ARTICLE

Diabetic Embryopathies
Saivaroon Gajagowni, BS,* Pooja Nair, BS,* Alka C. Bapat, MD,† Akshaya J. Vachharajani, MD‡
*University of Missouri School of Medicine, Columbia, MO
†
Department of Obstetrics and Gynecology, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, NY
‡
Division of Neonatology, Department of Child Health, University of Missouri School of Medicine, Columbia, MO

PRACTICE GAPS

The association between maternal diabetes and fetal embryopathies is

well-established. One such embryopathy is caudal regression syndrome.
Due to the rarity of the condition and lack of screening guidelines, this
diagnosis is often missed until later in infancy. Clinicians should be aware
of this condition to ensure early diagnosis and management.

OBJECTIVES After completing this article, readers should be able to:

1. Explain the existing literature about the relationship between maternal

diabetes and fetal embryopathies, with a focus on cardiac and neural
tube defects, fetal growth anomalies, caudal regression syndrome,
genitourinary abnormalities, and lesser-known long-term effects such as
obesity, cognitive disorders, autism spectrum disorders, and psychiatric
disorders.
2. Describe the pathophysiology and clinical correlates of caudal regression
syndrome with the goal of increasing awareness to assist in earlier
AUTHOR DISCLOSURES Mr Gajagowni
identification and management of the disease. and Mrs Nair, and Drs Bapat and
Vachharajani have disclosed no financial
relationships relevant to this article. This

ABSTRACT commentary does not contain a

discussion of an unapproved/
Diabetic embryopathy is defined as congenital anomalies that are linked to investigative use of a commercial
product/device.
maternal diabetes. The association between diabetes and fetal, neonatal,
and long-term complications is well-established. These complications
include organ or structural maldevelopment, fetal growth abnormalities, ABBREVIATIONS

and learning/psychiatric comorbidities. Recent studies have elucidated the ASD autism spectrum disorder
pathophysiology behind these conditions and outlined new management BMI body mass index
CAKUT congenital anomalies of the
approaches. Caudal regression syndrome, also known as sacral agenesis, is kidney and urinary tract
a well-known but less described complication of maternal diabetes. The CHD congenital heart defect
purpose of this review is to summarize existing research on common CRS caudal regression syndrome
DM diabetes mellitus
neonatal morbidities in infants of mothers with diabetes with a focus on
GDM gestational diabetes mellitus
caudal regression syndrome and its long-term associations. IADPSG International Association of
Diabetes and Pregnancy Study
Group
LGA large for gestational age
INTRODUCTION OGTT oral glucose tolerance test
PGDM pregestational diabetes mellitus
As the incidence of obesity continues to increase worldwide, the incidence of di-
T1DM type 1 diabetes mellitus
abetes mellitus (DM) in pregnancy continues to increase as well. Diabetes T2DM type 2 diabetes mellitus

