Management of Asymptomatic Hypoglycemia With Dextrose Oral Gel at 40% in Near Term at-risk Infants to Reduce Intensive Care Need and Promote Breastfeeding

Background: Neonatal hypoglycemia is a common disorder especially in at-risk infants and it can be associated with poor long-term neurological outcomes. Several therapeutic interventions are suggested, from the implementation of breastfeeding to the glucose intravenous administration. Oral dextrose gel massaged into the infant’s inner cheek is a recent treatment option of asymptomatic hypoglycemia, after which oral feeding is encouraged. This approach seems to reduce the admission of infants to neonatal intensive care unit (NICU) so favouring maternal bonding and breastfeeding success at discharge. Methods: In our unit we recently implemented the protocol for the management of asymptomatic hypoglycemia with the introduction of dextrose oral gel at 40%. Therefore we compared two cohorts of near term at-risk infants with asymptomatic hypoglycemia: a historical group managed with our old protocol and the second one prospectively followed after the introduction of dextrose gel at 40%. Results: Primary outcome was occurrence of NICU admission and glucose intravenous needs; breastfeeding success was the secondary outcome. Infants in the dextrose oral gel group showed statistically lower need of NICU admission and higher prevalence of exclusive breastfeeding at discharge compared with infants of the historical group. Conclusions: In our population the introduction of dextrose oral gel at 40% to the protocol, helped in the safe management of asymptomatic hypoglycemia in near term infants and, at the same time, implemented breastfeeding.


Background
Hypoglycemia is the most frequent metabolic disorder in neonates, with an incidence of 5-15% in healthy term infants and up to 50% in infants with risk factors [1]. During the pregnancy the fetus receives glucose from placental circulation, but at birth this supply stops abruptly and the neonates need to become independent to produce energy. In the rst two hours of life, glycemia reaches the lowest level, then the values stabilize between 4 and 6 hours of life [2].
Neonatal hypoglycemia, especially if prolonged, can be associated with brain injury and poor neurodevelopment outcomes, including cognitive impairment, sensor disability, cerebral palsy, seizures and developmental delay [3,4]. Despite this, uncertainty persists regarding the de nition of neonatal hypoglycemia and even for the correlation between the values of glycemia, the symptoms in newborns and the long-term sequalae [5,6]. Moreover, even the inaccuracy of the measurement tools can complicate the interpretation of the data [7]. The two most recent international guidelines from the Pediatric Endocrine Society and the American Academy of Pediatrics do not help to clarify the correct values to de ne hypoglycemia in neonates [8,9].
Treatment options vary according to the single case, the occurrence of symptoms and of blood glucose levels. The rst intervention is early and frequent oral feeding, focused on breastfeeding, and infant formula supplementation can be used if human milk is not available. Failing this approach, infants that remain hypoglycemic are often transferred in neonatal intensive care unit (NICU) or specialty care nursery and intravenous (IV) glucose is administered. NICU admission leads to physical separation between mothers and neonates, to a negative impact on bonding and to a delayed establishment of breastfeeding.
More recently, the buccal administration of dextrose gel showed positive effects on reducing the time of mother-infant separation and increasing the likelihood of breastfeeding at discharge [10]. By the direct application to the oral mucosa, glucose can rapidly enter the systemic circulation via the lingual and internal jugular veins, even if a rate of the dose may also be swallowed and absorbed from the gastrointestinal tract [11].
For these reasons, in late 2019, we decided to implement a protocol for the management of hypoglycemia in at-risk newborns in our Neonatal Unit including a commercially sourced dextrose gel at 40% (Destrogel, Orsana ®, Italy). After this, we conducted a comparison on the impact of intensive care need (NICU admission and intravenous glucose administration) and breastfeeding success at discharge between a population of near term at-risk infants for asymptomatic hypoglycemia managed with dextrose oral gel at 40% and a historical group.

