SMFM Papers ajog.

org

Prenatal exposure to gestational diabetes mellitus as an

independent risk factor for long-term neuropsychiatric
morbidity of the offspring
Kira Nahum Sacks, BMedSc; Michael Friger, PhD; Ilana Shoham-Vardi, PhD; Hanaa Abokaf, MD;
Efrat Spiegel, MD; Ruslan Sergienko, MA; Daniella Landau, MD, MPH; Eyal Sheiner, MD, PhD

BACKGROUND: The reported rates of gestational diabetes mellitus
are constantly escalating and little is known about long-term complications
in the offspring. Evidence from the field of epigenetics strongly advocates
the need for research on the neuropsychiatric complications in offspring
prenatally exposed to gestational diabetes mellitus.
OBJECTIVE: We sought to assess whether in utero exposure to
gestational diabetes mellitus increases the risk of long-term neuropsy-
chiatric morbidity in the offspring.
STUDY DESIGN: A population-based cohort study compared the
incidence of hospitalizations due to neuropsychiatric disease between
singletons exposed and unexposed to gestational diabetes mellitus. De-
liveries occurred in the years 1991 through 2014 in a regional tertiary
medical center. Perinatal deaths, multiple gestations, mothers with pre-
gestational diabetes or lack of prenatal care, and children with congenital
malformations were excluded from the study. A multivariate generalized
estimating equation logistic regression model analysis was used to control
for confounders and for maternal clusters.
RESULTS: During the study period 231,271 deliveries met the in-
clusion criteria; 5.4% of the births were to mothers diagnosed with
gestational diabetes mellitus (n ¼ 12,642), of these 4.3% had gesta-
tional diabetes type A1 (n ¼ 10,076) and 1.1% had gestational diabetes
type A2 (n ¼ 2566). During the follow-up period, a significant linear
association was noted between the severity of the gestational diabetes
(no gestational diabetes, gestational diabetes mellitus A1, gestational
diabetes mellitus A2) and neuropsychiatric disease of the offspring
(1.02% vs 1.36% vs 1.68%, respectively, P < .001). A Kaplan-Meier
curve demonstrated that children born to women with gestational dia-
betes mellitus had higher cumulative incidence of neuropsychiatric
morbidity. Using a generalized estimating equation multivariable logistic
regression model, controlling for time-to-event, maternal age, gesta-
tional age at delivery, maternal obesity, maternal preeclampsia and
fertility treatments, maternal gestational diabetes mellitus was found to
be an independent risk factor for long-term neuropsychiatric disease of
the offspring (gestational diabetes mellitus A1 [adjusted odds ratio, 1.83;
95% confidence interval, 1.53e2.19] and gestational diabetes mellitus
A2 [adjusted odds ratio, 1.64; 95% confidence interval, 1.18e2.27]).
Within the limits of our database, our findings also point to a possible
association between in utero exposure to gestational diabetes mellitus
and autistic spectrum disorder of the offspring (adjusted odds ratio,
4.44; 95% confidence interval, 1.55e12.69), which was found signif-
icant also after controlling for time-to-event, maternal age, gestational
age at delivery, and offspring weight at birth.
CONCLUSION: Exposure to maternal gestational diabetes mellitus is
an independent risk factor for long-term neuropsychiatric morbidity in the
offspring.
Key words: autistic disorder, gestational diabetes mellitus, long-term
effects, neuropsychiatric disorders, offspring, prenatal exposure

Introduction such as macrosomia, shoulder dystocia, to pre-GDM. Some studies have