Vol. 23 No. 10 OCTOBER 2022 e677

 during pregnancy can be classified as pregestational or
gestational. Pregestational diabetes mellitus (PGDM) refers
to type 1 diabetes mellitus (T1DM) or type 2 diabetes melli-
tus (T2DM) diagnosed before pregnancy, and gestational di-
abetes mellitus (GDM) is diagnosed during pregnancy,
usually with screening occurring between 24 and 28 weeks
of gestation. The Centers for Disease Control and Preven-
tion estimates that 1% to 2% of pregnant women in the
United States have T1DM or T2DM and that 6% to 9% of
pregnant women develop GDM. Recent studies found that
from 2000 to 2010, the percentage of pregnant women
with GDM increased 56% and the percentage of women Figure 1. Effects of maternal diabetes on the fetus and the placenta.
with PGDM increased 37%. (1)
GDM is one of the many conditions complicating a be performed during pregnancy and that the diagnosis of
pregnancy and several large studies have addressed the is- GDM be established when any single threshold value was met
sue of diagnosis of this condition. Because routine screen- or exceeded (fasting value, 92 mg/dL [5.1 mmol/L]; 1-hour
ing for DM is not common before pregnancy, it is at value, 180 mg/dL [10 mmol/L]; or 2-hour value, 153 mg/dL
times challenging to distinguish GDM from preexisting [8.5 mmol/L]). (10) Although IADPSG criteria are simpler, the
diabetes. In general, women with GDM have a higher risk American College of Obstetricians and Gynecologists still sup-
of developing preeclampsia and needing a caesarean deliv- ports the 2-step process. However, individual practices and in-
ery, emphasizing the importance of early diagnosis and stitutions may choose to use the IADPSG’s recommendation,
treatment of the condition. (2)(3) if appropriate, for the population they serve. (11)
In 2014, the United States Preventive Services Task Multiple studies have previously described neonatal out-
Force recommended that all pregnant women should be comes of diabetic pregnancies compared with nondiabetic
screened for GDM at or beyond 24 weeks of gestation. (4) pregnancies. Offspring of mothers with diabetes (ie, both
This timeline recommendation is based on the fact that a PGDM and GDM) have a higher incidence of congenital
large proportion of women who were negative on early birth defects, including those involving the heart and brain.
pregnancy screening for DM will go on to develop GDM The rate of congenital anomalies in infants born to mothers
due to the effect of placental hormones. (5) In the United without DM is 2.4%. This rate increases to 2.8% in the set-
States, a 2-step approach is most commonly used to test ting of GDM and up to 7.2% in PGDM. (12) The proposed
for GDM. (4)(6)(7) This involves first screening with the and well-known mechanisms for the commonly observed
administration of a 50-g oral glucose solution followed by features in diabetic embryopathy are summarized in Figs 1
a 1-hour venous glucose determination. Women whose and 2, respectively. The incidence of these outcomes is re-
glucose levels are above an institution’s screening thresh- lated to the onset and duration of glucose intolerance during
old then undergo a 100-g, 3-hour diagnostic oral glucose pregnancy and the severity of maternal diabetes.
tolerance test (OGTT). Two or more abnormal values are
required on the 3-hour OGTT for a diagnosis of GDM.
Cutoff values for an abnormal test result vary, and as men-
tioned, are determined on an individual basis by a clinic or in-
stitution. In general, a 1-hour glucose level greater than 130 to
140 mg/dL (7.2–7.7 mmol/L) after the 50-g OGTT is indicative
of further screening. The threshold value chosen influences
both the sensitivity and specificity of the screening test. Simi-
larly, the American Diabetes Association developed different
thresholds for diagnosis using the 100-g, 3-hour OGTT, with
the second study using lower thresholds. (8)(9) Due to the
complexity of the different tests and thresholds, the Interna-
tional Association of Diabetes and Pregnancy Study Group
Figure 2. Effects of fetal hyperglycemia. ACOG=American College of Ob-
(IADPSG) recommended that a universal 75-g, 2-hour OGTT stetrics and Gynecology, NEC=necrotizing enterocolitis.

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 Numerous clinical conditions have been associated with
maternal diabetes and explained in case reports. This review
focuses on the common and less common manifestations
of diabetic embryopathies and discusses the well-described
and newly described mechanisms for these manifestations.

CARDIOVASCULAR DEFECTS
Congenital heart defects (CHDs) are the most common type of
birth defect in the general population and the leading cause of
birth defect associated with infant illness and death. (13) Annu-
ally, 1%, or about 40,000 births per year in the United States
are associated with CHDs. (14) Offspring of mothers with diabe-
tes during pregnancy have a 3-fold increase in risk of CHD com-
pared with offspring of mothers without diabetes. (15) Offspring
of mothers with PGDM have a 3-fold higher risk and those born
to mothers with GDM had twice the risk compared with those
born to mothers without diabetes. (15) Although maternal DM Figure 3. Mechanism for congenital heart defect (CHD) and neural tube
has been associated with all subtypes of CHDs, the 3 most com- defect (NTD) in offspring of mothers with diabetes in pregnancy.
Decreased PAX3 leads to increased p53 which in turn increases apoptosis
mon are atrioventricular septal defects, double outlet right ven- and causes CHD and NTD. AMPK=adenosine monophosphate activated
tricle, and truncus arteriosus. (15) Overall, studies show that the protein kinase, DNMT3B=DNA methyltransferase 3B, GLUT2=glucose
transporter 2, ROS=reactive oxygen species, PAX3=paired box 3. (Based on
prevalence of CHDs in the setting of maternal DM is between Loeken MR. Mechanisms of congenital malformations in pregnancies with
5% and 10%. (16) pre-existing diabetes. Curr Diab Rep. 2020;20(10):54.)

