ARTICLE

Congenital Abnormalities in the Infant of

a Mother with Diabetes
Artemiy Kokhanov, MD*
*Department of Neonatology, Memorial Care Miller Children’s and Women’s Hospital Long Beach, Long Beach, CA

PRACTICE GAP

Diabetes mellitus rates are on the rise in the world. Many people who live
with diabetes are not aware of the diagnosis, including women of
childbearing age. Clinicians should be aware of the current knowledge of
the congenital abnormalities associated with maternal diabetes and be able
to identify mothers at risk of having offspring with these congenital defects.

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

1. Recognize the risks of congenital anomalies associated with maternal

diabetes.
2. Describe various mechanisms responsible for those anomalies.
3. Describe clinical features of congenital anomalies associated with
maternal diabetes.
4. Understand the importance of pregravid screening and management of
diabetes.

ABSTRACT
Diabetes mellitus is among the most common chronic diseases worldwide.
Infants of diabetic mothers are at increased risk of having congenital
abnormalities. Tremendous progress has been achieved in the pregnancy
care of diabetic women; however, the risk of birth defects associated with AUTHOR DISCLOSURES Dr Kokhanov
maternal diabetes still exists. These anomalies might arise in many organs has disclosed no financial relationships
relevant to this article. This commentary
and systems of the developing fetus. Many mechanisms have been does not contain a discussion of an
implicated in the teratogenicity of maternal diabetes and it is critical to unapproved/investigative use of a
achieve good glycemic control before conception in women with diabetes. commercial product/device.
Neonatal clinicians must be able to identify patients at risk and recognize
the signs of diabetic embryopathy. This article presents a review of ABBREVIATIONS
congenital anomalies associated with maternal diabetes. AGE advanced glycation end
products
CRS caudal regression syndrome
DM diabetes mellitus
INTRODUCTION GDM gestational diabetes mellitus
Diabetes mellitus (DM) is among the most common chronic diseases affecting OAVD oculo-auriculo-vertebral
disorder
humans. (1) There are many different forms of diabetes, with differing etiologies
ROS reactive oxygen species
and clinical manifestations, with the common feature among them being VSD ventricular septal defect

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by Clara Stamouli
 hyperglycemia. (2) In 2019, approximately 15.8% of
women experienced some degree of hyperglycemia during
pregnancy; of those, 83.6% were due to gestational diabe-
tes mellitus (GDM), 7.9% were due to pregestational dia-
betes, and 8.5% were due to diabetes first diagnosed
during pregnancy. (1)
Women with poorly controlled diabetes early in preg-
nancy have a ninefold increase in risk of delivering a neo-
nate with a congenital malformation. (3) The rate of birth
defects in women affected by the established type 1 DM is
identical to those with the established type 2 DM. (4)
Though true, the association of congenital abnormalities
in the offspring of those with maternal GDM remains
unclear (Table). (4)(5)(6) Furthermore, diabetic pregnan-
cies are more likely to result in spontaneous abortion or
stillbirth. (7)
MECHANISMS
Multiple mechanisms are implicated in the pathogenesis of
diabetes-induced birth defects. With hyperglycemia being
the unifying feature of different forms of DM, the embry-
onic and fetal exposure to high glucose concentrations is a
main teratogenic factor. (8) Hemoglobin A1c levels used as a
proxy for glycemic control in diabetic women have been
shown to correlate with the rates of congenital abnormalities.
(9) The crucial exposure time for the development of congeni-
tal abnormalities in infants of diabetic mothers is during
organogenesis, which takes place between 2 and 8 weeks of
gestation. (10) Even a brief periconceptual exposure to hyper-
glycemia is enough to undermine the embryonic develop-
ment. (11)
Baack et al, in an animal study, showed that even in
the absence of DM, hyperglycemia was capable of causing
birth defects in the offspring. (12) High glucose concentra-
tion has been shown to be able to alter the DNA methyla-
tion of crucial genes involved in embryonic development.
(13) Li et al showed that advanced glycation end products
(AGE), the production of which is accelerated under condi-
tions of hyperglycemia, are capable of inducing birth
defects even in the absence of hyperglycemia itself. (14)
Experimental DM in animal models has been shown to
be associated with overproduction of reactive oxygen species
(ROS) and disordered antioxidant defense. (15) Hyperglyce-
mia promotes the intake of glucose into embryonic cells
and as a result, mitochondria receive metabolic overburden
which results in increased formation of ROS. (16) Exces-
sive oxidative stress then leads to DNA damage, micro-
RNA alteration, and disruption of various signaling
pathways, all of which result in aberrant organ develop-
ment. (17)(18)(19)(20)(21) Laboratory experiments have

