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ORIGINAL
Association between early-term birth and hypoglycaemia inlarge-for-gestational-age neonates : A retrospective cohort
study
Makoto Irahara1, 2, 3, Takashi Nagai4, Shunsuke Takeuchi1, Takahiro Tayama1, 2, Mari Nii5, Sachiko Katayama5,
Kana Kasai5, Naoko Doi5, and Osamu Okitsu5
1
Department of Pediatrics, Tsurugi Municipal Handa Hospital, Tokushima, Japan, 2Department of Pediatrics, Tokushima University Hospital,
Tokushima, Japan, 3Allergy center, National Center for Child Health and Development, Tokyo, Japan, 4Department of Pediatrics, Tokushima
Prefectural Hospital, Tokushima, Japan, 5Department of Obstetrics and Gynecology, Tsurugi Municipal Handa Hospital, Tokushima, Japan

Abstract : Background : The effect of early-term birth on the development of hypoglycaemia in large-for-gestational-age (LGA) neonates is yet to be clarified. This study aimed to clarify the association between hypoglycaemia and early-term birth in LGA neonates. Methods : This single-centre retrospective cohort study evaluated
LGA neonates born at term at Tsurugi Municipal Handa Hospital, Japan. Blood glucose levels were measured
immediately and at 1, 2, and 4 hours after birth. The association between early-term birth and hypoglycaemia
was evaluated using logistic regression analysis. The prevalence of severe hypoglycaemia and hypoglycaemia
according to its timing of development was analysed using Fisher’s exact test. Results : In total, 295 neonates
were included. Among them, 113 neonates (38.3%) were born at early term and 91 infants (30.8%) had hypoglycaemia. Logistic regression analysis showed a significant association between early-term birth and hypoglycaemia (adjusted odds ratio [95% confidence interval] : 2.691 [1.597 to 4.535]). However, there was no significant between-group difference among those with severe hypoglycaemia. Conclusions : Among LGA neonates, early-term
birth is positively associated with neonatal hypoglycaemia. This indicates that among LGA neonates, those bornat early term require more careful observation for hypoglycaemia than do those born at later term. J. Med. Invest. 70 : 476-482, August, 2023
Keywords : early-term birth, hypoglycaemia, large for gestational age

INTRODUCTION
Neonatal hypoglycaemia is one of most common metabolic
disorders that require treatment in neonates (1, 2). Although
the definition for neonatal hypoglycaemia is not standardised,
5%–15% of neonates have hypoglycaemia at blood glucose level
cut-offs of 40–45 mg / dL (3, 4). Importantly, neonatal hypoglycaemia is associated with adverse neurodevelopmental outcomes
during early childhood (5, 6). Moreover, it is known to impose along-term economic burden and adversely affect quality of life (1).
Many neonates with hypoglycaemia are asymptomatic or havenon-specific symptoms (7, 8). Therefore, routine measurement ofblood glucose has been recommended as a screening strategy forhigh-risk neonates. Large for gestational age (LGA) is one of therepresentative targets of screening for neonatal hypoglycaemia,
along with preterm birth, small for gestational age, and neonateswith gestational diabetes mellitus (GDM) mothers (4, 9). Approximately 8.1%–45% of LGA neonates have low blood glucose level
during the infantile period (10-13).
Meanwhile, early-term birth is not considered as a target ofscreening for neonatal hypoglycaemia but as its risk factor (2,14). An overlap of risk factors of neonatal hypoglycaemia maylead to a more severe hypoglycemia (11). Moreover, pregnancy
periods are shorter in LGA neonates with hypoglycaemia thanin those without hypoglycemia (12). This indicates that LGA
Received for publication January 25, 2023 ; accepted August 10, 2023.
Address correspondence and reprint requests to Makoto Irahara,
Department of Pediatrics, Tsurugi Municipal Handa Hospital,
Tokushima Prefecture, Japan, Nakayabu-234-1 Handa, Mima,
Tsurugi, Tokushima, 779-4401, Japan and Fax : +81-0883-64-4138.
E-mail : Irahara-m@ncchd.go.jp

