Association of maternal nutrition with transient neonatal hyperinsulinism
Association of maternal nutrition with transient neonatal hyperinsulinism
Mathilde Louvigne 0 1
Stephanie Rouleau 0 1
Emmanuelle Caldagues 0 2
Isabelle Souto 0
Yanis Montcho 0
Audrey Migraine Bouvagnet 0
Olivier Baud 0
Jean Claude Carel 0
Geraldine Gascoin 0
Regis Coutant 0 1
0 Editor: Umberto Simeoni, Centre Hospitalier Universitaire Vaudois , FRANCE
1 Service de DiabeÂ tologie et Endocrinologie PeÂ diatrique, Departement de PeÂdiatrie, et Centre de Reference des Maladies Endocriniennes Rares de la Thyroïde et de l'Hypophyse, Centre Hospitalier Universitaire d'Angers, Angers, France, 2 Service de PeÂ diatrie, Centre Hospitalier du Mans, Le Mans, France, 3 Service de R eÂanimation et MeÂ decine NeÂ onatale, Centre Hospitalier Universitaire d'Angers , Angers , France
2 Service de DiabeÂ tologie et Endocrinologie PeÂ diatrique, Service de PeÂdiatrie, Centre Hospitalier Universitaire de Nantes, Nantes, France, 5 Service de R eÂanimation et MeÂ decine NeÂ onatale, Centre Hospitalier du Mans, Le Mans, France, 6 Service de N eÂonatologie, Centre Hospitalier Universitaire de Nantes, Nantes, France, 7 Service de R eÂanimation et PeÂdiatrie N eÂonatale, HoÃ pital Universitaire Robert- Debr eÂ , Paris , France , 8 Service d'Endocrinologie Diab eÂtologie PeÂ diatrique et Centre de R eÂfeÂ rence des Maladies Endocriniennes Rares de la Croissance, H oÃpital Universitaire Robert-DebreÂ , UniversiteÂ Paris Diderot, Sorbonne Paris Cit eÂ, AP-HP , Paris , France
Data Availability Statement: All data underlying
the findings of this study are within the paper and
its Supporting Information file.
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
transient neonatal hyperinsulinism (HI).
Design and setting
2008 and 2015.
Sixty-seven mothers of neonates diagnosed with transient hyperinsulinism and 113 mothers
of controls were included. The screening for hyperinsulinemic hypoglycemia in neonates
was performed because of clinical symptoms suggestive of hypoglycemia or in the presence
of conventional risk factors (small-for-gestational-age, prematurity, anoxo-ischemia,
hypothermia, macrosomia, gestational diabetes). Hyperinsulinemic hypoglycemia was confirmed
in the HI neonates and ruled out in the controls. This allowed for comparing maternal
nutrition in cases and controls in a context of similar risk factors. One to 2 mothers of control
neonates were included per case, and a food frequency questionnaire was addressed to the
mothers between day 5 and day 10 after the birth of their newborn.
Crude odds ratio showed that maternal weight gain, abnormal fetal rate, C-section, gender,
consumption of fresh cooked vegetables, fresh fruits and fruit juices, low fat diary products,
light fat products, and daily bread were significantly associated with hyperinsulinism.
Maternal body mass index, hypertension, gestational diabetes, birth weight percentile, gestational
age and 5-minute Apgar score were not related to HI. In a multiple backward logistic
regression model, consumption of fresh cooked vegetable 1/day (OR = 0.33 [0.14±0.77]) and
light-fat products 1/week (OR = 0.24 [0.08±0.71]) was protective against hyperinsulinism,
whereas gestational weight gain >20 kg (OR = 9.5 [2.0±45.5]) and between 15±20 kg (OR =
4.0 [1.2±14.0]), abnormal fetal heart rate (OR = 4.4 [1.6±12.0]), and C-section (OR = 3.4
[1.3±8.9]) were risk factors.
A diet rich in fresh cooked vegetable and reduced in fat, together with the avoidance of a
high gestational weight gain may be protective against transient neonatal hyperinsulinism.
