To stay with this recent “hot topic” of this blog; what low blood sugar threshold should be used for intervention in the neonatal period?

The usual risk factors (SGA, LGA, IDM, late preterm, maternal beta-blockers) select a group of babies whose blood sugar frequently falls below 2.6, 2.4, 2.0, or whatever threshold you want to choose. But what is not clear is how frequently infants who are not considered at-risk will fall below those thresholds. With modern early skin to skin contact, maintenance of normothermia, and breastfeeding starting early after delivery; what is the normal glucose concentration trajectory after birth? If we measure glucose continually, or intermittently, how often do babies fall below thresholds that are considered abnormal and meriting treatment?

Harris DL, et al. Glucose Profiles in Healthy Term Infants in the First 5 Days: The Glucose in Well Babies (GLOW) Study. The Journal of Pediatrics. 2020.

The important work which is continuing to appear from the Auckland group now includes the GLOW study which followed the continuous interstitial and intermittent capillary plasma glucose values of not-at-risk full-term infants. They enrolled 70 babies with birthweights between the 10th and the 90th percentiles, and no history of maternal diabetes, obesity or other risk factors. The sample was from births in Hamilton, a town a little way south of Auckland. A continuous monitor was placed as soon as possible after birth, capillary glucose was taken about 1 hour later, and then another 3 times in the first day, and then twice a day for 5 days, prior to feeds if possible. Highly reliable methods were used to analyse the blood samples, which are reported as plasma glucose concentration equivalents. They were able to include babies born in the hospital, birthing centre and at home, and 67 babies’ data were eventually included.

These are the ranges of results that they found.

One third of these healthy babies had at least one plasma glucose below a value of 2.6 mM/L; one of the most widely used thresholds (47 mg/dl). From continuous monitoring (interstitial glucose concentration) well over half of the babies were “hypoglycaemic” at some point. As you can see from the figure, the lower limit of normal plasma glucose (or interstitial glucose) doesn’t really start to increase until about 48 hours of age.

If you compare these results to the recommended thresholds for treatment of low glucose results from various learned societies (as in the table below from the publication), you can see that some recommendations lead to a majority of healthy newborn infants being defined as abnormal, and would be treated if the recommendation was followed for them.

The PES thresholds would, therefore, define 40 to 73% of healthy normally grown full-term infants as being hypoglycaemic, which is worrying; the WHO standards, and the new Canadian Pediatric Society guideline, define 24 to 63% of healthy babies as being abnormal and needing intervention.

To be fair the CPS guidelines do note that they only apply to at-risk babies, and that some healthy babies have low blood sugar below the thresholds; they accompany that by a statement that “outcome data support raising the interventional threshold” for at-risk infants. But is that true? I don’t know where the idea comes from that hypoglycaemia is more damaging to at-risk babies than to the remainder. The reason for defining at-risk groups was surely to try and define infants who are more likely to have low blood sugar, not because there was any data that they are more likely to have long-term adverse impacts. It used to be taught that hyperinsulinemic babies were more at risk than babies who were hypoglycemic because of low substrate (especially glycogen stores), and that was because hyperinsulinaemia inhibits the production of ketone bodies, but recent research shows that most “hypoglycaemic” newborns do not produce ketone bodies, even those with low insulin concentrations.

In fact, if you compare the incidence of low sugars in this new study to the previous results they obtained from “at-risk” infants (as they do in this publication) you find that at-risk infants are not at much more risk than not-at-risk infants.

Table V. Number of healthy and at-risk infants with episodes of low glucose concentrations

Data are number (%).

I took out the risk ratios and p-values, from the table. (Although I understand the desire to put them in, comparing 2 independent data sets and presenting a p-value of the result is questionable, it gives the probability that 2 samples are from the same population and we already know that is not true!) Just looking at the data shows that there is very little difference in the proportion of “at-risk” and “not-at-risk” babies who have low glucose concentrations.

In other words, “at-risk” infants have only a marginally increased chance of having a glucose that falls below each of these thresholds, compared to perfectly healthy, highly selected “not-at-risk” infants.