neonates who are also born at early term have a higher risk ofhypoglycaemia than those who are either only LGA or born earlyterm. However, the influence of early-term birth on the development of hypoglycaemia in LGA neonates is yet to be clarified.
Understanding the association between early-term birth andthe risk of neonatal hypoglycaemia will be helpful for a more
efficient resource allocation and patient management, especiallyin settings with limited medical equipment for blood glucose
measurement. Thus, this study aimed to clarify the association
between neonatal hypoglycaemia and early-term birth in term
LGA neonates.

METHODS

Study design, setting, and participantsThis retrospective cohort study was conducted in Tsurugi
Municipal Handa Hospital, a single secondary perinatal centre
in Japan that mainly attended to term births and birth from relatively low-risk deliveries. LGA neonates born at term between
November 2013 and October 2021 were evaluated. The inclusion
criteria were genetic Japanese and singleton birth. The exclusion criteria were requirement of intravenous treatment andtransport to tertiary perinatal centre within 4 hours after birth.
Breastfeeding was attempted in all neonates 1 hour before blood
glucose measurement depending on the postpartum condition of
the mother.
This study was approved by the appropriate institutional
review board on Tsurugi municipal Handa hospital (IRB number : 125) and complied with the Helsinki Declaration. The need
for written informed consent was waived owing to retrospective
nature of the study.

The Journal of Medical Investigation Vol. 70 2023

The Journal of Medical Investigation Vol. 70 August 2023

477

Study variables

Statistical analysis

Data, including sex, parity, maternal GDM, maternal overweight, delivery time, mode of delivery, using uterotonic agents,
pH in cord blood (CB), and birth weight, were obtained fromthe institutional medical records. Hypoglycaemia and severe
hypoglycaemia were defined as a blood glucose concentration of< 40 mg / dL and < 25 mg / dL in whole blood, respectively. LGA
was defined as weight ≥ 90th percentile on the Japanese neonatal anthropometric chart (15). Gestational age was determinedbased on the result of the ultrasound examination during earlypregnancy and birth, with 37–38 gestational weeks defined as
early term. The combination of full term (39–40 gestational
weeks), late term (41 gestational week), postterm (42 and latergestation weeks) was defined for the comparison to early termas later term, because we anticipated small number of neonatesborn at late term and postterm. Parity was classified into nulliparous and parous.
Maternal GDM was evaluated based on the result of the 75-g
oral glucose tolerance test and was diagnosed as fasting blood
glucose level of ≥ 92 mg / dL, 1-hour value of ≥ 180 mg dL, and2-hour value of ≥ 153 mg / dL (16). Maternal overweight was
defined as maternal BMI > 30 kg / m2 at the most recent measurement before delivery (17). Prolonged labour and delivery
was defined as a duration of ≥ 30 hours in nulliparous womenand ≥ 15 hours in parous women. Mode of delivery was classified
into caesarean section and normal transvaginal delivery. Useof uterotonic agents was defined as maternal administration ofoxytocin or prostaglandin F2α before delivery. Low pH in CB
was defined as a levels < 7.00 (18). Birth weight was calculated
as percentile based on the Japanese neonatal anthropometricchart (15).

Patient characteristics were compared between neonates bornat early term and at later term. Significant variables were identified based on p values in Fisher’s exact test. The percentiles ofbirth weight and pH in CB were compared between groups using
the Mann-Whitney U test. Items with significant differencesin these analyses were selected as covariates for the logistic
regression analysis. Logistic regression analysis was conducted
to analyse the association between early-term birth and hypoglycaemia by adjusting for covariates (parity and mode of delivery)
selected in the above analysis. In addition, the association ofearly-term birth with severe hypoglycaemia and the prevalenceof hypoglycaemia was analysed according to the timing of hypoglycaemia onset using Fisher’s exact test. Neonates who alreadyhad hypoglycaemia before the timing were excluded in this analysis. The prevalence of severe hypoglycaemia was also comparedusing Fisher’s exact test. Similarly, Fisher’s exact test was used
to compare the prevalence of hypoglycaemia between neonatesborn at 40 weeks of gestation and neonates born at 37–39 weeks
of gestation. All statistical analyses were performed using theStatistical Package for Social Sciences version 24.0 (SPSS, IBM
Corporation, Armonk, NY, USA). P values <0.05 were considered significant.