Table. Congenital Abnormalities in the Infant of a Diabetic Mother

Central nervous system Cardiovascular system

Neural tube defects Persistent truncus arteriosus
 Anencephaly Atrioventricular septal defect
 Encephalocele Heterotaxy
 Exencephaly Single ventricle complex
 Spina bifida Tetralogy of Fallot
Holoprosencephaly D-transposition of great arteries
Syntelencephaly Double outlet right ventricle
Schizencephaly Anomalous pulmonary venous return
Agenesis of the corpus callosum Coarctation of aorta
Hamartomas Aorto-pulmonary window
Craniofacial area Gastrointestinal system
Orofacial clefts Intestinal atresia
Oculo-auriculo-vertebral spectrum defects Imperforate anus
 Oculo-auriculo-vertebral disorder Ventral wall defects
 Hemifacial macrosomia  Gastroschisis
 Goldenhar syndrome  Omphalocele
Anophthalmia Musculoskeletal system
Microphthalmia Caudal regression syndrome
Congenital cataracts Sirenomelia
Coloboma Tibial hemimelia
Choanal atresia Absence of femur
Genitourinary system Polysyndactyly
Hypospadias Congenital lumbar hernia
Renal agenesis Lumbocostovertebral syndrome
Renal hypoplasia Femoral facial syndrome
Bladder exstrophy