The etiology of CHDs in general is thought to be both ge-

netic and environmental, with maternal DM being a well-de- epidemiologic data suggest that children of mothers with
scribed risk factor. Specifically, hyperglycemia found in the diabetes had increased rates of early-onset cardiovascular
setting of maternal DM is thought to be the main teratogenic disease from childhood to early adulthood. (19)
factor. Although the exact mechanism is unclear, numerous Due to medical advances, the management approaches for
animal studies are under way to investigate the pathway fur- infants with CHDs continue to improve. For screening, fetal
ther. At this time, one of the leading hypotheses is that hyper-
echocardiography should be considered when the fetal heart
glycemia induces the formation of reactive oxygen species in
and great vessels cannot be visualized adequately on morpholog-
the fetus, which causes oxidative stress. This in turn affects the
ical ultrasonography at 20 weeks’ gestation. In fact, Pham et al
expression of numerous genes and associated pathways. One
recommended that all pregnant women with PGDM undergo
such gene that has been well-studied in mouse models and
fetal echocardiography, but this is not routinely followed. (20)
thought to play a role in CHDs in the setting of maternal dia-
However, fetal echocardiography frequently misses CHDs due
betes is Pax3. This gene plays a role in cardiac neural crest mi-
to various factors including poor image quality, maternal body
gration to the heart and formation of the outflow tract in the
mass index (BMI), and fetal position. As a result, mandatory
organ. Decreased expression of Pax3 in the setting of maternal
screening via pulse oximetry postnatally is a key newborn
hyperglycemia and oxidative stress (Fig 3) is thought to be
screening guideline. This postnatal critical congenital heart dis-
associated with increased apoptosis and outflow tract defects
ease screen mandated in the United States is a proven screening
described earlier. (17) The critical stage of fetal heart develop-
method to detect serious undiagnosed heart defects and in the
ment is between 3 and 7 weeks of gestation, suggesting that
absence of prenatal screening is a safety net for detecting heart
hyperglycemia early in pregnancy (ie, in the setting of PGDM)
defects. (21) Treatment of CHDs is dependent on the severity of
leads to greater risk for CHDs.
the defect, with some requiring surgical intervention while
The developmental cardiac defects associated with ma-
ternal DM have been shown to persist into infancy. Com- others can be managed medically.
pared with controls, fetuses of pregnant women with
GDM had more globular hearts and reduced biventricular GROWTH ABNORMALITIES
systolic function in infancy, suggesting a prolonged ad- The most common adverse neonatal outcomes associated
verse effect. (18) These findings might explain why with maternal diabetes are being large for gestational age

