1. Neonatal Hypoglycemia: Strategies to decrease mother-infant separation and optimize safety in at-risk infants
Sarbattama (Rimi) Sen
Assistant Professor of Pediatrics, Harvard Medical School
Neonatologist, Brigham and Women’s Hospital
Breastfeeding in the Bay State 2017

2. Disclosure statement
I have no actual or potential conflict of interest in relation to this presentation.

3. Objectives
To review the incidence, risk factors and sequelae of neonatal hypoglycemia
To discuss the current national recommendations around neonatal hypoglycemia
To present the results from one institution’s change in approach to care for newborns at risk for hypoglycemia

4. NH risk factors NH is the most common neonatal biochemical abnormality
Risk factors for NH include:
Maternal diabetes
Fetal growth restriction or overgrowth (SGA or LGA)
Maternal beta blockers
Preterm or late-preterm

5. Incidence of NH All IDM Late Preterm SGA LGA Other Babies (n) Any NH
Severe NH
Recurrent NH
514
260 (51%)
97 (19%)
98 (19%)
202
98 (48)
39 (19)
31 (15)
193
103 (54)
39 (20)
37 (19)
152
77 (52)
27 (18)
32 (21)
133
61 (47)
27 (20)
25 (19) 18
11 (61)
5 (27)
BG measurements (n)
<47mg/dL
≤36mg/dL
4664
568 (12)
143 (3)
1714
202 (12)
65 (4)
1901
228 (12)
50 (3)
1514
175 (12)
37 (2)
1120
145 (13)
44 (4)
150
25 (17)
6 (4)
NH episodes (n)
In first 6h
In first 24h
24-48h
Number per baby
390
187 (48)
315 (81)
75 (19) 1
70 (52)
110 (83)
23 (17)
155
75 (48)
124 (80)
31 (20)
116
55 (47)
93 (80)
23 (20) 94
47 (50)
75 (80)
19 (20) 25
10 (40)
23 (92)
2 (8)
BG=blood glucose, IDM=Infant of a Diabetic Mother, LGA=large for gestational age , LPT=late preterm, NH=neonatal hypoglycemia, SGA=small for gestational age
Harris et al, J Peds, 2012.

6. Multiple Risk Factors
Harris et al, J Peds, 2012.

7. Why are neonates at risk? Physiology of fetal glycemic control
Maternal fetal glucose transport by facilitated diffusion
Fetal glucose “set point” is lower than adult to allow this diffusion
Stembera, 1966

8. Postnatal adaptations
Fetal insulin mainly functions as a growth factor, and is secreted even at low glucose values (when it would normally be suppressed in adults)
Postnatally, there is a period of transition during which the fetal physiology must transition to adult
This “regulated HI” usually occurs in the first 48 hours of life
Hay, 2006

9. Why are newborns at high risk?
Brain glucose utilization becomes limited at a PG concentration of approximately mg/dL
Because of their disproportionately larger brain size relative to body mass, infants have a 2- to 3-fold higher glucose utilization rate (4-6 mg/kg/min) per kilogram of body weight compared with adults
Alternate brain fuels: plasma ketones, FFA and lactate
In the transitional period, insulin is suppressed at a higher threshhold than for a child or adult. This relatively high (for glucose) level of insulin suppresses ketone and FFA production, leaving no alternate substrate for the neonatal brain
Hawdon, 1993, Arch Dis Childhood.

10. Kerstjens et al, 2012 Lollipop study
N=832, born , /7 wks, Netherlands
Exposure: One glucose <30 in first 24 hours of life
Outcome: ASQ at 46 months
Associated with risk of DD from 9 to 20% (OR 2.2, 95% 1.2, 4.5)
No other risk factor was significantly associated in multivariate analysis
Consider: late preterm, relatively healthy population, parental report of outcome, high loss to follow up

11. Kaiser et al, 2015
Retrospective population-based cohort study ,1998, Arkansas
N=1395
Exposure: glucose level less than 35 mg/dL (primary) and less than 40 and 45 mg/dL (secondary)
Outcome: Proficiency on 4th grade Student achievement test
Infants with prolonged hypoglycemia, congenital anomalies, or chromosomal abnormalities were excluded from the study.