Methods
In our Department at the beginning of November 2019, the protocol for the management of neonatal hypoglycemia was implemented with the use of a commercially sourced oral dextrose gel at 40% (Destrogel, Orsana ®,Italy).
This was a prospective cohort study with a retrospective control group. The study was approved by our local IRB and parental consents were obtained.
Two cohorts of asymptomatic near term neonates at risk for hypoglycemia, born at V. Buzzi Children's Hospital (ASST-FBF-Sacco, Milan, Italy), a tertiary level care center, were investigated: the historical group (May 2019-October 2019) (Gr1) and the prospective group (November 2019-April 2020) after the implementation of the revised protocol (Gr2).
All the infants after birth were initially maintained in skin-to-skin contact with mother and rooming-in was proposed.
For both cohorts of at-risk infants for hypoglycemia, the following inclusion criteria have been applied: mild prematurity (> 35 weeks'GA), post-term birth (> 41 + 6 weeks'GA), low birth weight (LBW; < 10°p ercentile), large for gestational age (LGA, > 90° percentile), intrauterine growth restriction (IUGR), birth weight under 2500 g or above 4000 g, maternal diabetes, transient mild neonatal respiratory distress, urgent cesarean section for foetal distress, maternal eclampsia and hypertension, meconium-stained amniotic uid, foetal eritroblastosis, polycythemia, mild hypothermia, metabolic acidosis at birth, maternal pharmacological therapy during pregnancy with β-blockers, β-sympathomimetics or oral hypoglycaemic agents, congenital syndrome and twins with discordant neonatal birth more than 10%. We excluded infants born before 35 weeks' GA, with signs and symptoms of hypoglycemia and with more than 15% of loss of weight at 48 hours of life.
A complete database with all newborn characteristics has been drafted.
Group 1: the protocol used in the rst period indicated values for hypoglycemia < 45 mg/dl in symptomatic term or preterm neonates and < 36 mg/dl in asymptomatic at-risk neonates. In case of persistent low value of blood glycemia despite frequent oral feeding with breastfeeding, squeezed human milk or formula milk, the algorithm suggested to start intravenous infusion of glucose. Blood glucose level monitoring was made by bedside tool. Primary outcome of the study was the need of intensive care (number of newborns transferred at NICU due to hypoglycemia and the requirement to intravenous glucose therapy). Secondary outcomes: the rate of exclusive breastfeeding at discharge (de ned as the newborn receiving only breast milk the last feeding before discharge) and the length of hospitalization.
A statistical analysis was performed: a t-Student test was used to analyze continuous variables, while for categorical variables like transfer to NICU, need for intravenous treatment and the rate of exclusive breastfeeding at discharge a χ 2 test was used. Statistical signi cance has been established for values of p < 0.05. The SPSS software was used to analyze data.

Results
The neonatal baseline characteristics of the two groups are shown in Table 1.  In Table 4 we reported outcomes of the two groups.