Vol. 23 No. 10 OCTOBER 2022 e679

 (LGA) and macrosomia. Although sometimes used inter-
changeably, both terms have specific definitions. New-
borns who weigh more than normal for gestational age,
generally greater than the 90th percentile based on stan-
dard population growth curves, are classified as LGA.
Newborns who weigh more than 4,500 g are generally de-
fined as having macrosomia. (22)
The rates of both conditions vary significantly. One study
found that the prevalence of macrosomia in women with
GDM was between 15% and 45%, which is 3 times the rate
of macrosomia in nondiabetic pregnant women. (23) A ret-
rospective chart review found that the rate of LGA was 50%
in women with T1DM and 23% in women with T2DM. (24)
Three major risk factors for LGA and macrosomia include
maternal obesity, poor glycemic control, and excessive ges-
tational weight gain. The prevalence of LGA is significantly
higher for overweight and obese women with GDM. A ret-
rospective study by Black et al found that the rates of LGA
were 13.6%, 16.4%, and 22.3% in mothers with GDM who
were normal weight, overweight, and obese, respectively.
These rates were double those seen in mothers in the same
weight category but without GDM. (25) Likewise, women
with increasing levels of glucose, regardless of screening
positivity for GDM, had a linearly increasing risk for macro-
somia. Lastly, excessive gestational weight gain, categorized
as weight gain of more than 40 lb (18 kg), was associated
with nearly twice the risk for fetal macrosomia. (26)
Women with excessive weight gain during pregnancy and
elevated hemoglobin A1c levels during the second trimester
are at greater risk of having an infant who is LGA in T1DM
pregnancies whereas excessive weight gain during preg-
nancy is a risk factor for LGA in T2DM pregnancies. (24)
The proposed pathophysiology of maternal DM and LGA/
macrosomia is related to the hyperinsulinemic state in the fe-
tus induced by maternal hyperglycemia. Specifically, high ma-
ternal glucose crosses the placenta and induces fetal b-cell
hyperplasia and subsequently hyperinsulinemia (Fig 1). This
causes growth of insulin-sensitive tissue, the most important
of which is adipose tissue. This adipose tissue deposits in the
fetal torso, in particular in the intrascapular and shoulder area,
leading to a disproportion between the upper body and the nor-
mally sized head. (26)(27) However, the presence of LGA and
fetal macrosomia in the setting of normal maternal fasting glu-
cose indicates that other factors may play a role in the patho-
physiology as well. Recent evidence points to fetal genetics.
Hughes et al created a fetal genetic score based on single nucle-
otide polymorphisms associated with birthweight. (28) When
tested against a large sample of mother-infant dyads, fetal ge-
netic score influenced birthweight independently of maternal
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fasting blood glucose and affected growth at all levels of mater-
nal glycemia. (28) Understanding these genetic influences is
important because maternal fasting glycemia accounts for only
a small percentage of the variance in birthweight, and the ma-
jority of LGA infants are not born to mothers with diabetes.
Fetal fat distribution in the setting of maternal diabetes in-
creases the risk for complications. The most notable of this is
shoulder dystocia. Compared with uncomplicated pregnan-
cies, pregnant women with diabetes have a 2- to-4-fold greater
risk of shoulder dystocia at delivery. The effect of increased
rates of shoulder dystocia includes complications in the neo-
nate, such as brachial plexus injury, facial nerve injury, and
cephalohematoma as well as the need for operative delivery
(Fig 1). However, when compared with infants who are appro-
priate for gestational age, LGA infants did not have an in-
creased risk of morbidities or mortality. (29)
Prevention of LGA and fetal macrosomia is aimed at
management of maternal DM. Interventions such as dietary
changes, monitoring of blood glucose levels, and treatment
with insulin was found to lead to a 67% reduction in the pri-
mary composite outcome of infant death, shoulder dystocia,
bone fracture, and nerve palsy compared with typical stan-
dard care. (30) Further, lifestyle modification, particularly
exercise, was associated with reduced risk of having LGA
offspring compared with dietary changes alone. (31)
CAUDAL REGRESSION SYNDROME
Caudal regression syndrome (CRS) is a rare disorder charac-
terized by partial or total agenesis of the terminal spinal cord
segments. Clinical associations of CRS include malformation
of the caudal spinal cord, hindgut, urogenital system, and
lower limbs. Four types of sacral agenesis are described (32):
• Type 1: Partial unilateral agenesis of sacrum or coccyx
• Type 2: Partial but bilaterally symmetric defects in the
sacrum; iliac bones articulate with S1, and distal seg-
ments of the sacrum and coccyx do not develop
• Type 3: Complete sacral agenesis, iliac bones articulate
with the lowest available segment of the lumbar spine
• Type 4: Complete sacral agenesis, iliac bones are fused
posteriorly along the midline
Caudal regression may present as part of other syndromes
including vertebral anomaly, anal atresia, cardiac anomaly, tra-
cheoesophageal fistula, renal anomaly, limb anomaly (VAC-
TERL), omphalocele, cloacal exstrophy, imperforate anus,
spinal defects (OEIS), and the Currarino triad (caudal agene-
sis, presacral mass, anorectal anomalies).
 The incidence of CRS is reported to be 1 to 3 newborns
per 100,000 live births. Maternal diabetes (both PGDM
and GDM) is a well-known risk factor for CRS, with the
incidence of CRS being 1 in 350 live births in infants of
mothers with diabetes (approximately a 200-fold increase).
Research shows that 1% of infants born to mothers with
diabetes have sacral agenesis, but 12% to 16% of infants
with sacral agenesis were born to mothers with diabetes. (33)
Embryologically, formation of the spinal cord occurs dur-
ing primary and secondary neurulation. Primary neurulation
refers to formation of the brain and spinal cord segments up
to the lumbar region. Secondary neurulation occurs during
the 4th week of pregnancy and involves formation of the
caudal cell mass, which undergoes canalization and differen-
tiation during the remainder of pregnancy. Based on this
embryologic model, pathogenesis of CRS could involve dis-
turbances in primary or secondary neurulation (34) or de-
rangement of cell migration/differentiation when the caudal
cell mass is formed. (35) Development of the caudal cell
mass occurs adjacent to the hindgut and mesonephros, po-
tentially explaining the association of CRS with gastrointesti-
nal and genitourinary anomalies.
The exact etiology of CRS is unclear, though it is be-
lieved to be based on a combination of environmental and
genetic factors. Apart from maternal diabetes, other envi-
ronmental teratogens include maternal hypoxia and mater-
nal ketone/amino acid abnormalities. (36) Whole-exome
sequencing suggests a multigenic model for CRS with im-
plicated genes including VANGLI1, HLXB9, and PTEN.
(37) Further studies are under way on the mechanism be-
hind how these genes lead to CRS.
Complications associated with CRS are dependent on what
structures are involved during initial presentation and the sever-
ity of the defects. A literature review shows a wide variation in
the prevalence of complications, likely because the rarity of the
condition makes it difficult to study. A review of patients admit-
ted for complications of sacral agenesis over 20 years from
Guy’s Hospital in London, United Kingdom (38) found that the
age of children at initial presentation was bimodally distributed,
with peaks before 1 year and between 4 and 5 years of age. Com-
plications seen in almost all children in the study were fecal in-