Measurement of neonatal blood glucose and cord blood pH
For neonates at high risk of hypoglycaemia, the timing of routine of blood glucose measurement was individualised according
to the risk factors (11). For LGA neonates, the blood glucose levelis normally the lowest at approximately the first 3 hours after
birth, and this trajectory is different from other factors of neonatal hypoglycemia (9, 10). Thus, we focused on the result until 4hours after birth. Blood glucose levels at the following four time
points were measured : immediately after birth and 1, 2, and 4
hours after birth. Whole blood was collected from the heel, andblood glucose was measured using Glutestmint portable glucose
meter (Sanwa Chemical Co, Nagoya, Japan) immediately after
blood collection.
Samples for pH measurement in CB were collected by anobstetrician by puncturing the artery of the umbilical cord
immediately after birth. pH values in these samples were measured using the iSTAT-1 (CG4+ cassettes, Abbott Point of Care,
Princeton, NJ, USA).

RESULTS

Patient characteristics
Among the 302 LGA neonates identified, 6 neonates were
given intravenous treatment and 1 neonate was transferred toanother hospital within 4 hours after birth for reasons aside
from hypoglycaemia. Finally, 295 LGA neonates were evaluated(Figure 1). Overall, 113 neonates (38.3%) were born at early term
(18 and 95 neonates were born at 37 and 38 weeks, respectively).
Meanwhile, 182 neonates were born at later term (94, 74, and 14
neonates were born at 39, 40, and 41 weeks, respectively). Seven
neonates (38.9%), 44 neonates (46.3%), 26 neonates (28.6%) and14 neonates (15.9%) were born at 37, 38, 39 and 40 and latergestational weeks had hypoglycaemia, respectively. Overall, 91
neonates (30.8%) were diagnosed with hypoglycaemia (13, 62,
12, and 4 neonates developed hypoglycaemia immediately, 1hour, 2 hours, and 4 hours after birth, respectively) (Table 1). Of

Bias and study size
To minimise bias, all neonates with complete information
were included. Previous studies showed that LGA accounts forapproximately 10% of total births, and hypoglycaemia occurs
in approximately 30% of LGA neonates (10-13). We planned to
conduct logistic regression analysis to evaluate the association
between early term hypoglycaemia and eight candidate covariates. The required sample size was 90 neonates with hypoglycaemia, which was 10 times higher than the number of factors(early term, sex, parity, maternal GDM, maternal overweight,
delivery time, mode of delivery, using uterotonic agents, low pH
in CB) (19).
Figure 1. Patient inclusion flowchart.
LGA ; large for gestational age

M. Irahara, et al. Early-term birth and hypoglycaemia

478

these, seven neonates had severe hypoglycaemia that occurred
1 hour after birth. All neonates with hypoglycaemia, including
those with severe hypoglycaemia, were asymptomatic.

Association between early-term birth and hypoglycaemia in LGA
neonates

Characteristics of early-term infants

Early-term birth was associated with hypoglycaemia in LGA
neonates. Unadjusted logistic regression analysis showed asignificant association between early-term birth and hypoglycaemia (odds ratio (OR) [95% confidence interval (CI)] : 2.920 [1.753
to 4.864], P < 0.001). The association remained in the logistic
regression analysis adjusted by parity classification and delivery
mode (adjusted OR [95% CI] : 2.691 [1.597 to 4.535], P < 0.001)(Table 3).

