Hypoglycemia in term newborns with a birth weight below the 10th percentile

Abstract

BACKGROUND:

Current recommendations suggest that routine screening for hypoglycemia should be performed in all term newborns with a birth weight (BW) below the 10th percentile. The impact of updated growth curves on the incidence of hypoglycemia in small-for-gestational-age (SGA) newborns has not been evaluated.

OBJECTIVES:

To evaluate the occurrence and severity of hypoglycemia in term newborns with a BW between the 10th and fifth percentile, and below the fifth percentile, using recently updated growth curves.

DESIGN:

A one-year prospective cohort study.

METHODS:

Inclusion criteria were gestational age of 37 weeks or greater and BW below the 10th percentile. Neonatal hypoglycemia was defined as a blood glucose level of less than 2.6 mmol/L measured after 2 h of life. Blood glucose was measured routinely for all SGA infants during the first 36 h of life.

RESULTS:

A total of 187 SGA infants met the study criteria: 85 infants with a BW between the 10th and fifth percentile, and 102 infants with a BW below the fifth percentile. The characteristics of the study cohort were similar between BW groups. Twenty-six per cent of the infants screened had at least one episode of hypoglycemia: 22% of infants in the 10th to fifth percentile group and 28% in the less than fifth percentile group. Hypoglycemia was symptomatic in four infants, all of whom were below the fifth percentile for BW. The mean (± SD) lowest blood glucose level was 2.1±0.4 mmol/L (range 0.6 mmol/L to 2.5 mmol/L) in the 10th to fifth percentile group and 2.0±0.5 mmol/L (range 0.8 mmol/L to 2.5 mmol/L) in the less than fifth percentile group (P=0.05).

CONCLUSION:

The present study demonstrates a high incidence of hypoglycemia among SGA infants with a BW below the 10th percentile using updated growth curves. There was no difference in the incidence of hypoglycemia among SGA infants with a BW below the fifth percentile versus those with a BW between the 10th and fifth percentile.

It has long been known that infants born with a low birth weight (BW) for their gestational age are at risk of hypoglycemia even though its definition remains controversial (1–6). Routine screening for low blood glucose is currently recommended for all term newborns with a BW below the 10th percentile (5,7). A few studies (8–10) have suggested that persistent glucose levels of less then 2.6 mmol/L in small-for-gestational-age (SGA) preterm newborns may have long-term effects on their neurodevelopment. Because of this evidence, current clinical practice guidelines recommend the use of 2.6 mmol/L for blood glucose concentration measured after 2 h of life as the threshold value, below which intervention is warranted in a term newborn (7).

Recently updated growth curves have demonstrated a considerable upward shift in the BW of North American newborns. This increase in the average BW can be explained by multiple sociodemographic factors (11–14) and may be a reflection of increasing maternal obesity, reduction in serious malnutrition and improvement in antenatal obstetrical care. Therefore, we hypothesized that the incidence of hypoglycemia in the current newborn population has decreased, especially in the ‘not so small’ infants such as those with a BW between the 10th and fifth percentiles relative to babies with a BW below the fifth percentile. The aim of the present study was to compare the incidence and severity of hypoglycemia in infants between the 10th and fifth percentiles for BW with those below the fifth percentile, using the cut-off values from the recently updated growth curves (12).

METHODS

A longitudinal prospective study of all full-term SGA infants born at the Centre Hospitalier Universitaire Sainte-Justine (Montreal, Quebec) between July 1, 2005, and June 30, 2006, was designed. Approval of the research protocol was obtained from both the Scientific and the Ethics Committees at the institution before the start of the present study. Infants in the hospital nursery were already routinely screened for neonatal hypoglycemia in accordance with the guidelines published by the Canadian Paediatric Society (7). Therefore, informed consent was not required by the institution. Infants with chromosome anomalies, congenital anomalies and congenital infection that could cause growth restriction were excluded. In the centre, mothers of SGA newborns are encouraged to breastfeed (if this was their intent) or to offer formula within the first 2 h after delivery. Infants with BW below the 10th percentile are screened for hypoglycemia at 2 h of life, or sooner if clinically indicated. Blood glucose measurements are subsequently performed every 3 h to 6 h before feedings for the first 36 h of life. In all cases, screening was performed by pricking the skin of the heel and collecting a drop of blood. The sample was applied to a glucose test strip and analyzed (SureStepPro Test Strip, SureStepFlexx, LifeScan Inc of Johnson & Johnson Company, USA). All glucose test strip values of less than 2.6 mmol/L were confirmed by a plasma glucose concentration analyzer (Coulter Lx Series, Beckman Coulter, USA) from capillary blood also obtained from a heel prick. Hypoglycemic infants were immediately fed and a blood sugar measurement was repeated 1 h after feeding. An intravenous (IV) dextrose infusion was used only if blood glucose values remained below 2.0 mmol/L after feeding, or between 2.0 mmol/L and 2.5 mmol/L on two or three consecutive samples despite having given supplements of breast milk or formula. Infants who were administered IV fluids on admission to the nursery for reasons other than hypoglycemia were excluded.