The reported rates of gestational diabetes
mellitus (GDM), defined as glucose
intolerance that begins or is first recog-
nized during pregnancy,1 are constantly
escalating. GDM occurs in approxi-
mately 7% of pregnancies and this
number is expected to double due to the
increasing prevalence of obesity and new
diagnostic criteria.2,3
Most of the current literature has
addressed adverse pregnancy outcomes
Cite this article as: Nahum Sacks K, Friger M, Shoham-
Vardi I, et al. Prenatal exposure to gestational diabetes
mellitus as an independent risk factor for long-term
neuropsychiatric morbidity of the offspring. Am J Obstet
Gynecol 2016;215:380.e1-7.
0002-9378/$36.00
ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.03.030
and preeclampsia,4 and short-term
neonatal complications such as hypo-
glycemia, hyperbilirubinemia, and res-
piratory distress syndrome.5,6 Scarce
information exists regarding long-term
complications of the offspring. Recent
studies have shown that in utero expo-
sure to GDM is associated with a higher
blood pressure and a predisposition
to obesity and metabolic syndrome.7,8
Data regarding other long-term com-
plications such as neuropsychiatric
morbidity are not well established, and
evidence from the field of epigenetics
strongly advocates the need for such
research.9-13
In contrast to the relative lack of in-
formation on long-term outcomes of
GDM, more is known about long-term
morbidity in children exposed in utero
addressed glycemic regulation or lipid
metabolism as a common pathology in
both GDM and pregestational diabetes.
Two such studies found significantly
lower intelligence quotient and worse
motor proficiency in children whose
mothers showed higher levels of lipid
metabolism.14,15 These studies suggest
an association between neuropsychiatric
morbidity and in utero exposure to any
type of diabetes.
Although cohort studies have shown
evidence of this associations between
neuropsychiatric morbidity and
maternal diabetes,16-19 many of these
studies lacked details regarding GDM
exposure. The objective of the present
population-based study is to investigate
whether in utero exposure to GDM is an
independent risk factor for long-term

380.e1 American Journal of Obstetrics & Gynecology SEPTEMBER 2016

ajog.org SMFM Papers

1991 through 2014 and their offspring.

TABLE 1
Perinatal deaths, multiple gestations,
Cohort characteristics by exposure to maternal gestational diabetes mellitus
mothers with pregestational diabetes or
No GDM GDM A1 GDM A2 lack of prenatal care, and children with
Characteristics n ¼ 218,629 n ¼ 10,076 n ¼ 2566 P valuea congenital malformations were excluded
Maternal age, y, mean  SD 27.93  6 32.16  6 33.82  6 <.001 from the study.
Birth order, % <.001
Study design
1 23.9 20.7 12.9 We conducted a population-based
2e4 51.4 44.7 42.1 cohort study. The primary exposure
5 24.7 34.5 45.0 was defined as in utero exposure to
either GDM A1, defined as GDM
Gender of offspring, % <.001
controlled by diet and exercise, or GDM
Male 51.1 52.8 52.5 A2, defined as GDM requiring insulin or
Female 48.9 47.2 47.5 oral hypoglycemic agents.21 Children
Gestational age at birth, 39.09  2 38.75  2 37.6  2 <.001 who were not exposed prenatally to
wk, mean  SD GDM comprised the comparison group.
Maternal obesity, % 1.0 1.1 3.7 <.001 The main outcome was defined as
neuropsychiatric morbidity of the
Obesity of offspring, % 0.2 0.5 0.8 <.001 offspring that was documented in the
GDM, gestational diabetes mellitus. hospitalization records. All encounters
a
Data evaluated with Pearson c2 test. with the hospital were analyzed so that
Nahum Sacks et al. GDM and long-term neuropsychiatric morbidity in offspring. Am J Obstet Gynecol 2016.
multiple neuropsychiatric diagnoses
could be given to a single child. The date
neuropsychiatric morbidity in the region of Israel, which serves the entire of the first hospitalization for any single
offspring. The contribution of the population in this region of Israel. Thus, cause was used to calculate time-to-
current study is its specific focus on the study is based on a nonselective event.
GDM, which is a far more common population data. The institutional review Neuropsychiatric morbidity was
in utero exposure than pregestational board (in accordance with the Declara- defined as autistic spectrum disorder
diabetes.20 tion of Helsinki) approved the study (ASD), disorders of eating, cerebral
(no. SOR-0236-13 approved November palsy (CP), obstructive sleep apnea
Materials and Methods 2013). (OSA), epilepsy, or infantile spasms
Setting (Supplemental Table 1). Autism spec-
The study was conducted at the Soroka Study population trum disorder, previously known as the
University Medical Center, the sole The study population included all pa- pervasive developmental disorders, in-
hospital of the Negev, the Southern tients who delivered between the years cludes a group of neurodevelopmental
syndromes characterized by a wide
range of impairments in social
TABLE 2 communication and restricted and re-
Incidence rates for disease-specific hospitalization petitive behaviors.22
These neuropsychiatric morbidities
Cohorta were chosen because they cover both a
No GDM GDM A1 GDM A2 wide range of clinical presentation and a
Neuropsychiatric morbidity n ¼ 218,629 n ¼ 10,076 n ¼ 2566 P valueb wide range of topographic locations in
Autistic spectrum disorders, n ¼ 32 27 (0.01) 3 (0.02) 2 (0.07) .007 the brain.23-25 Most importantly, these
conditions were selected due to the as-
Eating disorders, n ¼ 486 437 (0.19) 42 (0.42) 7 (0.27) <.001
sociations that have already been found
Obstructive sleep apnea, n ¼ 1347 1259 (0.58) 60 (0.60) 28 (1.09) .003 between neuropsychiatric conditions
Epilepsy or infantile seizures, n ¼ 431 399 (0.18) 28 (0.27) 4 (0.16) .089 and in utero exposure to GDM.16,17,26
Cerebral palsy, n ¼ 138 130 (0.06) 6 (0.06) 2 (0.08) .930 Data were collected from 2 databases
that were cross-linked and merged: the
Total neuropsychiatric hospitalization, 2228 (1.02) 138 (1.36) 43 (1.68) <.001
n ¼ 2409 computerized perinatal database and the
computerized hospitalization database
GDM, gestational diabetes mellitus.
of the Soroka University Medical
a
Data are no. (%) unless otherwise indicated; b Data evaluated with c2 test for trends.
Nahum Sacks et al. GDM and long-term neuropsychiatric morbidity in offspring. Am J Obstet Gynecol 2016. Center. The perinatal database consists
of information recorded directly after