Neonatal hyperinsulinism (HI) is the first cause of recurrent neonatal hypoglycemia [
severe persistent form is most often of genetic etiology [
]. The incidence of minor and
transient forms has been estimated to be 1/12000 births, four times more frequent than severe
persistent forms, and this incidence is believed to be underestimated [
]. They usually recover
spontaneously in several weeks [
The severity of neonatal HI results from neurological sequelae caused by neuroglycopenia
and the associated suppression of lactates or ketone bodies, which cannot be used as alternative
fuel to preserve neuronal function in the absence of glucose [
]. Indeed, neurological handicap
has been observed in children with neonatal HI [
], with motor, language, and cognitive delay
in 26 to 44% of cases, but also visual anomalies, convulsions or infantile spasms [
the outcome of transient HI was usually considered as benign compared to that of persistent
] some studies found that neurological consequences were similar in hypoglycemia due
to transient and persistent neonatal HI [
Because of the potential poor neurologic outcome, the identification of factors likely to be
involved in the development of transient neonatal HI is of crucial importance. Conventional
risk factors identified in transient forms of HI are prematurity, small weight for gestational age
(SGA), antenatal and perinatal anoxo-ischemia, macrosomia, and gestational diabetes[
Transient HI is believed to result either from antenatal and/or perinatal stress, or from excess
transplacental transfer of nutrients (such as glucose) with reactive fetal insulin overproduction
]. More recently, maternal obesity, excessive maternal weight gain during pregnancy, and
high carbohydrate intake have been associated with neonatal hypoglycemia, likely due to
hyperinsulinism [9±11]. Several environmental or nutritional factors that are known to cause
an increase in insulin production in the exposed subjects can also cross the placenta or be
delivered to the fetus through a more complex placental metabolism. For instance, sweeteners
or bisphenol A (a xeno-estrogen found in plastic bottles, microwavable ready meals and
canned food and drinks) were all able to increase insulin secretion in animal models or in
Overall, these studies suggested that maternal nutrition could be predictive of or protective
against transient neonatal HI. To explore this hypothesis, we collected a food frequency
questionnaire relative to dietary habits during pregnancy from 67 mothers of neonates diagnosed
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with transient neonatal HI, and compared to 113 mothers from neonates in whom HI was
screened because of the presence of clinical symptoms suggestive of hypoglycemia or of
conventional risk factors and excluded.
This multicenter, case-control study was conducted in four Obstetrics and Neonatology
Departments at Angers University Hospital, Nantes University Hospital, Robert DebreÂ (Paris)
University Hospital, and Le Mans General Hospital. All neonates were recruited because they
had risk factors for hypoglycemia or presented clinical signs suggestive of hypoglycemia and
all had blood glucose screening (see below). One hundred and twenty-three neonates less than
28 days-old were hospitalized between 01/01/2008 and 09/30/2015 with a diagnosis of
hyperinsulinemic hypoglycemia. Subjects with monogenic (mutation in genes implicated in insulin
secretion) or syndromic (Beckwith-Wiedemann syndrome) hyperinsulinism were excluded.
For one mother of a neonate with hyperinsulinism, 1 to 2 mothers of neonates with no
hypoglycemia were recruited.
Detection of neonates with hyperinsulinemic hypoglycemia and selection
Capillary blood glucose monitoring was performed in all neonates in the presence of clinical
symptoms suggestive of hypoglycemia (irritability, tremulation, hypotonia, lethargy, apnea,
tachypnea, poor feeding, hypothermia, or seizures), or in the presence of identified risk factors
for hyperinsulinemic hypoglycemia (prematurity, small-for-gestational-age, antenatal or
perinatal anoxo-ischemia, hypothermia, macrosomia, gestational diabetes). The capillary blood
glucose monitoring protocol included a first measurement at clinical symptoms, or after the
first feed at 4 hours of life, then before the second and third feed and finally every 12 hours. If
capillary blood glucose was > 50 mg/dL (2.7 mmol/L) between 4 and 72 hours of life or > 60
mg/dL (3.3 mmol/L) thereafter, normoglycemia was retained and glucose monitoring stopped
after the 5th capillary blood glucose test. If capillary blood glucose was below these thresholds,
a plasma blood glucose sample was taken and intensified capillary blood glucose monitoring
undertaken, before every feed or at clinical signs. Hypoglycemia was defined by plasma glucose
<30 mg/dL (1.7 mmol/L) between 4 and 48 hours of life which persisted after 48 hours or by
plasma glucose <45 mg/dL (2.5 mmol/L) after 48 hours of life, as these two thresholds have
been associated with later adverse cognitive outcomes [
7, 15, 16, 17
]. To avoid induced
hyperinsulinism, the treatment of hypoglycemia was always initially conservative, and consisted in
offering breast feeding more often under capillary blood glucose monitoring (to maintain