Study definitions

Neonatal hypoglycemia was defined as a plasma glucose value of less than 2.6 mmol/L at or after 2 h of life as confirmed by the laboratory (7–10). During the first 2 h of life, a blood glucose measurement greater than 1.8 mmol/L was considered to be normal and was not verified by a laboratory test. A laboratory-confirmed plasma glucose value of less than 1.8 mmol/L was considered to be hypoglycemic. Maternal diabetes included the diagnoses of gestational diabetes, and type 1 and 2 diabetes. Gestational age was calculated using the date of the last menstrual period or from the ultrasound performed in the first trimester and/or at 18 to 20 weeks of gestation. Ultrasound dating was used in cases of more than one week discrepancy with last menstrual period. Infants were categorized as SGA if their BW was below the 10th percentile using recently updated growth curves (12). The decision to classify infants according to BW between the 10th and fifth percentile and BW below the fifth percentile was arbitrary and because the information was readily available to the investigators. The choices of exclusive breastfeeding, formula feeding or mixed feeding were recorded according to what the infant actually received over the first 36 h of life.

Statistical analysis

Descriptive statistics were obtained for all variables. Mean values between groups were compared using the Student’s t test. χ² tests were used to compare dichotomous data. A logistic regression was used to identify whether covariates were associated with an increased risk for hypoglycemia.

RESULTS

During the study period, 219 newborns were identified as being SGA. Ten charts were excluded from the analysis because of missing data. Twenty-two infants who required IV dextrose infusions at birth for reasons other than hypoglycemia were also excluded from further analysis. Of the 187 remaining newborns, none met the exclusion criteria: 85 infants had a BW between the 10th and fifth percentile, and 102 infants had a BW below the fifth percentile. The characteristics of the two groups are shown in Table 1. Significantly higher proportions of infants with BW below the fifth percentile compared with those between the 10th and fifth percentile had a head circumference less than the third percentile and were exclusively formula fed. All patients but one had an Apgar score of 7 or greater at 5 min. Fifteen infants had blood glucose values between 1.8 mmol/L and 2.6 mmol/L within the first 2 h of life (seven in the 10th to fifth percentile group, eight in the below fifth percentile group), which were not considered to be indicative of hypoglycemia. Five of these patients had persistent episodes of hypoglycemia beyond the first 2 h of life. Therefore, these patients were defined as having hypoglycemia and were included in further analyses.

TABLE 1.

General characteristics of the population

Variables	Birth weight
	10th–5th percentile, n=85	<5th percentile, n=102
Gestational age, mean ± SD, weeks	39.2±1.3	39.3±1.1
Weight*, mean ± SD, g	2779±210	2548±254
Weight, median (range), g	2795 (2300–3165)	2598 (1535–2960)
Male sex	52 (61)	55 (54)
Head circumference <3rd percentile* (14)	7 (8)	23 (23)
Hypoglycemia	19 (22)	29 (28)
Diabetes	5 (6)	4 (4)
Primiparous	61 (72)	63 (62)
Singleton	79 (93)	88 (86)
Caesarean	28 (33)	31 (30)
IV dextrose for hypoglycemia	4 (5)	3 (3)
Exclusive breastfeeding	57 (67)	59 (58)
Formula feeding*	8 (9)	22 (22)
Mixed (breast and formula) feeding	20 (24)	21 (21)
Weight loss >10%	3 (4)	10 (10)

Values are given as n (%), unless indicated otherwise.

^*P<0.05 for the 10th to fifth percentile versus less than the fifth percentile. IV Intravenous

Incidence

Overall, 26% (n=48) of the infants screened experienced at least one episode of hypoglycemia: 22% (n=19) in the 10th to fifth percentile group and 28% (n=29) in the less than fifth percentile group. Characteristics of newborns with and without episodes of hypoglycemia are shown in Table 2. The proportion of infants who had a head circumference below the third percentile was significantly lower among those with hypoglycemia than those without hypoglycemia. Infants with hypoglycemia were less likely to be exclusively breastfed and a greater proportion received mixed (formula and breast) feeding. Univariate analysis did not allow identification of any other specific risk factors for the development of hypoglycemia in the study cohort (Table 3). The number of infants presenting two or more episodes of hypoglycemia did not differ between BW groups (12 in the less than fifth percentile group versus nine in the 10th to fifth percentile group).