continence, lower urinary tract dysfunction, and abnormal
neurology of the lower limbs. Other abnormalities occurring
at varying rates included orthopedic anomalies, skin defects,
anorectal/tracheoesophageal anomalies, and psychological or
behavioral problems. In this study and others, the prevalence of
complications such as fecal incontinence and urinary tract dys-
function was as high as 100%. (39)(40) The prevalence of other
complications described before ranged from 10% to 50%. (38)
Although the retrospective nature of the studies described
herein limit potential conclusions on complications, some im-
portant themes can be emphasized. First, due to the rarity of
CRS, the associated complications are not well known clini-
cally. This leads to delayed diagnosis as seen in the data on age
at initial diagnosis of CRS. A study by Dewberry et al found
that the most common symptoms that eventually led to a diag-
nosis of CRS were severe diaper rash and failure to toilet train
by an appropriate age. (41) With earlier identification, manage-
ment of the most common complications (bowel and bladder)
can be optimized to decrease the incidence of long-term sequa-
lae (eg, renal scarring). This leads to the second point, which is
to understand signs that can lead to early diagnosis of CRS.
This can be difficult due to the wide variety of clinical pheno-
types of CRS and its association with other syndromes. How-
ever, the clinical signs of an abnormal sacrum include
flattening of the buttocks, loss of a gluteal cleft, widely spaced
buttock dimples, or palpable sacral defect or groove. (38) The
presence of any of these findings indicates the need for addi-
tional imaging including abdominal radiography and spinal
magnetic resonance imaging. Lastly, these previous studies
show that surgical intervention is common for infants with
CRS. Twenty of the 22 children in the Wilmshurst study
underwent surgical procedures for urogenital, orthopedic, or
rectal anomalies, and 10 of these surgeries were performed be-
fore a diagnosis of sacral agenesis was made. (38)
In the era of universal screening for inborn errors of me-
tabolism, critical CHDs, and targeted screening of at-risk
neonates for retinopathy of prematurity and developmental
dysplasia of the hips, screening for sacral dysgenesis in off-
spring of diabetic mothers should be considered. Universal
screening of all offspring of diabetic mothers would be ideal
but probably not cost effective. The odds of sacral anomalies
in offspring of PGDM mothers is 80 compared with those
born to mothers without diabetes, and the odds in the off-
spring of GDM mothers is 4 compared with those born to
nondiabetic mothers. Universal screening aimed at all in-
fants born to mothers with PGDM may be a cost-effective
screening method for sacral anomalies and aid with earlier
diagnosis as mentioned earlier.
NEURAL TUBE DEFECTS
Neural tube defects occur when the neural tube fails to
close correctly during embryonic development, causing
central nervous system defects. (42) This could be caused
by several factors including vitamin deficiencies and ma-
ternal diabetes. (43) Some examples of neural tube defects
are spina bifida and anencephaly. (42) It is well docu-
mented that maternal diabetes is associated with fetal
Vol. 23 No. 10 OCTOBER 2022 e681
 neural tube defects. (42) The rise of diabetes and obesity
is a major contributor to neural tube defects.
Several metabolic pathways and genes have been found
to contribute to neural tube defects in infants of diabetic
mothers. A general understanding is that high glucose con-
centrations lead to neuronal cell death, which interrupts the
closing of the neural tube. (42) A proposed mechanism for
the increased incidence of neural tube defects and CHDs is
shown in Fig 3. There is an upregulation of GLUT2 chan-
nels, which then increases radical oxygen species and leads
to decreased levels of PAX3. The normal function of PAX3 is
to stimulate p53 degradation. Therefore, the decrease in
PAX3 seen in the setting of hyperglycemia leads to an in-
crease in p53 stability. The downstream effect of increased
p53 includes increased apoptosis via multiple processes, in-
cluding cell cycle withdrawal, decreased pluripotency, and
increased oxidative metabolism, the net effect of which is
neural tube defects and CHDs. (44) Preventing maternal hy-
perglycemia via a tightly controlled preconception blood glu-
cose may thus prevent neural tube defects in the offspring
of mothers with PGDM.
Overall, the genetics of neural tube defects in infants of
diabetic mothers remains unclear because there is no sin-
gular mechanism or gene that can fully explain it. More
research is needed to better understand this mechanism.
CONGENITAL ANOMALIES OF THE KIDNEY AND
URINARY TRACT
Congenital anomalies of the kidney and urinary tract
(CAKUT) include a range of disorders that exist at birth and
can affect the kidneys, ureter, bladder, and/or urethra. (45)
Usually, the development of the kidneys and urinary system
begins in the 3rd week of gestation and continues until the
36th week of gestation. Because of how long it takes for this
system to fully form in utero, many genes and environmen-
tal risk factors, such as maternal diabetes, can interrupt the
development and cause abnormalities. (45)
A retrospective study with 945 infants of those with
CAKUT versus 4,725 controls who were matched for ges-
tational age, sex, and birth year suggested an association
of CAKUT with maternal diabetes. (46) Infants of mothers
with PGDM have a 50% increased risk of CAKUT and
those with GDM have a 37% increased risk of CAKUT
compared with infants whose mothers did not have diabe-
tes. (47) This study acknowledged that other factors, in-
cluding other environmental factors and genetics, could
affect the incidence of CAKUT in these infants. (47) The
authors of this study recommend that up to 2% to 3.7% of
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the cases of CAKUT in the United States could be pre-
vented if maternal GDM was prevented.
LONG-TERM COMPLICATIONS
Evidence has shown that some important long-term outcomes
continue to affect offspring of women with diabetes well after
infancy. (48) These include long-term adiposity, cardiometa-
bolic syndromes, and impaired cognitive ability. (48)
The association between LGA and maternal diabetes has
already been established (Figs 1 and 2). The fetal hyperinsuli-
nemia leading to LGA can impair glucose metabolism in an
infant, which can persist into adulthood. (49) This effect is
seen in infants born to mothers with both PGDM and
GDM. A study evaluated 970 mother-infant dyads for up to
7 years after delivery. (40) After that period, it was found
that infants born to diabetic mothers showed higher rates of
obesity/greater BMI, higher blood pressures, an overall de-
clining trend in pancreatic b-cell function, and higher rates
of abnormal glucose tolerance. (50)
The proposed mechanism behind higher rates of obesity
is leptin resistance (Fig 4). Leptin resistance prevents activa-
tion of hypothalamic receptors. This then reduces the release
of pro-opiomelanocortin from the hypothalamus. Release of
this transmitter is essential for promoting a balance between
food intake and energy expenditure. In the absence of pro-
opiomelanocortin, increased food intake, reduced satiety,
and obesity are seen. (51) Further, research has shown an as-
sociation between maternal medication usage and obesity. A
mechanism has been proposed correlating metformin pre-
scribed to pregnant women with PGDM or GDM and later
fetal obesity. (52) Figure 5 depicts the theory in a simplified
manner. Obesity via these mechanisms can lead to adverse
Figure 4. Mechanism of obesity in offspring of mothers with diabetes in
pregnancy. (Based on M
arquez-Valadez B, Valle-Bautista R, Garc
ıa-L