The rate of early-term birth was significantly higher in neonates with hypoglycaemia than in those without hypoglycaemia(56.0% vs 30.4%, P < 0.001). The rate of first birth was relatively
lower in the hypoglycaemia group than in the no hypoglycaemia
group (41.8% vs 55.9%, P = 0.032). The prevalence of normaltransvaginal delivery was also lower in the hypoglycaemia group(41.8% vs 55.9%, P=0.032). No other factors were significantly
different between groups. Birth weight percentile was not significantly different between the hypoglycaemia and no hypoglycaemia groups (median (first quartile–third quartile) : 95.9%(92.4–98.4%) vs 95.6% (92.8–97.6%), P = 0.347) (Table 2).

Association between hypoglycaemia onset time and severe
hypoglycaemia
Treatment for hypoglycaemia depends on the timing of
its development and severity. Therefore, we investigated theTable 1. Patient characteristics (N = 295)
Characteristics
Sex (male), N (%)

161 (54.6)

Parity (first delivery), N (%)

152 (51.5)

GDM (yes), N (%)

14 (4.7)

Maternal BMI (overweight*), N (%)

70 (23.7)

Duration of labor (prolonged delivery), N (%)

14 (4.7)

Gestational age (weeks)37

18 (6.1)

38

95 (32.2)

39

94 (31.9)40

74 (25.1)

41

14 (4.7)

Early term (yes), N (%)

113 (38.3)

Mode of delivery (vaginal), N (%)

224 (75.9)

Use of uterotonic agents (yes), N (%)

149 (50.5)

pH in CB (percentile), median (IQR)

7.27 (7.24–7.31)

Low pH in CB† (yes), N (%)
Weight percentile (percentile), median (IQR)
Hypoglycaemia‡ (yes), N (%)

1 (0.4)95.7 (92.7–98.1)
91 (30.8)

Observational time
Immediately after birth

13 (4.4)

1 hour after birth

62 (21.0)

2 hours after birth

12 (4.1)

4 hours after birth

4 (1.3)

Gestational age
37 weeks

7 (38.9)

38 weeks

44 (46.3)

39 weeks

26 (28.6)

40 weeks and later

14 (15.9)

Severe hypoglycaemia§

7 (2.4)*Maternal overweight : BMI > 30 kg / m2 at immediately before delivery†

Low pH in CB : pH < 7.000
Hypoglycaemia : blood glucose level < 40 mg / dL
Severe hypoglycaemia : blood glucose < 25 mg / dL
Abbreviations : BMI : body mass index ; CB : cord blood ; GDM : gestational diabetes
mellitus ; IQR : interquartile range

‡
§

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The Journal of Medical Investigation Vol. 70 August 2023
association of hypoglycaemia onset time with severe hypoglycaemia and early-term birth. The prevalence of hypoglycaemia
immediately, 1 hour, and 4 hours after birth were significantly
higher in the early term group than in the later term group(8.0% vs 2.2%, P = 0.037 ; 31.7% vs 16.3%, P = 0.004 ; and 6.1% vs
0.0%, P = 0.010, respectively). Meanwhile, there was no significant between-group difference for the prevalence at 2 hours after
birth (7.0% vs 4.7%, P = 0.530). The prevalence of severe hypoglycaemia was also not significantly between the two groups (1.8%
vs 2.7%, P = 0.712).

Subgroup analyses

lower in neonates born at ≥ 40 weeks than in those born at 37, 38,
or 39 weeks (≥ 40 weeks vs 37 weeks : 8.9% vs 45.5%, P = 0.008 ; vs38 weeks : 8.9% vs 40.5%, P < 0.001 ; vs 39 weeks : 8.9% vs 25.6%,
P = 0.031). In the second or later birth subgroup, the prevalence of
hypoglycaemia was lower in neonates born at ≥ 40 weeks than inthose born at 38 weeks (28.1% vs 50. 9%, P = 0.045). In subgroup
analysis by mode of delivery, in both the caesarean section andnormal delivery subgroups, the prevalence of hypoglycaemia
was lower among those born ≥ 40 weeks than among those bornat 38 weeks (16.2% vs 44.6%, P = 0.001 for the caesarean section
subgroup and 14.3% vs 48.7%, P = 0.029 for the normal delivery
subgroup) (Figure 2).