TABLE 2.

Characteristics of the population with and without hypoglycemia

Variables	With hypoglycemia, n=48	Without hypoglycemia, n=139
Weight, mean ± SD, g	2639±257	2658±263
Weight, median (range), g	2668 (1985–3125)	2705 (1535–3165)
Male sex	18 (38)	62 (45)
Head circumference <3rd percentile* (14)	4 (8)	26 (19)
Diabetes	2 (4)	7 (5)
Primiparous	32 (67)	92 (66)
Singleton	42 (88)	125 (90)
Caesarean	12 (25)	47 (34)
IV dextrose	4 (8)	3 (2)
Exclusive breastfeeding*	19 (40)	97 (70)
Formula feeding	8 (17)	22 (16)
Mixed (breast and formula) feeding*	21 (44)	20 (14)
Weight loss >10%	4 (8)	9 (7)

Values are given as n (%), unless indicated otherwise.

^*P<0.05 for the 10th to fifth percentile versus less than the fifth percentile. IV Intravenous

TABLE 3.

Univariate analysis and risk factors for hypoglycemia

Risk factor	OR (95% CI)
Diabetes	0.82 (0.16–4.09)
Singleton	1.28 (0.46–3.53)
Gestational age	1.10 (0.84–1.44)
Mode of delivery	0.73 (0.43–1.22)
Male sex	0.75 (0.38–1.46)
Weight loss	0.93 (0.56–1.55)

Timing

Fifty-six per cent (n=27) of the infants with hypoglycemia had only one such episode (11 in the 10th to fifth percentile group and 16 in the less than fifth percentile group; P not significant). Of the 21 infants (44%) who had two or more episodes of hypoglycemia, 10 had their first episode at 3 h or less of life (three in the 10th to fifth percentile group and seven in the less than fifth percentile group). The timing of the first episode of hypoglycemia for each infant is shown in Figure 1. The median time at which the first episode of hypoglycemia occurred was 5.5 h (range 1 h to 48 h). Overall, 15% of patients with hypoglycemia continued to present episodes after 36 h of age.

Figure 1).

Timing of the first episode of hypoglycemia. Opaque circle represents newborns with birth weight between the 10th and fifth percentile (median age of 7 h at the first episode of hypoglycemia). Open circle represents newborns with birth weight below the fifth percentile (median age of 4 h at the first episode of hypoglycemia)

Severity

The mean values of the lowest blood glucose measurements recorded for each patient in the cohort were 2.1±0.4 mmol/L (range 0.6 mmol/L to 2.5 mmol/L) in the 10th to fifth percentile group and 2.0±0.5 mmol/L (range 0.8 mmol/L to 2.5 mmol/L) in the less than fifth percentile group (P=0.05; ie, not statistically significant). Overall, there were four infants in the 10th to fifth percentile group versus eight infants in the less than fifth percentile group with glucose values of less than 1.8 mmol/L. Four patients were treated with IV dextrose because of persistent hypoglycemia (n=2 in each BW group); three of them required initiation of IV therapy within the first 3 h of life.

Only four infants were noted to have manifested symptoms simultaneously with hypoglycemic episodes (jitteriness and tachypnea). All four of these infants were in the group with BW less than the fifth percentile. Two of these infants had only one episode of hypoglycemia; one episode occurred at 4 h of life and the other at 11 h of life. Both infants had a blood sugar value of 2.5 mmol/L. The two other symptomatic infants had more than three episodes of hypoglycemia, and their lowest blood sugar values were 1.8 mmol/L and 1.9 mmol/L. Only one of the four symptomatic infants required IV dextrose for persistent hypoglycemia.

DISCUSSION

Twenty-six per cent of all SGA infants screened in our study had at least one episode of hypoglycemia in the first 36 h of life. This incidence is surprisingly high despite our use of recently updated growth curves to identify infants at risk, with higher weight cut-offs for the 10th percentile. We did not observe a significant difference in the incidence of hypoglycemia in the groups characterized by BW between the fifth and 10th percentile versus those with BW less than the fifth percentile. The results of our study do not support our initial hypothesis that the upward shift in BW results in a decrease in the incidence of hypoglycemia, particularly in infants between the fifth and 10th percentile.