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by Clara Stamouli
 shown that the congenital abnormalities can be reversed
by treatment with antioxidants such as N-acetylcysteine,
resveratrol, and melatonin. (22)(23)(24) Moreover, it has
been demonstrated that hyperglycemia disturbs intracellu-
lar calcium homeostasis, which leads to organelle function
perturbation and subsequent increase in apoptosis. (25)
CENTRAL NERVOUS SYSTEM
Maternal diabetes is known to disturb the development of
the central nervous system and cause congenital defects.
(13)(26)(27)(28)(29) The central nervous system is among
the commonly affected systems in an infant of a diabetic
mother. Birth defects commonly encountered are neural
tube defects, holoprosencephaly, and hydrocephaly. (30)(31)
Other central nervous system defects reported to be associ-
ated with maternal diabetes are schizencephaly, agenesis of
corpus callosum, and hamartomas. (32)(33)(34)(35)
• Neural tube defects are a heterogenous group of defor-
mities characterized by an opening in the vertebral col-
umn or cranium, resulting from failure of normal
neural tube closure during early embryo development.
(36)(37)
• Anencephaly is characterized by absence of major por-
tions of skull and brain resulting from failure of the ros-
tral neuropore to close. (38)
• Encephalocele is a defect consisting of a saclike hernia-
tion of neural tissue through an opening in the cra-
nium. (39)
• Exencephaly is characterized by complete or partial
absence of the bones of the skull roof with a properly
formed brain.
• Spina bifida occurs when the spinal column is split
(bifid) as a result of failure of the embryonic neural tube
to close at the posterior end during the fourth week of
embryonic development. It may manifest as meningo-
cele, myelomeningocele, or spina bifida occulta. (37)
• Holoprosencephaly is an abnormality of brain formation
in which complete or partial absence of division into
hemispheres is observed. Symptoms of this condition
include abnormal facial formation with the development
of cyclopia, proboscis nose (or absent nose), cleft lip,
and cleft palate. (40)
• Syntelencephaly is a rare anomaly in which cleavage of
the prosencephalon is absent in the region of the poste-
rior parts of the frontal and parietal lobes with normal
interhemispheric splitting seen anterior and posterior to
the affected region. (41)
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CARDIOVASCULAR SYSTEM
The most common congenital heart defects associated with
maternal diabetes include persistent truncus arteriosus,
atrioventricular septal defect, heterotaxy, and single ventri-
cle complex. (42) The cardiogenesis is an elaborate process,
involving numerous types of tissues. Among the causative
mechanisms of diabetes-induced cardiac defects are dysre-
gulation of the hypoxia-inducible factor 1, notch signaling,
wingless-related integration signaling and transforming
growth factor b signaling pathways. (18)(43)(44)(45)(46)
Persistent truncus arteriosus is a defect featuring a ven-
tricular septal defect (VSD), a single truncal valve, and a
single ventricular outflow tract. Pulmonary venous blood
mixes with systemic venous blood at the level of VSD and
is then ejected to the single great artery. (47)(48) The
defect arises from improper creation of conotruncal septal
wall, and the common truncal root fails to separate into
aortic and pulmonary outflow tracts. (49)
Atrioventricular septal defect, also known as “atrioventricular
canal defect,” is a cardiac defect that is characterized by a varied
level of the atrial and ventricular septal defects in conjunction
with a single or partly divided atrioventricular orifice. (50) This
defect results from the failure of fusion of endocardial cush-
ions. These cushions constitute paired (superior and inferior)
bulbous mesenchymal structures that develop early in embryo-
genesis at the atrioventricular junction. They develop toward
each other and eventually fuse at about 4 weeks of develop-
ment to form a continuous septum and later form valves. Lack
of fusion results in different degrees of atrioventricular septal
defects. (51)(52) Embryos of diabetic pregnancies have been
shown to have impaired development of endocardial cushions.
(53)(54)
Heterotaxy is a broad term covering various conditions
characterized by an anomalous arrangement of thoracic
and abdominal organs across the left-right axis of the
heart that cannot be described as situs inversus. (55)(56)
There is a wide variety of cardiac structure lesions that
might involve atrial anomalies, conotruncal anomalies,
atrioventricular canal defects, total and partial anomalous
venous return, and ventricular outflow abnormalities. (57)
Systemic venous abnormalities and a range of arrhythmias
may also be present. (57)(58)
Single ventricle complex is a summation of congenital
cardiac abnormalities in which 1 of the ventricles is sub-
stantially underdeveloped or the interventricular septum
failed to form. (59) This defect originates during the first
8 weeks of development. (60)
Among other congenital heart defects less commonly
associated with diabetes are tetralogy of Fallot, D-
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 transposition of great arteries, double outlet right ventri-
cle, anomalous pulmonary venous return, coarctation of