capillary blood glucose > 30 mg/dl before 48 hours, and > 45 mg/dl thereafter), or offering
formula for premature babies (which are slightly enriched in carbohydrates in comparison with
classical formula). Neonatal HI was defined as plasma insulin concentration > 2 mIU/L during
hypoglycemia and daily glucose needs > 10 mg/kg/min before the introduction of any specific
]. When performed, a glucagon test (1 mg IM or IV) showing a glucose
response > 30 mg/dl was considered indicative of hyperinsulinism [
hyperinsulinism was retained when daily glucose needs > 10 mg/kg/min and/or diazoxide treatment
was necessary for at least 5 days, as the duration likely allowed for ruling out of transitional
hypoglycemia, and could be stopped before 3 months [
]. Children from twin pregnancy
and with gestational age < 34 weeks were not included. Control neonates had capillary blood
glucose measurements in the same conditions as HI neonates, and hypoglycemia was ruled
out. No venous puncture for plasma glucose and insulin measurements was performed in the
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The mothers were contacted by phone or directly between day 5 and day 10 following birth,
and were asked to answer a questionnaire relative to food- and drink- frequency during
pregnancy. The questionnaire was compiled from the MONA LISA-NUT study questionnaire and
the ISIS-DIAB questionnaire [
], both validated in French. It was short and qualitative to
quickly assess the usual intake of French women during pregnancy. It contained 50 main
questions, about foods commonly consumed in France. Items were grouped into the following
macronutrient categories: starches (rice, bread, pasta, potatoes, etc.), animal-derived proteins
(meat, fish, sea food, eggs, cured meat products such as ham and sausages), vegetables and
fruits (fresh cooked vegetable, fresh fruits or fresh fruit juices, fruit juices with added sugar,
100% fruit juices, canned vegetable and canned fruits), dairy product (regular or low-fat), fast
foods (pizza, hamburgers), microwavable ready meal, fat product (regular or light), sweets
(sweet desserts, candies, chocolate bar, chocolate spread), sweeteners, soft drinks (regular, diet,
canned), water (tap or bottled water), coffee and alcohol. Food consumption was divided into
5 categories: 1/day; 1/week, 1/month, < 1/month or never. The time taken to fill in the
questionnaire ranged from 10 to 20 minutes.
Maternal and neonatal data were collected in the obstetrical and neonatal medical records.
Total weight gain during pregnancy was recorded (difference between weight at the onset of
labor, measured by the team in the Obstetrics Departments, and self-reported pre-pregnancy
weight), as a reliable estimate of true caloric intake during pregnancy [
]. The mothers were
screened for carbohydrates intolerance or gestational diabetes, as recommended [
From 2007 to 2010, the pregnant women underwent a two-step screening process for
gestational diabetes, as recommended by the American College of Obstetricians and Gynecologysts:
first, a glucose challenge test was performed between 24 and 28 weeks of gestation followed by
an oral glucose tolerance test if necessary . From 2011, French recommendation changed
for a one-step screening process using OGTT (75g) [
]. Mean annual household income,
maternal age at birth, BMI at the onset of pregnancy, total weight gain during pregnancy,
tobacco consumption, gestation number, and method of delivery were recorded. Newborn
birth weight, length and head circumference, gender, 1- and 5-minute Apgar score, and
gestational age (using ultrasonographic criteria from early ultrasound scans) were recorded.
The variables were presented as means ± SD, or medians (25th; 75th percentiles). Comparisons
between subjects were performed using the Student t test or Mann-Whitney U test. For
discrete variables, significance was assessed using the Chi-squared test. The 5 initial categories
were dichotomized at the cutoff closest to the 25th or the 75th percentile of controls, according
to clinical relevance [
]. By doing so, we contrasted the upper (or the lower) quartile with the
combination of the other quartiles. First, we examined the crude association of maternal food
intake and maternal and fetal characteristics with transient congenital HI, and presented the
odds ratio if p < 0.05. Five-minute Apgar score was used in the analyses since it is considered
a better predictor of neonatal outcome as 1-minute Apgar score [
]. To select the best
combination of predictors, we constructed a backward multiple logistic regression model with all
variables significantly related to HI in simple logistic regression. Since our main objective was
to study whether maternal nutrition could be predictive of or protective against transient
neonatal HI, maternal BMI as well as gestational weight gain were kept in the final model. To
compare the estimated to observed likelihood of transient congenital HI, the Hosmer-Lemeshow
goodness-of-fit test was performed. All analyses were performed using the SPSS 19.0 package.
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This study was approved by Angers University Hospital Ethics Committee, and written
informed consent was collected from the parents.