In the first birth subgroup, the prevalence of hypoglycaemia was

Table 2. Patient characteristics by presence of hypoglycaemia
Hypoglycaemia

Items

P-values

Yes (91)

No (204)

Early-term birth, N (%)

51 (56.0)

62 (30.4)< 0.001

Sex (male), N (%)

50 (54.9)

111 (54.4)> 0.999

Parity (first delivery), N (%)

38 (41.8)

114 (55.9)

0.032

GDM, N (%)

5 (5.5)9 (4.4)

0.777

Maternal overweight*, N (%)

24 (26.4)

46 (22.5)

0.554

Prolonged delivery, N (%)

3 (3.3)

11 (5.4)

0.561

Mode of delivery (vaginal), N (%)

61 (67.0)

163 (79.9)

0.019

Use of uterotonic agents, N (%)

44 (48.4)

105 (51.5)

0.705

Low pH in CB†, N (%)

0 (0.0)1 (0.5)> 0.999

pH in CB, median (IQR)

7.283(7.243–7.318)

7.266(7.236–7.305)

0.135

Weight percentile (percentile), median (IQR)

95.9(92.4–98.4)

95.6(92.8–97.6)

0.347*Maternal overweight : BMI > 30 kg / m2 at immediately before delivery†

Low pH in CB : pH < 7.000
Comparisons in weight percentile and pH in CB between the early term and later term groups are conducted using Mann-Whitney U test. Comparisons in other items are conducted using Fisher’s exact test.
P values < 0.050 are considered statistically significant.
Abbreviations : CB : cord blood ; GDM : gestational diabetes mellitus ; IQR : interquartile range

Table 3. Logistic regression analysis for factors associated with hypoglycaemia
Items
Gestational age(Early term)

Unadjusted
OR (95% CI)
2.920(1.753 to 4.864)

Adjusted
P value

OR (95% CI)

P value< 0.001

2.691(1.597 to 4.535)< 0.001

Odds ratios and P values are calculated using logistic regression analysis. Bold numbers indicate statisticalsignificance at P < 0.050.
These analyses are adjusted by parity and mode of delivery.
Abbreviations : CI : confidence interval ; OR : odds ratio

M. Irahara, et al. Early-term birth and hypoglycaemia

480

Figure 2. Associations between each gestational age and hypoglycaemia by subgroup of parity classification (firstbirth and second or higher birth) and mode of delivery (transvaginal and caesarean section). A : First birth subgroup.
B : Second or higher birth subgroup. C : Transvaginal delivery subgroup. D : Caesarean section delivery subgroup.
The prevalence of hypoglycaemia is compared between neonates born at 40 weeks and neonates born at 37 weeks,
38 weeks, and 39 weeks using Fisher’s exact tests. Black bars and grey bars indicate the number of neonates withhypoglycaemia and without hypoglycaemia, respectively. P < .05 is considered significant.