aorta, and aortopulmonary window. (42)(61) Animal data
have also shown that pregestational diabetes may impair
the development of coronary vasculature and cause coro-
nary artery hypoplasia. (20)
CRANIOFACIAL AREA
Craniofacial defects encountered in infants of diabetic
mothers include orofacial clefts, the oculo-auriculo-verte-
bral disorder (OAVD) spectrum, anophthalmia and micro-
phthalmia, cataracts, coloboma, choanal atresia, and
others. (5)(62)
Orofacial clefts develop consequent to an aberrant
embryonic development of the nasomaxillary complex.
They can be defined by the absence of continuity of the
palate, upper alveolar margins, and upper lips. The defects
can be of various degrees and lateralities. (63)(64) On
occasion, cleft defects may involve other various soft-tissue
and bony structures of the face. (65) Such defects have
also been associated with maternal DM. (66)
The OAVD spectrum includes a heterogenous group of
disorders characterized by abnormalities of the structures
derived from the first and second pharyngeal arches dur-
ing embryogenesis. (67) These disorders, as the name
suggests, are characterized by the anomalies of the ear,
eyes, and vertebral column. The spectrum is subdivided
into 3 disorders: OAVD, hemifacial macrosomia, and
Goldenhar syndrome. Associated clinical features also
include brain anomalies and developmental delay. (68)
Noting that most of the anomalies are found in the struc-
tures derived from the neural crest cells, it has been
hypothesized that poorly controlled maternal diabetes dis-
turbs cephalic neural crest cell migration. (69) Moreover,
it has been suggested that the cause might be alteration of
the Pax3 gene path by hyperglycemia and subsequent oxi-
dative stress. (70)
Anophthalmia and microphthalmia are birth defects
viewed as a spectrum of developmental ocular malforma-
tions spanning from the eyes being underdeveloped and
abnormally small to entirely absent. Frequently, develop-
mental ocular malformations are present as part of a
genetic disorder; however, the prevalence of nonsyndromic
anophthalmia and microphthalmia has been found to be
higher among children of diabetic mothers. (71)
Abnormal facial features may be present in infants of
diabetic mothers as part of a syndrome, such as femoral-
facial syndrome, in which upward-slanting palpebral fis-
sures, low-set poorly formed pinnae, short and broad nose,
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thin upper lip, long philtrum, and micrognathia may be
seen. (72)(73)
GASTROINTESTINAL SYSTEM
Gastrointestinal system defects in infants of diabetic
mothers include, but are not limited to, intestinal atresia,
imperforate anus, and ventral wall defects. (5)(62) (74)(75)
Intestinal atresia is an absence or complete closure of the
intestinal lumen. It can take place at any site in the bowel.
It may manifest as solitary or multiple lesions. (76)(77)
Imperforate anus refers to the congenital anorectal mal-
formation in which the normal opening of the anus is not
patent. (78) The anomaly ranges in severity from the very
minor to those that are very complex, associated with other
abnormalities and are hard to manage. (79) The anorectal
defects result from failure of normal hindgut development
in weeks 4 to 6 of embryogenesis. (74) Historically imper-
forate anus has been divided into high, intermediate, and
low in accordance with the distance between the end of the
rectal pouch to the level of the levator ani muscle. (80)
Abdominal wall defects are abnormal openings in the
abdomen across which different internal abdominal
organs may protrude. (81) In gastroschisis, the defect is
paraumbilical and the bowels are not covered by a mem-
brane. As a result, the bowel is exposed in utero, and
becomes matted, dilated, and covered with fibrinous sub-
stance. (82) Omphalocele is a defect at the base of the
umbilical cord where the contents are covered by a mem-
branous sac. (83)
GENITOURINARY SYSTEM
Among the genitourinary defects associated with maternal
diabetes are hypospadias, renal agenesis/hypoplasia, and
bladder exstrophy. (42)(84)(85)
Hypospadias is the second most common urologic con-
genital abnormality in boys secondary to undescended testes.
(86) It is a congenital condition characterized by proximal
displacement of the urethral meatus, downward curvature of
the penile shaft, and hooded prepuce that is deficient on the
underside in male neonates. (87) Hypospadias is caused by
the aberrant or incomplete urethral closure during the first
weeks of embryonic development. (88)
Renal agenesis is congenital absence of 1 (unilateral) or
both (bilateral) kidneys at birth. It results from failure of
the ureteric bud to form or to reach/induce the metaneph-
ric mesenchyme, leading to cell death by apoptosis. (89)
Bilateral renal agenesis leads to severe oligohydramnios
and the development of Potter sequence. This condition is
characterized by a complex of features that result from
 paucity of amniotic fluid and compression in utero. Pul-
monary hypoplasia is present and is dependent on the
degree of both deficit of amniotic fluid and compression
of the fetal chest. Facial features are referred to as Potter
facies which is described as having a flattened nose,
recessed chin, prominent epicanthal folds, and abnormally
