During normal pregnancy, increased insulin resistance acts as an adaptation to enhance materno-foetal nutrient transfer and meet the nutritional needs of the developing foetus, particularly in relation to glucose requirements. However, about 1 in 6 pregnancies worldwide is affected by the inability of the mother’s metabolism to maintain normoglycaemia, with the combination of insulin resistance and insufficient insulin secretion resulting in gestational diabetes mellitus (GDM). A growing body of epidemiologic work demonstrates long-term implications for adverse offspring health resulting from exposure to GDM in utero. The effect of GDM on offspring obesity and cardiometabolic health may be partly influenced by maternal obesity; this suggests that improving glucose and weight control during early pregnancy, or better still before conception, has the potential to lessen the risk to the offspring. The consequences of GDM for microbiome modification in the offspring and the impact upon offspring immune dysregulation are actively developing research areas. Some studies have suggested that GDM impacts offspring neurodevelopmental and cognitive outcomes; confirmatory studies will need to separate the effect of GDM exposure from the complex interplay of social and environmental factors. Animal and human studies have demonstrated the role of epigenetic modifications in underpinning the predisposition to adverse health in offspring exposed to suboptimal hyperglycaemic in utero environment. To date, several epigenome-wide association studies in human have extended our knowledge on linking maternal diabetes-related DNA methylation marks with childhood adiposity-related outcomes. Identification of such epigenetic marks can help guide future research to develop candidate diagnostic biomarkers and preventive or therapeutic strategies. Longer-term interventions and longitudinal studies will be needed to better understand the causality, underlying mechanisms, or impact of GDM treatments to optimize the health of future generations.

1.
American Diabetes Association
.
2. Classification and diagnosis of diabetes
.
Diabetes Care
.
2016 Dec
;
40
(
Suppl 1
):
S11
24
.
2.
International Diabetes Federation
.
IDF diabetes atlas
. 9th ed.
Brussels, Belgium
:
International Diabetes Federation
;
2019
. .
3.
Landon
MB
,
Spong
CY
,
Thom
E
,
Carpenter
MW
,
Ramin
SM
,
Casey
B
,
.
A multicenter, randomized trial of treatment for mild gestational diabetes
.
N Engl J Med
.
2009
;
361
(
14
):
1339
48
.
4.
Fleming
TP
,
Watkins
AJ
,
Velazquez
MA
,
Mathers
JC
,
Prentice
AM
,
Stephenson
J
,
.
Origins of lifetime health around the time of conception: causes and consequences
.
Lancet
.
2018
;
391
(
10132
):
1842
52
.
5.
Burlina
S
,
Dalfrà
MG
,
Lapolla
A
.
Short- and long-term consequences for offspring exposed to maternal diabetes: a review
.
J Matern Fetal Neonatal Med
.
2019
;
32
(
4
):
687
94
.
6.
Steculorum
SM
,
Bouret
SG
.
Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring
.
Endocrinology
.
2011
;
152
(
11
):
4171
9
.
7.
Morris
MJ
,
Chen
H
.
Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth
.
Int J Obes
.
2009
;
33
(
1
):
115
22
.
8.
Pedersen
J
.
Glucose content of the amniotic fluid in diabetic pregnancies; correlations with the maternal blood sugar
.
Acta Endocrinol
.
1954
;
15
(
4
):
342
54
.
9.
Godfrey
KM
,
Costello
PM
,
Lillycrop
KA
.
The developmental environment, epigenetic biomarkers and long-term health
.
J Dev Orig Health Dis
.
2015
;
6
(
5
):
399
406
.
10.
Lowe
WL
,
Scholtens
DM
,
Lowe
LP
,
Kuang
A
,
Nodzenski
M
,
Talbot
O
,
.
Association of gestational diabetes with maternal disorders of glucose metabolism and childhood adiposity
.
JAMA
.
2018
;
320
(
10
):
1005
16
.
11.
Chen
YL
,
Han
LL
,
Shi
XL
,
Su
WJ
,
Liu
W
,
Wang
LY
,
.
Adverse pregnancy outcomes on the risk of overweight offspring: a population-based retrospective study in Xiamen, China
.
Sci Rep
.
2020
;
10
(
1
):
1549
.
12.
Kawasaki
M
,
Arata
N
,
Miyazaki
C
,
Mori
R
,
Kikuchi
T
,
Ogawa
Y
,
.
Obesity and abnormal glucose tolerance in offspring of diabetic mothers: a systematic review and meta-analysis
.
PLoS One
.
2018
;
13
(
1
):
e0190676
.
13.
Brown
J
,
Alwan
NA
,
West
J
,
Brown
S
,
Mckinlay
CJ
,
Farrar
D
,
.
Lifestyle interventions for the treatment of women with gestational diabetes
.