SEPTEMBER 2016 American Journal of Obstetrics & Gynecology 380.e2

SMFM Papers
FIGURE
Cumulative incidence of neuropsychiatric hospitalizations according to
prenatal GDM exposure
Kaplan-Meier curve of cumulative (Cum) incidence of neuropsychiatric hospitalizations in those
exposed vs unexposed to maternal gestational diabetes mellitus (GDM).
Nahum Sacks et al. GDM and long-term neuropsychiatric morbidity in offspring. Am J Obstet Gynecol 2016.
delivery by an obstetrician. Skilled
medical secretaries routinely review the
information before entering it into the
database. The hospitalization database
includes demographic information and
International Classification of Diseases,
Ninth Revision codes for all medical di-
agnoses made during hospitalization.
Statistical analysis
Statistical analysis was performed with
software (SPSS, Version 21; IBM Corp,
Armonk, NY). Statistical significance
was calculated with the c2 test for trends
(the linear-by-linear association test).
Kaplan-Meier survival curve was used to
compare cumulative incidence of
neuropsychiatric morbidity. Multivar-
iate generalized estimating equation lo-
gistic regression model analysis was used
to control for confounders and for
maternal clusters. A probability value of
<.05 was considered statistically
significant.
380.e3 American Journal of Obstetrics & Gynecology SEPTEMBER 2016
Results
During the study period the births of
320,875 children were documented. Af-
ter excluding perinatal deaths (n ¼
2491), multiple gestations (n ¼ 23,797),
pregestational diabetes (n ¼ 12,889),
lack of prenatal care (n ¼ 22,926), and
congenital malformations (n ¼ 27,501),
the remaining 231,271 deliveries were
included in our analysis. Of the 231,271
deliveries, 5.4% of the births were to
mothers diagnosed with GDM (n ¼
12,642), of whom 4.3% had GDM A1
(n ¼ 10,076) and 1.1% had GDM A2
(n ¼ 2566).
Table 1 presents a comparison be-
tween the clinical characteristics of
pregnancies with and without GDM.
Pregnancies in the GDM groups were in
significantly older mothers and births in
the GDM groups were of a higher birth
order than births in the group without
GDM. The incidence rate of obesity
among mothers and among children was
ajog.org
significantly higher in the GDM groups.
Of these variables, maternal age, parity,
and maternal obesity were found
significantly associated with neuropsy-
chiatric morbidity, in accordance with
the current literature.27-29
A significant linear association was
noted between the severity of the GDM
(no GDM, GDM A1, GDM A2) and
neuropsychiatric disease of the offspring
(1.02% vs 1.36% vs 1.68%, respectively,
P < .001). During the follow-up period,
children exposed in utero to GDM had
significantly higher rates of ASD, eating
disorders, and OSA (Table 2). In contrast
to the linear association seen in ASD and
OSA, eating disorders were most com-
mon in the GDM A1 group rather than
in the GDM A2 group (0.42% vs 0.27%,
respectively).
The Figure presents a Kaplan-Meier
curve for the cumulative incidence of
long-term neuropsychiatric morbidity
in each study groups (no GDM, GDM
A1, GDM A2). Children born to women
with GDM had higher cumulative inci-
dence of neuropsychiatric morbidity and
developed their condition at a younger
age than their unexposed counterparts.
The cumulative incidence was higher for
GDM A2 as compared with GDM A1 and
no GDM.
We used a generalized estimating
equation multivariable logistic regres-
sion model to control for maternal age,
obesity, preeclampsia, fertility treatment,
gestational week, and time-to-event.
Maternal GDM was found to be an in-
dependent risk factor for long-term
neuropsychiatric disease of the
offspring (GDM A1: adjusted odds ratio
[OR], 1.83; 95% confidence interval
[CI], 1.53e2.19, and GDM A2: adjusted
OR, 1.64; 95% CI, 1.18e2.27) (Table 3).
Furthermore, in utero exposure to GDM
was found to be an independent risk
factor for ASD in hospitalized offspring
(adjusted OR, 4.44; 95% CI,
1.55e12.69) (Table 4).
Comment
The major finding of the current study
is that GDM is an independent risk
factor for long-term neuropsychiatric
morbidity in the offspring. The Kaplan-
Meier curve (Figure) demonstrates that
ajog.org SMFM Papers