shaped ears. (90) Limb abnormalities include clubbed
feet, hip dislocation, and limb shortening. Skeletal anoma-
lies, such as sacral agenesis or hemivertebrae may also be
seen. (90)
Bladder exstrophy is a complex congenital anomaly that
includes a subumbilical abdominal wall defect and partial
closure of the bladder, with bladder mucosa being contin-
uous with the abdomen wall. (91) The presentation may
vary and include associated defects, such as epispadias
and abnormalities of the pelvic muscles and bones. (92)
MUSCULOSKELETAL
Among the defects associated with maternal diabetes, cau-
dal regression syndrome (CRS) has been reported to have
the highest odds ratio. (42) This syndrome includes a
broad spectrum of musculoskeletal anomalies that include
total or partial agenesis of the sacrum, coccyx, and lumbar
spine as well as anomalies of the pelvis and lower extremi-
ties. Clinical manifestations involve neurologic symptoms
such as segmental deficit (predominantly motor with rela-
tive sensory function sparing) matching the level of verte-
bral agenesis. (93) Frequently urinary and bladder as well
as gastrointestinal anomalies and dysfunction are present.
(94) The most widely adopted theory of CRS genesis is
failure of induction of the caudal elements before the sev-
enth week of gestation. (95) The exact mechanism under-
lying CRS is not known. Mechanisms that may play a role
include fetal hypoperfusion, vascular steal, hypoxemia,
and amino acid imbalances. (96) Renshaw classified CRS
into 4 types (97):
• Type I is defined as the total or partial unilateral sacral
agenesis that is limited to the sacrum or coccygeal area.
• Type II (most common form) involves a partial sacral
agenesis with a bilaterally symmetric defect between the
ilia and a normal or hypoplastic first vertebra.
• Type III is characterized by variable lumbar and total
sacral agenesis with the ilia attached to the sides of the
lowest vertebra present.
• Type IV is the most severe form and is characterized by
fusion of iliac bones or presence of iliac amphiarthrosis
along with the characteristics of type III. (97)
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Sirenomelia is a condition characterized by fusion of
the lower extremities. Some consider it to be a severe
form of CRS; however, it is also argued to be a distinct
diagnostic entity. (98)(99)
Other musculoskeletal abnormalities associated with
maternal diabetes include tibial hemimelia, absence of
femur, polysyndactyly, congenital lumbar hernia, lumbo-
costovertebral syndrome, and femoral facial syndrome.
(73)(100)(101)(102)(103) Tibial hemimelia is a rare defect
characterized by complete or partial absence of tibia. (104)
Lumbo-costovertebral syndrome is a clinical entity charac-
terized by hemivertebrae, costal anomalies, and hypoplasia
of abdominal muscles presenting as congenital lumbar
hernia. (105) As the name implies, femoral facial syn-
drome is composed of unusual facial features as well as
aplasia or hypoplasia of femoral bones. (72) Facial features
may include upslanted palpebral fissures, low-set ears,
short nose, long philtrum, cleft palate, and micrognathia.
(106)
PREVENTION
Pregnancy in women with type 1 and type 2 DM is associ-
ated with high risk of complications for both the mother
and fetus. Thereby, pregravid preparation is of great
importance. The action toward the modifiable risk factors
for such complications leads to significantly improved out-
comes of pregnancy and lower frequency of congenital
defects in newborns. Beginning at puberty and continuing
in all reproductive age women, preconception counseling
must be a part of routine surveillance for diabetes. The
American Diabetes Association advises maintaining hemo-
globin A1c levels at less than 6.5% at the time of concep-
tion and at less than 6% during gestation. (107) Before
these levels are achieved, it is recommended that women
be on long-term reversible forms of contraception. (108)
Pregnant women with diabetes are in need of closer
fetal monitoring. Detailed fetal anatomy scan is warranted
at 18 to 20 weeks of gestation to screen for congenital
anomalies. Fetal echocardiography should be considered.
Earlier delivery may be required if maternal or fetal health
concerns are present. (109)
CONCLUSION
The worldwide incidence of diabetes is projected only to
keep increasing in the coming decades. (1) Moreover, 1 in 2
adults living with diabetes is not aware of their condition. (1)
These facts underscore the importance of the ability to rec-
ognize and address the congenital defects in children born
to women with diabetes. Appropriate resources should be
Vol. 23 No. 5 MAY 2022 e323
 directed to increase prompt detection and management of
diabetes in women of childbearing age to prevent the con-
genital anomalies in offspring.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Recognize the effect of maternal diabetes on a
developing fetus.
• Recognize mechanisms of maternal diabetes
teratogenicity.
• Identify congenital defects of the infants of
diabetic mothers.
• Identify measures to prevent congenital abnor-
malities in the infants of diabetic mothers.
Acknowledgment
I thank Theodore De Beritto, MD, for his expertise through-
out this study and for his help in writing this article.
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