12. Consider: why were the babies hypoglycemic?
Adjusted for gestational age group, race, sex, multifetal gestation, insurance status, maternal educational level and socioeconomic status, and gravidity
Consider: why were the babies hypoglycemic?
Blood sugar
<35
<40
<45
Reading
0.49 ( )
0.43 ( )
0.62 ( )
Math
0.49 ( )
0.51 ( )
0.78 ( )

13. Mckinlay et al, 2015
Children with Hypoglycemia and Their Later Development (CHYLD)
New Zealand,
n=616, >32 weeks, with one or more risk factors for NH: (IDM, preterm <37, SGA, LGA, acute illness)
Infants were recruited to 1 of 2 studies (102 in the Babies and Blood Sugar’s Influence on EEG Study [BABIES] and 514 in the Sugar Babies
Exposure: glucose<47
Outcomes:
2 yrs: BSID III, BRIEF-P, global motion perception testing
4 yrs: WPPSI-3, MABC-2, 5 executive function tasks, Beery-Buktenica Developmental Test ofVisual Motor Integration,

14. McKinlay CJ et al. N Engl J Med 2015;373:1507-1518.
Effect of Hypoglycemia on the Primary Outcome and Relation between Continuous Glycemic Exposure and the Primary Outcome.
Figure 2. Effect of Hypoglycemia on the Primary Outcome and Relation between Continuous Glycemic Exposure and the Primary Outcome. Panel A shows the effect of hypoglycemia on the risk of the primary outcome. A hypoglycemic episode was defined as a blood glucose concentration of less than 47 mg per deciliter (2.6 mmol per liter) on a single measurement or consecutive measurements; severe hypoglycemia was defined as a blood glucose concentration of less than 36 mg per deciliter (2.0 mmol per liter). Results were adjusted for socioeconomic decile,20 sex, and primary risk factor for neonatal hypoglycemia. Panel B shows the relationship between continuous glycemic exposure and the primary outcome. Logistic regression was used to compare the risk of an adverse outcome according to the quintile of the continuous glycemic variable in the first 48 hours. Results were adjusted for socioeconomic decile, sex, and primary risk factor for neonatal hypoglycemia. Diamonds denote quintile 1, upward-pointing triangles quintile 2, circles quintile 3 (reference), squares quintile 4, and downward-pointing triangles quintile 5. Values for quintiles 1 through 5 (Q1–5) represent the lowest value for each quintile. The central band was defined as a blood glucose or an interstitial glucose concentration of 54 to 72 mg per deciliter. To convert the values for glucose to millimoles per liter, multiply by
McKinlay CJ et al. N Engl J Med 2015;373:

15. McKinlay CJ et al. N Engl J Med 2015;373:1507-1518.
Results of Interstitial Glucose Monitoring in Children with and Those without Neurosensory Disability at 2 Years.
Figure 3. Results of Interstitial Glucose Monitoring in Children with and Those without Neurosensory Disability at 2 Years. Data are means and 95% confidence intervals and represent the per-child 0.5-hour average of continuous interstitial glucose concentrations. ∆IG denotes the mean difference in the first 12 hours or first 48 hours, as determined from repeated-measures analysis, and IG*t the group–time interaction. Panel A shows data for all 302 children who underwent interstitial monitoring in the first 48 hours after birth, Panel B shows data for the 162 children with neonatal hypoglycemia, Panel C shows data for the 104 children with neonatal hypoglycemia who were treated with dextrose (buccal dextrose gel, intravenous dextrose, or both), Panel D shows data for the 58 children with neonatal hypoglycemia who were not treated with dextrose, Panel E shows interstitial glucose values after the first hypoglycemic episode in the 104 children treated with dextrose, and Panel F shows data for the 140 children without neonatal hypoglycemia.
McKinlay CJ et al. N Engl J Med 2015;373:

16. 4.5 year follow-up

17. II. Current recommendations
Two national organizations have provided recommendations for evaluation and management of NH.
Both recommend IV glucose as the treatment of choice
AAP (2011)
First 24 hours of life
PES (2015)
Two sets of recommendations: First 48 hours of life and after 48 hours of life

18. AAP ( )

19. PES (2015 consensus statement)
The committee’s consensus was that during the first 48 hours of life, a safe target PG concentration should be close to the mean for healthy newborns on the first day of life and above the threshold for neuroglycopenic symptoms (>50 mg/dL ).
The committee recommended raising the glucose target after 48 hours of age (>60 mg/dL) to above the threshold for neurogenic symptoms and close to the target for older infants and children, because of the increased concern for an underlying hypoglycemia disorder.