Cochrane Database Syst Rev
.
2017
;
5
(
5
):
CD011970
.
14.
Godfrey
KM
,
Reynolds
RM
,
Prescott
SL
,
Nyirenda
M
,
Jaddoe
VW
,
Eriksson
JG
,
.
Influence of maternal obesity on the long-term health of offspring
.
Lancet Diabetes Endocrinol
.
2017
;
5
(
1
):
53
64
.
15.
Boeke
CE
,
Oken
E
,
Kleinman
KP
,
Rifas-Shiman
SL
,
Taveras
EM
,
Gillman
MW
.
Correlations among adiposity measures in school-aged children
.
BMC Pediatr
.
2013
;
13
:
99
.
16.
Mooney
A
,
Kelsey
L
,
Fellingham
GW
,
George
JD
,
Hager
RL
,
Myrer
JW
,
.
Assessing body composition of children and adolescents using dual-energy X-ray absorptiometry, skinfolds, and electrical impedance
.
Meas Phys Educ Exercise Sci
.
2011
;
15
(
1
):
2
17
.
17.
Shafaeizadeh
S
,
Harvey
L
,
Abrahamse-Berkeveld
M
,
Muhardi
L
,
van der Beek
EM
.
Gestational diabetes mellitus is associated with age-specific alterations in markers of adiposity in offspring: a narrative review
.
Int J Environ Res Public Health
.
2020
;
17
(
9
):
3187
.
18.
Nattero-Chávez
L
,
Luque-Ramírez
M
,
Escobar-Morreale
HF
.
Systemic endocrinopathies (thyroid conditions and diabetes): impact on postnatal life of the offspring
.
Fertil Steril
.
2019
;
111
(
6
):
1076
91
.
19.
Pathirana
MM
,
Lassi
ZS
,
Roberts
CT
,
Andraweera
PH
.
Cardiovascular risk factors in offspring exposed to gestational diabetes mellitus in utero: systematic review and meta-analysis
.
J Dev Orig Health Dis
.
2020
;
6
:
1
18
.
20.
Blotsky
AL
,
Rahme
E
,
Dahhou
M
,
Nakhla
M
,
Dasgupta
K
.
Gestational diabetes associated with incident diabetes in childhood and youth: a retrospective cohort study
.
CMAJ
.
2019
;
191
(
15
):
E410
7
.
21.
Lowe
WL
Jr
,
Scholtens
DM
,
Kuang
A
,
Linder
B
,
Lawrence
JM
,
Lebenthal
Y
,
.
Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism
.
Diabetes Care
.
2019
;
42
(
3
):
372
80
.
22.
Yu
Y
,
Arah
OA
,
Liew
Z
,
Cnattingius
S
,
Olsen
J
,
Sørensen
HT
,
.
Maternal diabetes during pregnancy and early onset of cardiovascular disease in offspring: population based cohort study with 40 years of follow-up
.
BMJ
.
2019
;
367
:
l6398
.
23.
Øyen
N
,
Diaz
LJ
,
Leirgul
E
,
Boyd
HA
,
Priest
J
,
Mathiesen
ER
,
.
Prepregnancy diabetes and offspring risk of congenital heart disease: a nationwide cohort study
.
Circulation
.
2016
;
133
(
23
):
2243
53
.
24.
Parnell
AS
,
Correa
A
,
Reece
EA
.
Pre-pregnancy obesity as a modifier of gestational diabetes and birth defects associations: a systematic review
.
Matern Child Health J
.
2017
;
21
(
5
):
1105
20
.
25.
Martinez
MP
,
Lin
J
,
Chow
T
,
Chung
J
,
Wang
X
,
Xiang
AH
.
Maternal gestational diabetes and type 2 diabetes during pregnancy and risk of childhood asthma in offspring
.
J Pediatr
.
2020
;
219
:
173
79.e1
.
26.
Kumar
R
,
Ouyang
F
,
Story
RE
,
Pongracic
JA
,
Hong
X
,
Wang
G
,
.
Gestational diabetes, atopic dermatitis, and allergen sensitization in early childhood
.
J Allergy Clin Immunol
.
2009
;
124
(
5
):
1031
4
.
27.
Zugna
D
,
Galassi
C
,
Annesi-Maesano
I
,
Baïz
N
,
Barros
H
,
Basterrechea
M
,
.
Maternal complications in pregnancy and wheezing in early childhood: a pooled analysis of 14 birth cohorts
.
Int J Epidemiol
.
2015
;
44
(
1
):
199
208
.
28.
Wang
J
,
Zheng
J
,
Shi
W
,
Du
N
,
Xu
X
,
Zhang
Y
,
.
Dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus
.
Gut
.
2018
;
67
(
9
):
1614
25
.
29.