opez G,
D
ıaz NF, Molina-Hern
andez A. Maternal diabetes and fetal
programming toward neurological diseases: beyond neural tube defects.
Front Endocrinol (Lausanne). 2018;9:664.)
Figure 5. Mechanism of obesity in offspring of mothers with diabetes in pregnancy treated with metformin. (Based on Owen MD, Baker BC, Scott EM,
Forbes K. Interaction between metformin, folate and vitamin B12 and the potential impact on fetal growth and long-term metabolic health in
diabetic pregnancies. Int J Mol Sci. 2021;22(11):5759.)

health outcomes during adulthood including atherosclerosis study suggests that diabetes in pregnancy alone is unlikely to
and cardiovascular disease, a finding that is consistent with explain the cognitive differences and that epigenetic phenom-
the well-supported Barker hypothesis. (53) ena may be involved. (57) A proposed theory for the cognitive
defects found in infants born to mothers with diabetes is
DISORDERS OF COGNITION shown in Fig 6, emphasizing the likely multifactorial origin.
Cognition is the ability to regulate social and emotional cues. It
is measured formally with intelligence tests and includes mem- NEUROPSYCHIATRIC MORBIDITIES
ory and attention. Various aspects of cognitive function have Obese mothers without diabetes had an increased risk
been studied in infants of diabetic mothers including language, (11=2 times) of having a child with mild neurodevelopmental
learning, memory, motor coordination, perception, and prob-
lem solving. (51) Ornoy et al reported that “children under 9
years old born to GDM women had lower scores in verbal tasks
and fine and gross motor skills.” (54) Bola~ nos et al found that
“in utero hyperglycemia was associated with a lower average
IQ and poor performance in working memory skills, such as
graphic and visuospatial tasks, in children from 7 to 9 years old
born to control and GDM women.” These results show that
GDM leads to minor neurologic deficits in children. (55)
A Swedish linkage study found that offspring of mothers
with diabetes in pregnancy were unlikely to complete compul-
sory schooling at 16 years of age. (55) Similarly, a United
Kingdom study (Avon Longitudinal Study of Parents and Chil-
dren) found that PGDM, GDM, and glucosuria in pregnancy
resulted in lower offspring school assessment entry scores at
age 4 years, lower IQ at age 8 years, and poorer school results
at age 16 years even when adjusted for many confounders.
(56) The findings from these 2 studies conflict with the
Figure 6. Mechanism of cognitive defects in offspring of mothers with
finding of the sibling study from Sweden by Fraser and Lawlor diabetes in pregnancy. (Based on M
arquez-Valadez B, Valle-Bautista R,
Garc
ıa-L

opez G, D
ıaz NF, Molina-Hern
andez A. Maternal diabetes and fetal
in 2014. (48) Siblings born to mothers with diabetes in preg-
programming toward neurological diseases: beyond neural tube defects.
nancy had higher IQs than their unexposed siblings. This Front Endocrinol (Lausanne). 2018;9:664.)