The study flow chart is shown in Fig 1. Data from 67 newborns with transient neonatal HI and
113 controls were analyzed. Twenty-three neonates with HI had a glucagon test (1 mg IM or
IV) showing blood glucose response > 30 mg/dl following hypoglycemia. Thirty-three
children received diazoxide treatment due to persistent hypoglycemia after a mean 11.5 ± 8.3 days,
in order to decrease daily glucose needs. Maternal and neonatal characteristics are provided in
Table 1. Maternal age, BMI, gestation number, gestational diabetes frequency, gestational age,
birth weight percentiles (and percentages of small for gestational age and large for gestational
age neonates), and 1- and 5-minutes Apgar score were similar in the HI and the control
groups. The two groups were different for weight gain during pregnancy, rate of abnormal
fetal heart rate, rate of cesarean section, and gender (p < 0.05).
There were significant differences between HI and control groups in consumption of fresh
cooked vegetables, fresh fruits and fruit juices, low-fat dairy products, light fat-products,
chocolate bar, and bread (S1 Table). The corresponding crude odds ratios for HI are shown in
Table 2. Among maternal and fetal characteristics, maternal weight gain, abnormal fetal heart
rate, C-section, and gender were also related to HI (Table 2).
In a multiple backward logistic regression model including all significant maternal and fetal
characteristics, and all significant dietary factors, consumption of fresh cooked vegetable 1/
day (OR = 0.33 [0.14±0.77]) and light-fat products 1/week (OR = 0.24 [0.08±0.71]) was
protective against HI, whereas gestational weight gain >20 kg (OR = 9.5 [2.0±45.5]) and between
15±20 kg (OR = 4.0 [1.2±14.0]), abnormal fetal heart rate (OR = 4.4 [1.6±12.0]), and C-section
(OR = 3.4 [1.3±8.9]) were risk factors. Maternal body mass index, hypertension, gestational
diabetes, birth weight percentile, gender, gestational age, and 5-minute Apgar score were not
related to HI in the analyses (Table 3).
In this study, we found that mothers of newborns with transient HI compared to controls had
significantly higher gestational weight gain, suggesting a higher caloric intake, and a ªless
health-conscious dietº in comparison to control mothers: they consumed fresh cooked
vegetables and light-fat products significantly less frequently.
We found that light-fat products consumption provided protection from transient neonatal
HI. This association was significant after adjustment for gestational weight gain, suggesting
that it was independent of caloric intake. Fat from usual diet is typically of the saturated type.
Animal studies have shown that the administration of a diet high in fat, especially saturated
fat, during gestation led to increased plasma insulin and glucose levels in mothers, increased
insulin secretion and lower plasma glucose in the pups, and increased plasma glucose and
insulin in later life [
]. In humans, a high fat intake during pregnancy was associated with
increased fasting insulin concentration after adjustment for BMI, however the effects on the
neonates were not evaluated . Our data may indicate that the preferential consumption of
a diet reduced in fat in humans may protect from neonatal HI and hypoglycemia, as opposed
to the effects observed in the offspring of animals fed a high-fat-diet.
We found that fresh cooked vegetable consumption provided protection against neonatal
HI. In humans, lower vegetable fiber intake during pregnancy has been associated with an
increase in plasma glucose and insulin, metabolic changes that were similar to those observed
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Fig 1. Flow chart of the HI and control groups. BMI: body mass indexÐHI: hyperinsulinism.
with a high fat intake [
]. No data were available regarding blood glucose and insulin in their
neonates. No animal study has examined the effect of a diet rich in vegetables in pregnant
mothers and in the pups. Although multiple confounding factors may exist, such as a more
controlled caloric intake or other features of a ªhealth-conscious dietº, fresh cooked vegetable
consumption during pregnancy could provide protection against the development of
hyperinsulinemia in newborns.
6 / 11
In this study, gestational weight gain over 15 kg was a risk factor for transient neonatal HI,
independent of birth weight as well as 5-minute Apgar score. This was in agreement with
studies that have shown that excessive gestational weight gain has been associated with a higher
risk of hypoglycemia [
]. In 2009, the American Institute of Medicine recommended the
optimal gestational weight gain to be 11.5 to 16 kg if maternal BMI was between 19.8 and 26
kg/m2 . Gestational weight gain is considered a reliable index of true caloric intake during
pregnancy, likely better than food questionnaires, as most individuals underreport energy
intake even during pregnancy [
]. Moreover, it has been shown that excessive gestational
weight gain occurred as a result of increased energy intake and not of a decreased energy
expenditure and that this association was independent of BMI before pregnancy . We
therefore believe that the higher gestational weight gain in mothers of HI neonates reflected a
higher caloric intake during pregnancy.