Sifnaios
E
,
Mastorakos
G
,
Psarra
K
,
Panagopoulos
ND
,
Panoulis
K
,
Vitoratos
N
,
.
Gestational diabetes and T-cell (Th1/Th2/Th17/Treg) immune profile
.
In Vivo
.
2019 Jan–Feb
;
33
(
1
):
31
40
.
30.
Ornoy
A
,
Reece
EA
,
Pavlinkova
G
,
Kappen
C
,
Miller
RK
.
Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes
.
Birth Defects Res C Embryo Today
.
2015
;
105
(
1
):
53
72
.
31.
Kelstrup
L
,
Bytoft
B
,
Hjort
L
,
Houshmand-Oeregaard
A
,
Mathiesen
ER
,
Damm
P
,
.
Diabetes in pregnancy: long-term complications of offsprings
.
Front Diabetes
.
2019
;
28
:
201
22
.
32.
Robles
MC
,
Campoy
C
,
Fernandez
LG
,
Lopez-Pedrosa
JM
,
Rueda
R
,
Martin
MJ
.
Maternal diabetes and cognitive performance in the offspring: a systematic review and meta-analysis
.
PLoS One
.
2015
;
10
(
11
):
e0142583
.
33.
Zhao
L
,
Li
X
,
Liu
G
,
Han
B
,
Wang
J
,
Jiang
X
.
The association of maternal diabetes with attention deficit and hyperactivity disorder in offspring: a meta-analysis
.
Neuropsychiatr Dis Treat
.
2019
;
15
:
675
84
.
34.
Xiang
AH
,
Wang
X
,
Martinez
MP
,
Getahun
D
,
Page
KA
,
Buchanan
TA
,
.
Maternal gestational diabetes mellitus, type 1 diabetes, and type 2 diabetes during pregnancy and risk of ADHD in offspring
.
Diabetes Care
.
2018
;
41
(
12
):
2502
8
.
35.
Wan
H
,
Zhang
C
,
Li
H
,
Luan
S
,
Liu
C
.
Association of maternal diabetes with autism spectrum disorders in offspring: a systemic review and meta-analysis
.
Medicine
.
2018
;
97
(
2
):
e9438
.
36.
Kong
L
,
Norstedt
G
,
Schalling
M
,
Gissler
M
,
Lavebratt
C
.
The risk of offspring psychiatric disorders in the setting of maternal obesity and diabetes
.
Pediatrics
.
2018 Sep
;
142
(
3
):
e20180776
.
37.
Li
M
,
Fallin
MD
,
Riley
A
,
Landa
R
,
Walker
SO
,
Silverstein
M
,
.
The association of maternal obesity and diabetes with autism and other developmental disabilities
.
Pediatrics
.
2016
;
137
(
2
):
e20152206
.
38.
Nahum Sacks
K
,
Friger
M
,
Shoham-Vardi
I
,
Abokaf
H
,
Spiegel
E
,
Sergienko
R
,
.
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
(
3
):
380
7
.
39.
Franke
K
,
Harder
T
,
Aerts
L
,
Melchior
K
,
Fahrenkrog
S
,
Rodekamp
E
,
.
“Programming” of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats
.
Brain Res
.
2005
;
1031
(
2
):
276
83
.
40.
Yu
DQ
,
Lv
PP
,
Yan
YS
,
Xu
GX
,
Sadhukhan
A
,
Dong
S
,
.
Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue
.
FASEB J
.
2019
;
33
(
4
):
5425
39
.
41.
Zhu
Z
,
Chen
X
,
Xiao
Y
,
Wen
J
,
Chen
J
,
Wang
K
,
.
Gestational diabetes mellitus alters DNA methylation profiles in pancreas of the offspring mice
.
J Diabetes Complications
.
2019
;
33
(
1
):
15
22
.
42.
de Sousa
RAL
,
de Lima
EV
,
da Silva
TP
,
de Souza
RV
,
Figueiredo
CP
,
Passos
GF
,
.
Late cognitive consequences of gestational diabetes to the offspring, in a new mouse model
.
Mol Neurobiol
.
2019
;
56
(
11
):
7754
64
.
43.
Elliott
HR
,
Sharp
GC
,
Relton
CL
,
Lawlor
DA
.
Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and their use to explore epigenetic mediation and improve prediction
.
Diabetologia
.
2019
;
62
(
12
):
2171
8
.
44.
Yang
IV
,
Zhang
W
,
Davidson
EJ
,
Fingerlin
TE
,
Kechris
K
,
Dabelea
D
.
Epigenetic marks of in utero exposure to gestational diabetes and childhood adiposity outcomes: the EPOCH study
.
Diabet Med
.
2018
;
35
(
5
):
612
20
.
45.
Chen
P
,
Piaggi
P
,
Traurig
M
,
Bogardus
C
,
Knowler
WC
,
Baier
LJ
,
.