Vol. 23 No. 10 OCTOBER 2022 e683


Figure 7. Mechanism of autism spectrum disorder in offspring of mothers
with diabetes in pregnancy. Decreased expression of the EN2 gene
ultimately leads to a smaller cerebellum. A small cerebellum is seen on
autopsy of patients with autism of all ages. (Based on M
arquez-
Valadez B, Valle-Bautista R, Garc
ıa-L

opez G, D
ıaz NF, Molina-Hern
andez A.
Maternal diabetes and fetal programming toward neurological diseases:
beyond neural tube defects. Front Endocrinol (Lausanne). 2018;9:664.
disorder; conduct disorder; attention-deficit/hyperactivity dis-
order; and psychotic, mood, and stress-related disorder com-
pared to mothers with normal BMI. In addition to being
obese, women with PGDM had a risk of having offspring with
autism spectrum disorders (ASDs), attention-deficit/hyperac-
tivity disorder, and conduct disorders that was 6 times greater
compared to mothers with GDM. (58)
AUTISM SPECTRUM DISORDERS
As discussed before, rates of ASD are higher in infants
born to mothers with diabetes. Animal data on ASDs in
diabetic pregnancy are presented in Fig 7. All patients
with ASD, irrespective of age, sex, and cognitive abili-
ties, show a small cerebellum and specifically decreased
Purkinje cells in the cerebellar cortices. (51) Some pro-
posed mechanisms for the ASD and the decreased Pur-
kinje cells are shown in Fig 7. Several genes are
implicated in the etiology of ASDs and include engrailed
homeobox 2, g-aminobutyric acid type A receptor b3
subunit, MET proto-oncogenes, and receptor tyrosine
kinases. All have specific roles in cerebellar develop-
ment. This may contribute to the increased rates of ASD
in offspring of mothers with diabetes.
SCHIZOPHRENIA
Female infants born to mothers with GDM had a higher
chance of developing schizophrenia. This suggests a
susceptibility of the female sex to developing schizo-
phrenia. (59) It has been proposed that there is an in-
crease in proinflammatory cytokines such as tumor
necrosis factor a and interleukin 8 which increases the
offspring’s susceptibility to schizophrenia in later life.
e684 NeoReviews
(60) Using DNA methylation, 57 genes associated with
schizophrenia were affected when placentas and cord
blood samples of offspring of mothers with GDM were
analyzed. Thus, a 2-hit hypothesis is suggested for the
pathogenesis of schizophrenia: a genetic susceptibility
followed by an epigenetic phenomenon of increased in-
flammatory cytokines.
HEARING LOSS
Children born to mothers with diabetes in pregnancy
have a higher risk of hearing loss compared with chil-
dren born to mothers without diabetes in pregnancy.
(61) The hearing loss was more likely to be bilateral and
sensorineural in nature. The incidence of conductive
hearing loss was similar in both groups of children. (61)
Children of diabetic pregnancies demonstrated higher
sensorineural hearing loss when associated with the co-
morbidities of hyperbilirubinemia, asphyxia, and CHD.
(61) Lee et al conducted a study using the audiological and
genetic database, which represents a selected cohort of children
referred for audiologic evaluation, and hence the data may not
be generalizable to the entire population. Close audiologic fol-
low-up for hearing loss is recommended in children born to
mothers with diabetes in pregnancy by Lee et al. (61)
Summary
• There are many effects on offspring born to women
with diabetes during pregnancy. Many of the
embryopathies are well known and mechanisms for
these defects are well understood.
• Some of the long-term morbidities such as obesity,
autism, and psychiatric disorders are not well understood
and may not be well known to neonatal clinicians.
• Diabetes may be the result of epigenetic phenomena on
an altered milieu caused by abnormal maternal glucose
control, which may explain many of these morbidities.
• It is important to realize that tight glucose control
before conception may prevent these embryopathies.
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Know the effects on the fetus and/or newborn infant of
maternal diabetes mellitus (including gestational diabetes)
and their management.

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 NEOREVIEWS QUIZ

NEO
QUIZ

1. Several different strategies exist for screening and diagnosis of gestational

diabetes mellitus. Which of the following strategies is correctly matched to
the procedures involved in the diagnosis of gestational diabetes?