This study has some limitations. Firstly, the definition of transient HI could be questioned
with respect to the so-called physiological transitional hypoglycemia. In transitional neonatal
7 / 11
hypoglycemia, plasma glucose levels are low in the first hours of life and then progressively
increase over 2 days to reach normal ranges [
]. The policy of the Obstetrics and Neonatology
Departments participating in the study was to stabilize plasma glucose during the first
HI: hyperinsulinismÐOR: odds ratio±CI: confidence interval. Light fat products referred to products (used in
cooking, spreads, and dressings) where the fat was lightened. Maternal hypertension, gestational age, 5-minute Apgar
score, and birth weight percentile were not significantly related to HI, and were not entered in the multiple logistic
regression analyses, whereas gender was no longer significant in the backward multiple logistic regression analyses.
Maternal BMI, although non-significant, was forced as an adjusting variable (see methods). All the macronutrients
that were associated (with p < 0.05) with neonatal HI were included in the multiple backward logistic regression
analyses (see methods). The model correctly classified 84% of the subjects. Cox and Snell pseudo R square was 0.32. P
value for Hosmer and Lemeshow goodness of fit was 0.28.
8 / 11
48 hours and to explore hypoglycemia which persisted after 48 hours of life [
]. To avoid
induced hyperinsulinism, the treatment of hypoglycemia was initially conservative, and
consisted in offering breast feeding more often under capillary blood glucose monitoring (to
maintain capillary blood glucose > 30 mg/dl before 48 hours, and > 45 mg/dl thereafter), or
offering formula for premature babies (which are slightly enriched in carbohydrates in
comparison with classical formula). In normal and at-term newborns, lower limits for plasma
glucose have been established as 30 mg/dL after 4 hours and 45 mg/dL after 48 hours of life [
]. Here, we only selected neonates whose hypoglycemia persisted after 48 hours of life and
required treatment for at least 5 days, in order to rule out transitional hypoglycemia. Even if
we cannot ascertain that transitional hypoglycemia was ruled out in all cases, it should be
noted that our study also pointed to conventional factors of transient HI, such as perinatal
stress (abnormal fetal heart rate), and cesarean section [
]. C-section has been shown to
hamper hormonal transition in the neonate and favor hypoglycemia in some studies [
the reliability of the food frequency questionnaires may be brought into question .
Nevertheless the differences in food frequencies observed in this study were consistent, highlighting
that mothers of newborns with transient HI ate less frequently a ªhealth-conscious dietº during
pregnancy. To reinforce these results our two populations were comparable for maternal BMI
at the onset of pregnancy, maternal age, gestation number, gestational age, gestational diabetes
and birth weight percentile, and the regression analyses were adjusted to maternal weight gain
during pregnancy and BMI. Finally, mean annual household income was similar between the
2 groups, and in the range of the mean French household income [
In conclusion, our findings could reinforce the recommendations for optimal weight gain
during pregnancy and also put forward some recommendations on macronutrient intake in
order to reduce the risk of transient neonatal HI.
S1 Table. Frequency of food and drinks consumption in the HI and control groups.
S1 File. Excel data set.
Conceptualization: Mathilde Louvigne, Stephanie Rouleau, Olivier Baud, Geraldine Gascoin,
Data curation: Mathilde Louvigne, Emmanuelle Caldagues, Isabelle Souto, Yanis Montcho,
Audrey Migraine Bouvagnet, Olivier Baud, Jean Claude Carel, Geraldine Gascoin, Regis
Formal analysis: Mathilde Louvigne, Geraldine Gascoin, Regis Coutant.
Investigation: Stephanie Rouleau, Emmanuelle Caldagues, Isabelle Souto, Yanis Montcho,
Audrey Migraine Bouvagnet, Olivier Baud, Jean Claude Carel, Regis Coutant.
Methodology: Stephanie Rouleau, Geraldine Gascoin, Regis Coutant.
Project administration: Regis Coutant.
Supervision: Jean Claude Carel, Geraldine Gascoin, Regis Coutant.
9 / 11
Validation: Emmanuelle Caldagues, Yanis Montcho, Audrey Migraine Bouvagnet, Olivier
Baud, Regis Coutant.
Writing ± original draft: Mathilde Louvigne, Stephanie Rouleau, Isabelle Souto, Olivier Baud,
Jean Claude Carel, Geraldine Gascoin, Regis Coutant.
10 / 11
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