association. Maternal GDM has been

TABLE 3
Multivariable analysis of neuropsychiatric hospitalizations in offspring
exposed in utero to gestational diabetes mellitus
Variable OR 95% CI
No GDM ref
GDM A1 1.83 1.53e2.19
GDM A2 1.64 1.18e2.27
Obesity 1.59 1.10e2.23
Fertility treatments 0.21 0.14e0.33
Preeclampsia 1.33 1.10e1.60
Maternal age at delivery, y 0.97 0.96e0.98
Time-to-event, d 0.99 0.99e0.99
Gestational age at birth, wk 0.91 0.89e0.93
CI, confidence interval; GDM, gestational diabetes mellitus; OR, odds ratio.
a
Data evaluated by multivariate generalized estimating equation logistic regression model analysis.
Nahum Sacks et al. GDM and long-term neuropsychiatric morbidity in offspring. Am J Obstet Gynecol 2016.
children exposed to GDM who devel- adjusting for potential confounders, only
oped a neuropsychiatric disease did so at GDM diagnosed by 26 weeks was asso-
a younger age than their unexposed ciated with ASD. In our study, although
counterparts. Our results add new in- the numbers of ASD cases were relatively
formation to the data from previous low, the association between maternal
studies regarding the relationship be- GDM and offspring ASD remained sig-
tween in utero exposure to GDM and nificant also after adjusting for potential
neuropsychiatric morbidity, and are confounders including time-to-event,
unique in that they characterize a wide maternal age at delivery, gestational
spectrum of neuropsychiatric morbid- week, and offspring weight at birth.
ities, in nearly a quarter of a million Regarding CP, maternal GDM showed
children, with a long follow-up period. no significant association with CP in the
The neuropsychiatric diseases that offspring. This finding is in line with the
were included in this study were ASD, CP, findings of a recent study by Thorngren-
seizures, eating disorders, and OSA. ASD Jerneck and Herbst16 that found that
in the offspring of mothers with GDM although maternal insulin-dependent
has previously been addressed in a study diabetes mellitus doubled the risk for
by Xiang et al.26 In their study, after CP, GDM showed no significant
TABLE 4
Multivariable analysis of autistic spectrum disorder in offspring exposed in
utero to gestational diabetes mellitus
Variable OR 95% CI
GDM 4.44 1.55e12.69
Maternal age at delivery, y 0.97 0.92e1.04
Time-to-event, d 0.99 0.99e0.99 b
Offspring weight at birth, g 1.000 1.000e1.000 c
Gestational age at birth, wk 1.08 0.87e1.31
CI, confidence interval; GDM, gestational diabetes mellitus; OR, odds ratio.
a
Data evaluated by multivariate generalized estimating equation logistic regression model analysis.; b OR¼0.9995, 95% CI
0.9994e0.9997; c OR¼1.0002, 95% CI 1.00007e1.0003
Nahum Sacks et al. GDM and long-term neuropsychiatric morbidity in offspring. Am J Obstet Gynecol 2016.
associated with the risk of seizures
occurring immediately after birth,17 but
in our study no such association was
P valuea found. To our knowledge, the current
study is also the first to find associations
between OSA in the offspring and in utero
<.001
exposure to GDM and between eating
.003 disorders and in utero exposure to GDM.
.012 Interestingly, in our study, a signifi-
cant linear association was documented
.003
between the severity of the GDM (no
<.001 GDM, GDM A1, GDM A2) and the risk
<.001 of neuropsychiatric morbidity in the
<.001 offspring. To our knowledge, a similar
“dose-response” association has not
<.001
been previously demonstrated.
The main strength of the study lies in
the fact that our hospital is the only
hospital serving the entire population of
southern Israel. The hospital provides
both maternity services and pediatric
services; thus, as long as a mother and
child live in this area, they would use this
hospital. However, because some
neuropsychiatric conditions can be
diagnosed and treated in the commu-
nity, the ascertainment of children who
were never treated in the hospital at one
time or another could not be accom-
plished. Children who in fact had a
diagnosis of ASD but did not encounter
the hospital for any reason during the
follow-up were missed, leading to an
underestimation of the prevalence of
ASD. Although our findings point to an
interesting association between ASD and
maternal GDM, further research of ASD
from a community database is war-
ranted. In any case, there seems to be no
reason to suspect differential rates of
such cases between the 2 study groups.
While better estimates of the mor-
bidities could be found in community
P valuea clinics specializing in each condition, the
regional hospitalization database is still
.005
the most comprehensive database for
.414 covering both the entire population of
<.001 southern Israel and this variety of con-
<.001
ditions. The conditions included in the
study are significant health problems
.541 often accompanied by comorbidities,
and therefore are likely to necessitate
hospitalization at one time or another.
Furthermore, it is common practice that
physicians add any chronic condition