A. US Preventive Services Task Force 2014 recommendation: Screen all

women of child-bearing age annually with 50-g 1-hour oral glucose
tolerance test before pregnancy, with those missed before pregnancy
receiving serial testing monthly for the first 3 months of pregnancy.
B. American College of Obstetricians and Gynecologists: Two-step process
with initial screening of 50-g oral glucose solution followed by 1-hour
venous glucose, with subsequent 100-g, 3-hour diagnostic oral glucose REQUIREMENTS: Learners can
tolerance test as indicated, with allowance for using the International take NeoReviews quizzes and
claim credit online only at:
Association of Diabetes and Pregnancy Study Group (IADPSG) protocol
https://publications.aap.org/
based on population served. neoreviews.
C. American Diabetes Association: Same cutoffs for the 3-hour glucose
tolerance test of 1-hour value exceeding 200 mg/dL (11.1 mmol/L) or 2- To successfully complete 2022
hour value exceeding 180 mg/dL (10 mmol/L). NeoReviews articles for AMA PRA
Category 1 Credit™, learners
D. IADPSG recommendation: Six-hour oral glucose tolerance test for all
must demonstrate a minimum
pregnancies at 20 weeks’ gestation, with thresholds for diagnosis performance level of 60% or
varying by age and parity. higher on this assessment. If
E. American Diabetes Association: Its own method of screening that is you score less than 60% on the
based on hemoglobin A1C levels drawn serially during pregnancy. assessment, you will be given
additional opportunities to
2. A pregnant woman is diagnosed with gestational diabetes mellitus. As part answer questions until an
of prenatal care testing, she undergoes routine ultrasonography at 20 weeks, overall 60% or greater score is
and because some cardiac structures are not well visualized, she is referred achieved.
for fetal echocardiography because the risk for congenital heart defect is
This journal-based CME activity
increased with maternal diabetes mellitus. Which of the following are the 3 is available through Dec. 31,
most common congenital heart defects associated with maternal diabetes? 2024, however, credit will be
recorded in the year in which
A. Double outlet right ventricle, atrioventricular septal defect, truncus
the learner completes the quiz.
arteriosus.
B. Hypoplastic left heart, aortic stenosis, interrupted aortic arch.
C. Pulmonary stenosis, total anomalous pulmonary venous return,
coronary aneurysm.
D. Tetralogy of Fallot, cordis ectopia, ventricular septal defect.
E. Ebstein anomaly, mitral prolapse, tricuspid atresia. 2022 NeoReviews is approved
3. A 38-year-old pregnant woman who has been diagnosed with gestational for a total of 30 Maintenance of
Certification (MOC) Part 2
diabetes mellitus is being followed regularly. The fetal size is being tracked
credits by the American Board
closely because of a previous pregnancy resulting in an infant with of Pediatrics (ABP) through the
macrosomia. Which of the following would constitute the highest risk for AAP MOC Portfolio Program.
large for gestational age and macrosomia in this current pregnancy? NeoReviews subscribers can
claim up to 30 ABP MOC Part 2
A. Multiparity, advanced maternal age, and prior surgery. points upon passing 30 quizzes
B. Lower hemoglobin A1c levels associated with high insulin use. (and claiming full credit for
C. Excess exercise during second trimester. each quiz) per year. Subscribers
can start claiming MOC credits
D. Excessive weight gain during pregnancy, poor glycemic control, and
as early as October 2022. To
maternal obesity. learn how to claim MOC points,
E. Below average height and high intake of complex carbohydrates during go to: https://publications.aap.
pregnancy. org/journals/pages/moc-credit.

Vol. 23 No. 10 OCTOBER 2022 e687

 4. An infant born to a woman who had gestational diabetes mellitus is noted
to have several congenital abnormalities at birth, including partial sacral
agenesis, and is diagnosed with caudal regression syndrome. Which of the
following statements about this condition is correct?
A. Type 4 caudal regression syndrome refers to a partial sacral agenesis
that is also associated with seizures.
B. The incidence of caudal regression syndrome in infants of mothers with
diabetes is approximately 200-fold that of nondiabetic mothers.
C. Caudal regression syndrome presents with symptoms that would inevitably
lead to confirmatory diagnosis within the first few days after delivery for all
affected infants.
D. Caudal regression syndrome is a clinical diagnosis and imaging studies
are generally not helpful for screening, diagnosis, or to guide
management.
E. Complete sacral agenesis can occur with caudal regression syndrome,
but that type has not been associated with gestational diabetes.
5. Infants of mothers with diabetes are at risk for longer-term complications
beyond the neonatal period. Which of the following statements describes a
known long-term risk for infants of mothers with diabetes?
A. Impaired metabolism and feeding regulation leads to 3-fold increase in
risk of eating disorder in teenage years and risk of malnutrition.
B. Swedish population studies have shown that although offspring of
mothers with diabetes in pregnancy were more likely to graduate from
high school than their peers, they had lower IQ scores than unexposed
siblings.
C. Rates of autism spectrum disorder are higher in infants born to mothers
with diabetes, with added risk when the mother was obese.
D. Infants of mothers with diabetes are more likely to be introverted and
have 5-fold risk of having extreme anxiety disorder, often manifesting
as social reclusion.
E. Peripheral neuropathy occurs in about 20% of offspring of diabetic
mothers, generally presenting in teenage years as poor balance or
clumsiness.

e688 NeoReviews