DISCUSSION
This study found that early-term birth was positively associated with neonatal hypoglycaemia in LGA neonates. In addition,
hypoglycaemia occurring immediately, 1 hour, and 4 hours after
birth was positively associated with early-term birth. Meanwhile, there was no association between early-term birth andsevere hypoglycaemia. In subgroup analyses by parity classification (first and second or higher birth) and mode of delivery(transvaginal delivery and caesarean section), the prevalence of
hypoglycaemia was relatively higher in neonates born at earlyterm than in neonates born at later term.
Insulin is mainly involved in decreasing blood glucose levels ; accordingly, high insulin levels for stored glycogen is a maincause of hypoglycaemia. LGA neonates have relatively higher
levels of insulin in CB than do non-LGA neonates (20, 21). One
study showed that insulin levels in CB were higher in neonatesborn at early term than in those born at later term (22). Thishigh insulin level after birth might explain the high rate of hypoglycaemia in early-term birth and LGA neonates.
Meanwhile, the prevalence of hypoglycaemia at 2 hours after
birth was not significantly different between the early term andlater term groups. As stated above, early-term birth was associated with hypoglycaemia (i.e. blood glucose levels < 40 mg / dL),but not with severe hypoglycaemia (i.e. blood glucose levels< 25 mg / dL). After birth, regardless of term, low blood glucose
induces secretion of hormones that increase blood glucose (e.g.
epinephrine and glucagon) (23-25). Therefore, the decrease inblood glucose levels induced by high insulin levels might also
return to normal and maintain blood glucose without severe
hypoglycaemia by secretion of these hormones.
In the current study, the prevalence of hypoglycaemia occurring 4 hours after birth was significantly different between theearly term and later term groups. Storage of glycogen, which isused to raise blood glucose levels by epinephrine and glucagon, islower in neonates born at early term than in those born at laterterm (2, 14). A previous study showed that unlike in adults, innormal neonates, even low blood glucose does not suppress insulin secretion within 2 hours of age (23). Moreover, another study
showed a lower breastfeeding rate within 1 hour after birth ininfants born at early term than in those born at later term (26).
These complex effects might lead to a significant difference inthe prevalence of hypoglycaemia at 4 hours after birth between
neonates born at early term and those born at later term.
Harris et al. reported that among healthy neonates, thoseborn at early term have a lower mean blood glucose level thanthose born at later term (14). They showed that neonates bornat early term had approximately 3 times more hypoglycaemia

The Journal of Medical Investigation Vol. 70 August 2023
episodes (blood glucose level < 47 mg / dL) than did those born atlater term. Although this study showed similar odds ratios andsuggested that this result might be applicable even to neonateswith conditions other than LGA, there was a difference in observation term and the definition of blood glucose level between ourstudy and that study. The association between early-term birthand hypoglycaemia in neonatal conditions other than LGA, andthe effect of LGA in neonates with early-term birth needs to beclarified in the future.
Early-term birth might have a confounding effect on theassociation between hypoglycaemia and neurodevelopment. As
mentioned above, hypoglycaemia is negatively associated withneurodevelopment (5, 6, 27). Early-term birth is also negatively
associated with neurodevelopment in children (28-30). Although
we could not show whether hypoglycaemia influences the association between early-term birth and neurodevelopment, futurestudies should consider early-term birth as a covariate wheninvestigating the association between neurodevelopment andhypoglycaemia.
This study has some limitations. First, this was a single-centre retrospective study, and thus, inherent biases (e.g. in gestational age at birth, indication for caesarean section, and use ofuterotonic agents by obstetricians) could not be avoided. However, we attempted to reduce these biases by using multivariate
analysis and increasing the number of obstetricians involved inthis study through a long study period. Second, our data werelimited to data until 4 hours after birth. With respect to the trajectory of blood glucose after birth in LGA, hypoglycaemia wasreported to occur at an average of 2.9 hours (9, 10). This might
indicate that similar results would be observed in studies with alonger period. Finally, hypoglycaemia was defined as blood glucose levels > 40 mg / mL. The most accurate blood glucose level for
defining hypoglycaemia is still debated. As mentioned above, thedefinition of blood glucose may alter the results of the association
between early-term birth and hypoglycaemia. Future studies
using different blood glucose levels for defining hypoglycaemia
are needed.
In conclusion, early-term birth is positively associated withneonatal hypoglycaemia in LGA neonates. Thus, neonates bornat early term require more careful observation for hypoglycaemia than those born at later term. Although further studies witha concise definition of blood glucose levels for hypoglycaemia are
still needed, the current findings support that early-term birth is
an important risk factor for hypoglycaemia.

FUNDING
This research received no specific grant from any funding
agency in the public, commercial or not-for-profit sectors.

CONFLICT OF INTERESTS-DISCLOSURE
All authors have no interest-disclosure.

ACKNOWLEDGMENTS
We thank the children and their families for participatingin this study and all individuals involved in data collection. We
would like to thank Editage (www.editage.com) for English language editing.

481

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