We also did not identify any statistically significant risk factors for the development of hypoglycemia in SGA infants. The majority of the infants in the study who had a head circumference below the third percentile (14) did not present with hypoglycemia. This suggests that etiologies of more ‘symmetrical’ growth restriction decrease the risk of neonatal hypoglycemia (such as constitutional SGA, environmental toxins or infectious exposures with early perturbation of fetal cell hyperplasia) or, alternatively, that more severe growth restriction is associated with relative insulin resistance (15) and, therefore, maintained normal glucose.

The difference in feeding patterns between BW groups and between with versus without hypoglycemia groups probably reflects either the worry of the mother and health care provider that the smaller infants (ie, BW below the fifth percentile) would not receive enough nutrition solely from breastfeeding, or a ‘treatment’ response to an episode of hypoglycemia. We cannot exclude that a higher formula intake over the first 36 h of life in this cohort of SGA infants contributed to preventing episodes of hypoglycemia.

The rationale for the systematic screening of hypoglycemia in infants with a BW below the 10th percentile can be questioned in light of our results. Given our surprisingly high incidence, one might even be tempted to screen more infants. Alternatively, considering that in appropriate-for-gestational-age full-term healthy breastfed infants, incidence of blood glucose values of less than 2.6 mmol/L is not infrequent and has been reported to be as high as 12% to 14% (16–19), we could postulate that the blood glucose threshold of 2.6 mmol/L may be too high and not discriminatory for truly clinically relevant hypoglycemia in term (SGA) infants. In 1971, Lubchenco and Bard (20) defined neonatal hypoglycemia as a blood glucose level of less than 1.7 mmol/L and reported an incidence of 25% in 44 SGA newborns and 10% in 126 appropriate-for-gestational-age newborns on samples obtained before the first feed (20,21). By applying their threshold to our study, the incidence of hypoglycemia in our current cohort of SGA newborns decreases to 5.3%. The latter observation would support our hypothesis that the infants labelled SGA with the recent BW curves represent, in fact, a ‘healthier’ newborn population. In 1993, Holtrop (5) defined hypoglycemia as a serum glucose value of less than 1.9 mmol/L in the first 3 h of life, less than 2.2 mmol/L at 3 h to 24 h of life and less than 2.4 mmol/L after 24 h of life, and reported an incidence of hypoglycemia in SGA infants of 14.7%. Using Holtrop’s threshold value (5), the incidence in our group would be similar at 18%. The nonunanimous definitions of hypoglycemia and of the methods of assessment used in each of these studies (22) hinder our ability to reliably compare our results.

The level at which hypoglycemia becomes clinically important is not well understood (23), and the neurodevelopmental consequences of asymptomatic hypoglycemia in term SGA infants are still unknown (24,25). Glucose is the primary organic fuel for energy production, especially for the brain. However, alternative substrates such as ketone bodies, lactate, glycerol, B-hydroxybutarate and acetoacetate play an important role in glucose deprivation status; they support brain metabolism and may, therefore, prevent clinical manifestations in neonates (26–28). Because our study does not provide follow-up data regarding the neurodevelopmental outcomes of the infants studied, we cannot add insight into a meaningful threshold for hypoglycemia. Our small cohort size has also limited our ability to identify risk factors associated with the occurrence of hypoglycemia, which might have helped refine screening criteria.

For obvious practical purposes, a lowest acceptable blood glucose level needs to be agreed on for optimal management of all patients in newborn nurseries and neonatal units. The threshold of 2.6 mmol/L currently recommended in guidelines is heavily influenced by outcomes reported by Lucas et al (8) and Duvanel et al (9) from cohorts of mostly symptomatic SGA preterm infants with hypoglycemia. Conclusions drawn from a cohort of infants already at increased risk of neurodevelopmental sequelae should be extrapolated cautiously to a small but otherwise healthy and asymptomatic term newborn population. Cornblath and Ichord (29) suggest that a plasma glucose level of 2.6 mmol/L should be an ‘operational threshold’, ie, an indication for action but not diagnostic of a disease. Determining the relationship between operational, epidemiological and physiological thresholds for hypoglycemia and abnormal neurological and developmental outcomes would require a prospective, controlled longitudinal study of asymptomatic term neonates.

CONCLUSION

Our study shows a high percentage of SGA infants (26%) presenting with blood glucose levels below the threshold of 2.6 mmol/L. We observed no difference in the incidence of hypoglycemia in newborns with BW between the 10th and fifth percentile compared with those with BW less than the fifth percentile. Long-term neurodevelopmental studies of these asymptomatic infants, along with measures of other energy substrates, are necessary to refine our screening criteria for pathological hypoglycemia in newborns.