Discussion
Neonatal hypoglycemia still remains a challenge, due to the uncertainty in its de nition and in the threshold to consider intervention [12]. For asymptomatic at-risk neonates, management is focused on normalizing their blood glucose levels and preventing both short and long-term severe neurological sequelae. Secondary but relevant target is to reduce physical separation between mothers and newborns so enhancing bonding and breastfeeding success. The introduction of the administration of 40% dextrose gel in the protocols for hypoglycemia was targeted to control neonatal asymptomatic hypoglycemia until feeding was established, to reduce the need of glucose intravenous therapy and NICU admission, and to promote breastfeeding and maternal bonding.
We analyzed the data from two groups of newborns at-risk for hypoglycemia, managed with (Gr2, prospective study group) or without the administration of 40% dextrose gel (Gr1, historical control group).
In the last decades, the incidence of neonatal hypoglycemia in otherwise healthy infants is 5-15% [1,13]; in our experience this data is respected, because we found an incidence of 10% (39/389) in the historical group (Gr1) and 12% (37/308) in the cohort of infants managed with the new protocol (Gr2).
Gr2 presented a reduced need of NICU admission, of iv therapy and a shorter length of hospitalization.
Moreover, the rate of exclusively breastfed newborns at discharge, was higher in this group of infants when compared to the infants of the historical group (Gr1).
We found a signi cative different incidence of NICU admission for hypoglycemia: 48.7% (19/39) in the historical cohort of patients (Gr1) versus 10% (3/30) in the cohort of patients treated with dextrose gel at 40% (Gr2). This nding is similar to data reported in the literature. Rawat et al [14] demonstrated that the introduction of dextrose oral gel for the management of hypoglycemia reduced the hospitalization rate from 42-26% (p < 0.01). Similar ndings were found by Scheans et al [15], who demonstrated that in the rst year of use of dextrose gel the admission at NICU due to hypoglycemia was reduced of 73%. In other two studies performed in Australia [16] and USA [17], the Authors found a reduction of admission to NICU for the treatment of hypoglycemia of 15% and 7.7%, respectively. On the contrary, two recent studies did not demonstrate the e cacy of the dextrose gel to reduce NICU admission rates. In the former study [18], the Authors found a non-signi cant reduction from 2.5-1.5%; they tried to explain this result suggesting that the study took place in a Baby-Friendly Hospital with a low NICU admission rates already before the introduction of dextrose gel for the management of hypoglycemia. Ponnapakkam et al [19] explained their controversial results by pointing out that despite a high compliance with dextrose gel usage, the skin-to-skin care and the early feeding are more comfortable measures for healthcare to prevent neonatal hypoglycemia.
In our study the percentage of patients who required iv treatment was signi cantly reduced from 35.9-10% in the cohort of newborns managed with dextrose oral gel at 40%. Similar conclusions were reached in other studies. Rawat et al [14] demonstrated a reduction of iv therapy of 15.5%, Gregory et al. [20] showed a reduction from 8.6-5.6% after the introduction of dextrose oral gel in clinical practice and, at last, even the retrospective study of Makker et al [21] emphasized the signi cant impact of the oral treatment on the NICU admission rate and the number of iv dextrose administration. The Cochrane review of 2016 [10] showed no signi cant differences in the need of iv treatment between the group of patients treated with dextrose oral gel and placebo group, but the authors underlined the low quality of the two included studies due to inaccuracy of data collection, the presence of bias and deviations on outcomes analyzed.
Our data showed that even the length of hospital stay of asymptomatic hypoglycemic newborns managed with dextrose oral gel (Gr2) was signi cantly shorter than newborns in Gr1. This conclusion is, of course, linked to the reduced transfer of patients at NICU and the reduced need of iv treatment. In the same way, Rawat et al [14] and Stewart et al [22] showed a signi cant decrease of the length of hospital stay from 7.3 ± 4.3 to 3.1 ± 1.1 days and from 5.8 to 3.8 days, respectively. Conversely, Makker et al [21] found no differences in the length of hospitalization between newborns managed with dextrose oral gel and iv treatment. The authors concluded that this non-randomized and not-controlled study could have some limitations regarding especially the impact of the new protocol on healthcare routine and the maximum number of doses of dextrose oral gel xed at 4 times instead of 6 administrations as usually made in the other studies.
Although in our study we did not directly perform a cost analysis, we observed the results of similar studies in literature [23] and we can assume that a reduced number of NICU admission, less iv treatment and a shorter length of hospitalization, make dextrose oral gel a less costly option for the management of neonatal asymptomatic hypoglycemia.
The rate of exclusive breastfeeding at discharge was the last secondary outcome evaluated in our study. Many data from the literature [24,25] underline the crucial role of early initiation of breastfeeding and the skin-to-skin care immediately after birth. This is crucial to increase and promote maternal bonding and breastfeeding and to achieve successful exclusive breastfeeding during hospitalization and at discharge. Our results showed a signi cantly increased rate of newborns exclusively breastfed in group 2: 30% (9/30) in Gr2 vs 7.7% (3/39) in Gr1. This is certainly related to the fact that it was possible, in the rst hours of life, to keep mothers and newborns together thanks to the use of dextrose gel. Several others studies in literature con rmed our result. Rawat et al [13] and Makker et al [21] demonstrated an increase of exclusive breastfeeding in newborns managed with dextrose oral gel from 19-28% and from 6-19%, respectively. Weston et al in 2016 [10] con rmed the increase in the percentage of exclusive breastfeeding at discharge in the group of newborns treated with dextrose oral gel during hospital stay. Two studies in literature showed different results. Stanzo et al [18] found an increase in exclusively breastfed newborns from 56.6-59.1%. This not signi cant result could be linked to the high rate of breastfeeding even before the introduction of management of hypoglycemia with dextrose oral gel, due to the Baby-Friendly practices. Ponnapakkam et al [19] showed an increase only of 3 percentage points in exclusive breastfed infants and they attributed this result to the critical issues related to the new protocol for healthcare personnel but also to the frequent rotation of the same staff.
In order to reduce this bias, before the application of the new protocol for the management of at-risk infants for hypoglycemia, in our department we performed several training sessions with doctors, nurses and residents. Although we have not assessed it directly, we can say that the administration of dextrose oral gel was tolerated by newborns, and, especially, by parents and staff. Moreover, the administration of dextrose oral gel appears safe even in the long term, as indicated by the data in literature [26].
One of our concerns was the possible adverse effect of dextrose gel on breastfeeding; in fact it is reported that the administration of any supplements in the neonatal period may delay the establishment of breastfeeding, and decreased its duration [27,28]. However, our data show that newborns managed with dextrose oral gel present higher rate of exclusive breastfeeding.
Our study has several limitations. First of all, the COVID 19 pandemic forced us to interrupt the Group 2 recruitment (due to less availability of hospital staff) and this group is less numerous. Some inhomogeneities between groups are shown in Table 1: birth weight and gestational age differences, though statistically signi cant, do not change the clinical de nition of the neonates, who remain adequate for gestational age (AGA) and term neonates. Moreover this is a comparison between a prospective group and a historical group managed with two different protocols for the management of asymptomatic hypoglycemia. The analysis of retrospective data may limit the stringency and robustness of data quality, and it was dependent on the accuracy of documentation by clinical staff. Finally, we did not evaluate the rate of breastfeeding after discharge; this data could be interesting to con rm the relevant role of dextrose gel to improve breastfeeding during the hospital stay in hypoglycemic infants.

Conclusions
Future large randomized control trials are needed to provide further insight into the management with dextrose gel at 40% for neonatal symptomatic hypoglycemia and to provide data about neurological outcomes. Once the effectiveness of the dextrose gel for the treatment of asymptomatic neonatal hypoglycemia has been con rmed, it would also be interesting to investigate, the role of this therapy in every single different risk factor for hypoglycemia, evaluating the short and long term outcomes.
Abbreviations NICU: neonatal intensive care unit; IV: intravenous; LGA: large for gestational age; IUGR: intra uterine growth restriction; GA: gestational age; SGA: small for gestational age; AGA: adequate for gestational age; LBW: low birth weight Declarations Ethics approval and consent to participate The study was approved by our local IRB and parental consents were obtained.