Differential methylation of genes in individuals exposed to maternal diabetes in utero
.
Diabetologia
.
2017
;
60
(
4
):
645
55
.
46.
Allard
C
,
Desgagné
V
,
Patenaude
J
,
Lacroix
M
,
Guillemette
L
,
Battista
MC
,
.
Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns
.
Epigenetics
.
2015
;
10
(
4
):
342
51
.
47.
Côté
S
,
Gagné-Ouellet
V
,
Guay
SP
,
Allard
C
,
Houde
AA
,
Perron
P
,
.
PPARGC1α gene DNA methylation variations in human placenta mediate the link between maternal hyperglycemia and leptin levels in newborns
.
Clin Epigenetics
.
2016
;
8
:
72
8
.
48.
West
NA
,
Kechris
K
,
Dabelea
D
.
Exposure to maternal diabetes in utero and DNA methylation patterns in the offspring
.
Immunometabolism
.
2013
;
1
:
1
9
.
49.
Howe
CG
,
Cox
B
,
Fore
R
,
Jungius
J
,
Kvist
T
,
Lent
S
,
.
Maternal gestational diabetes mellitus and newborn DNA methylation: findings from the pregnancy and childhood epigenetics consortium
.
Diabetes Care
.
2020
;
43
(
1
):
98
105
.
50.
Blazevic
S
,
Horvaticek
M
,
Kesic
M
,
Zill
P
,
Hranilovic
D
,
Ivanisevic
M
,
.
Epigenetic adaptation of the placental serotonin transporter gene (SLC6A4) to gestational diabetes mellitus
.
PLoS One
.
2017
;
12
(
6
):
e0179934
.
51.
Lillycrop
KA
,
Garratt
ES
,
Garratt
ES
,
Titcombe
P
,
Melton
PE
,
Murray
RJS
,
.
Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood
.
Int J Obes
.
2019
;
43
(
5
):
974
88
.
52.
Jiang
Y
,
Yu
YC
,
Ding
GL
,
Gao
Q
,
Chen
F
,
Luo
Q
.
Intrauterine hyperglycemia induces intergenerational Dlk1-Gtl2 methylation changes in mouse placenta
.
Oncotarget
.
2018
;
9
(
32
):
22398
405
.
53.
Aiken
CE
,
Ozanne
SE
.
Transgenerational developmental programming
.
Hum Reprod Update
.
2014
;
20
(
1
):
63
75
.
54.
Heard
E
,
Martienssen
RA
.
Transgenerational epigenetic inheritance: myths and mechanisms
.
Cell
.
2014
;
157
(
1
):
95
109
.
55.
Horsthemke
B
.
A critical view on transgenerational epigenetic inheritance in humans
.
Nat Commun
.
2018
;
9
(
1
):
2973
.
56.
Crowther
CA
,
Hiller
JE
,
Moss
JR
,
McPhee
AJ
,
Jeffries
WS
,
Robinson
JS
.
Effect of treatment of gestational diabetes mellitus on pregnancy outcomes
.
N Engl J Med
.
2005
;
352
(
24
):
2477
86
.
57.
Landon
MB
,
Rice
MM
,
Varner
MW
,
Casey
BM
,
Reddy
UM
,
Wapner
RJ
,
.
Mild gestational diabetes mellitus and long-term child health
.
Diabetes Care
.
2015
;
38
(
3
):
445
52
.
58.
Gillman
MW
,
Oakey
H
,
Baghurst
PA
,
Volkmer
RE
,
Robinson
JS
,
Crowther
CA
.
Effect of treatment of gestational diabetes mellitus on obesity in the next generation
.
Diabetes Care
.
2010
;
33
(
5
):
964
8
.
59.
Rowan
JA
,
Rush
EC
,
Plank
LD
,
Lu
J
,
Obolonkin
V
,
Coat
S
,
.
Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age
.
BMJ Open Diabetes Res Care
.
2018
;
6
(
1
):
e000456
.
60.
van Weelden
W
,
Wekker
V
,
de Wit
L
,
Limpens
J
,
Ijäs
H
,
van Wassenaer-Leemhuis
AG
,
.
Long-term effects of oral antidiabetic drugs during pregnancy on offspring: a systematic review and meta-analysis of follow-up studies of RCTs
.
Diabetes Ther
.
2018
;
9
(
5
):
1811
29
.
61.
Godfrey
KM
,
Cutfield
W
,
Chan
SY
,
Baker
PN
,
Chong
YS
;
NiPPeR Study Group
.
Nutritional intervention preconception and during pregnancy to maintain healthy glucose metabolism and offspring health (“NiPPeR”): study protocol for a randomised controlled trial
.
Trials
.
2017
;
18
(
1
):
131
.
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