20. What is “normal”?
Lubchenko and Bard (1971), N=126 FT AGA, mean PG 54 mg/dL at 8 HOL; by 72 HOL, no baby had PG<50
Cornblath (1965), First 2 HOL mean PG 60mg/dL; by 72 HOL mean of 80mg/dL
Hoseth (1993), N=243 FT breastfed infants
Srinivasan (1986), N=344 FT breastfed infants 72 54 36
Hoseth, 1993
Srinivasan et al, 1986

21. How do these values compare to “norms”?
PES
PES
AAP
AAP

22. III. Changes in practice at BWH
Main goals of new CPG (2015):
To integrate/reconcile the AAP and PES guidelines using source evidence
To develop separate guidelines for transitional and persistent NH
3) To minimize mother/infant separation
Institute dextrose gel
Safely encourage breastfeeding in at-risk infants
Encourage in-room monitoring

23. Glucose Gel
Harris et al, Lancet 2013.

24. Glucose Gel and Feeding
The change in blood glucose concentration after episodes treated with dextrose gel was greater than after those treated with placebo gel (P = .007).
After feedings, the blood glucose concentration increased more after formula than after breast feeding or expressed breast milk or no milk (P = .004).
Neither breast feeding nor expressed breast milk was associated with a significantly greater change in blood glucose concentrations than not receiving these feeds.
Mean change in blood glucose with gel 1: 13.1 mg/dL vs gel 2: 15.4 mg/dL
Harris et al, J Peds, 2017.

25. Implementation analysis
Questions of interest in our population:
What risk factors were associated with NH in our population?
What is the glycemic response to gel?
How does infant feeding type affect response?
*Data/results to be presented at meeting*

26. Infants of obese mothers
Infants born to obese mothers are at higher risk of NH
Others have also found that maternal obesity is an independent risk factors for NH
In addition, obese women have delayed and impaired lactogenesis II, increasing likelihood

27. Dextrose Gel in Clinical Practice
Dextrose gel is effective in raising blood glucose
The median blood glucose concentration rose beyond the threshold (45mg/dL) after gel
This first-line therapy allows for mothers and infants to remain together
We did not note “rebound” hypoglycemia after gel administration
Feeding type was associated with different blood glucose changes

28. Blood glucose to guide feeding type
Based on our data, infants with BG>40 (50% of infants) may not need supplemental formula with gel
Infants with BG may benefit from supplemental formula and gel to avoid requiring IVF
Babies can be put to breast after receiving formula
Infants with BG <36 have a high odds of requiring IV dextrose, despite formula supplementation

29. Other considerations: Donor Milk
Donor milk for hypoglycemia
No published data regarding use of donor milk for NH
80%
Wojcik, 2009
Pumping breastmilk before delivery is currently being investigated

30. Providing more than two gels
Many centers have started using 3 and even 4 gels
No safety concerns reported
BWH will be adding a third gel for infants with NH who do not adequately respond to the first two gels

31. Preparing parents for NH
Prenatal counseling should address:
Importance of avoidance and rapid treatment of NH
Immediate skin to skin and breastfeeding
BG measurements
Potential for gel/formula supplementation
Possibility of separation from infant if IVF are needed

32. Conclusions NH has serious, long-term sequelae
Ensuring optimal glycemic monitoring and treatment is essential
Separating mother and infant after birth affects bonding and breastfeeding outcomes
Dextrose gel and targeted feeding supplementation may prevent separation of the majority of infants from their mothers
Research is needed to further optimize NH prevention/treatment within a framework that minimizes separation and promotes breastfeeding