up of a sensor connected to a transmitter and used to manage
glucose levels in the interstitial tissue, were inserted into the child’s
subcutaneous thigh tissue. After withdrawing the needle, the sensor was
connected to the transmitter. The use of RT-CGMS real-time readout of glucose
levels employed by continuous glucose monitoring indicate much higher number of
hypoglycemic episodes than those repeated with capillary blood glucose testing
as demonstrated by the IGM-group. The hypoglycemia risk was not predictable in
the patients who had the glucose supply increased prematurely at the time of
hypoglycemia, and no distinction was found between patients who received higher
intakes of glucose a few days after birth, from VLBW babies experiencing
different prenatal characteristics or demographics. Thus, the use of RT-CGMS
enabled the identification of these neonates and provided the opportunity for
an individual management of the glucose supply, closest to their needs.

In summation, between
5 and 15% of otherwise healthy babies become hypoglycemic, and the prevalence
is growing due to the increasing incidence of preterm birth and maternal
diabetes. Screening is recommended for babies with known risk factors, of whom
half are likely to become hypoglycemic (Harris et al., 2016). There remains no
evidence that identification and treatment of infants with low glucose levels
born to diabetic mothers improves their outcomes.). While a single dose of
prophylactic oral dextrose gel is shown to reduce the occurrence of neonatal
hypoglycemia in those babies born with a higher chance of developing the
condition, more research is required to determine if oral dextrose gel also lowers
NICU admission and neuro-developmental impairment. Other than encouraging early
feeding, there are no effective prophylactic interventions for infants at risk
of neonatal hypoglycemia (Hegarty et al., 2016). Further research and education
are required to better equip mothers in recognizing the signs and symptoms of
hypoglycemic episodes in neonates and the need for consistent definition in
what constitutes as hypoglycemia in infants.