SEPTEMBER 2016 American Journal of Obstetrics & Gynecology 380.e4

SMFM Papers
that has previously been diagnosed in the
community to the medical chart, even
when the primary indication for hospi-
talization is not due to a neuropsychi-
atric condition.
Possible theories than could explain
this association between neuropsychi-
atric morbidity and in utero exposure to
gestational diabetes include the direct
effect on the developing central nervous
system,30-33 or the indirect effect of epi-
genetics,34 both due to the imbalanced
glucose levels in the in utero environ-
ment. Direct tissue damage could be
explained for example by hyperglycemia
causing fetal hypoxia30,31 or oxidative
stress.32,33
Although the chosen conditions cover
a broad spectrum of neuropsychiatric
morbidities, the findings of our study
warrant further research of maternal
GDM as a possible risk factor for other
neuropsychiatric morbidities. Possible
areas for further investigation can be
selected based on findings from the field
of epigenetics. Lehnen et al9 studied the
epigenetic effect of GDM and found that
in the placentas of mothers with GDM,
the MEST (mesoderm specific transcript)
and NR3CI (Nuclear Receptor Subfamily
3, Group C, Member 1) genes had
significantly decreased methylation levels.
In mouse knockout experiments the
MEST gene has been found associated
with the development of a “social brain”
after birth,10 and in human beings
changes in the NR3CI gene have been
associated with increased stress reactivity
and risk of adult psychopathology.11
Keeping these findings in mind, motor
neuron diseases and possibly even psy-
chopathologies from the field of pediatric
psychiatry should be investigated.9,12,13
In conclusion, in this large
population-based study, exposure to
maternal GDM was found to be an in-
dependent risk factor for long-term
neuropsychiatric morbidity in the
offspring. Further studies should focus
on the level of glycemic control and
long-term neuropsychiatric morbidity.n
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Author and article information
From the Department of Public Health, Faculty of Health
Sciences (Ms Nahum Sacks; Drs Friger, Shoham-Vardi,
and Abokaf; and Mr Sergienko); and Departments of
Obstetrics and Gynecology (Drs Abokaf, Spiegel, and
Sheiner) and Pediatrics (Dr Landau), Faculty of Health
Sciences, Soroka University Medical Center, Ben-Gurion
University of the Negev, Beer-Sheva, Israel.
Received March 5, 2016; accepted March 17, 2016.
SEPTEMBER 2016 American Journal of Obstetrics & Gynecology
SMFM Papers
This study was conducted at Soroka University Med-
ical Center and Ben-Gurion University using internal
research support available to researchers of those
institutions.
The authors report no conflict of interest.
Presented orally at the 36th annual meeting of the
Society for Maternal-Fetal Medicine, Atlanta, GA, Feb.
1-6, 2016.
Corresponding author: Eyal Sheiner, MD, PhD.
sheiner@bgu.ac.il
380.e6
SMFM Papers ajog.org

SUPPLEMENTAL TABLE 1
International Classification of Diseases, Ninth Revision codes for neuropsychiatric morbidities analyzed
Code Diagnosis
Autistic spectrum disorders
2990 AUTISTIC DISORDER
2990 INFANTILE AUTISM
2998 OTHER SPECIFIED PERVASIVE DEVELOPMENTAL DISORDERS
29900 AUTISTIC DISORDER, CURRENT OR ACTIVE STATE
29901 AUTISTIC DISORDER, RESIDUAL STATE
29910 CHILDHOOD DISINTEGRATIVE DISORDER, CURRENT OR ACTIVE STATE
29981 OTHER SPECIFIED PERVASIVE DEVELOPMENTAL DISORDERS, RESIDUAL STATE
29990 UNSPECIFIED PERVASIVE DEVELOPMENTAL DISORDER, CURRENT OR ACTIVE STATE
Disorders of eating
3071 ANOREXIA NERVOSA
3075 OTHER AND UNSPECIFIED DISORDERS OF EATING
30750 EATING DISORDER, UNSPECIFIED
30751 BULIMIA NERVOSA
30752 PICA
30753 RUMINATION DISORDER
30759 OTHER DISORDERS OF EATING
Obstructive sleep apnea
32723 OBSTRUCTIVE SLEEP APNEA (ADULT) (PEDIATRIC)
Epilepsy and infantile spasms
3450 GENERALIZED NONCONVULSIVE EPILEPSY
3452 PETIT MAL STATUS, EPILEPTIC
3453 GRAND MAL STATUS, EPILEPTIC
3455 PARTIAL EPILEPSY, WITHOUT IMPAIRMENT OF CONSCIOUSNESS
3456 INFANTILE SPASMS
3459 EPILEPSY, UNSPECIFIED
34500 GENERALIZED NONCONVULSIVE EPILEPSY WITHOUT INTRACTABLE EPILEPSY
34501 GENERALIZED NONCONVULSIVE EPILEPSY WITH INTRACTABLE EPILEPSY
34510 GENERALIZED CONVULSIVE EPILEPSY WITHOUT INTRACTABLE EPILEPSY
34511 GENERALIZED CONVULSIVE EPILEPSY WITH INTRACTABLE EPILEPSY
34540 PARTIAL EPILEPSY þ IMPAIRMENT OF CONSCIOUSNESS WITHOUT INTRACTABLE EPILEPSY
34550 PARTIAL EPILEPSY WITHOUT IMPAIRMENT OF CONSCIOUSNESS WITHOUT INTRACTABLE EPILEPSY
34560 INFANTILE SPASMS WITHOUT INTRACTABLE EPILEPSY
34590 EPILEPSY, UNSPECIFIED WITHOUT INTRACTABLE EPILEPSY
34591 EPILEPSY, UNSPECIFIED WITH INTRACTABLE EPILEPSY
Cerebral palsy
3439 INFANTILE CEREBRAL PALSY, UNSPECIFIED
Nahum Sacks et al. GDM and long-term neuropsychiatric morbidity in offspring. Am J Obstet Gynecol 2016.

380.e7 American Journal of Obstetrics & Gynecology SEPTEMBER 2016