Infants of Women With Diabetes

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Infants of women with diabetes

Authors: Arieh Riskin, MD, MHA, PhD, Joseph A Garcia-Prats, MD
Section Editors: Leonard E Weisman, MD, Joseph I Wolfsdorf, MD, BCh
Deputy Editor: Laurie Wilkie, MD, MS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2022. | This topic last updated: Feb 10, 2020.
INTRODUCTION
Diabetes in pregnancy is associated with an increased risk of fetal, neonatal, and long-term
complications in the offspring. Maternal diabetes may be pregestational (ie, type 1 or type 2
diabetes diagnosed before pregnancy with a prevalence rate of approximately 1.8 percent)
or gestational (ie, diabetes diagnosed during pregnancy with a prevalence rate of
approximately 7.5 percent). The outcome is generally related to the onset and duration of
glucose intolerance during pregnancy and severity of the mother's diabetes. (See
"Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and
management".)
This topic will review the complications seen in the offspring of women with diabetes and the
management of affected neonates. The prenatal management of pregestational and
gestational diabetes mellitus is discussed in separate topic reviews. (See "Gestational
diabetes mellitus: Screening, diagnosis, and prevention" and "Pregestational (preexisting)
diabetes mellitus: Obstetric issues and management" and "Gestational diabetes mellitus:
Obstetric issues and management" and "Gestational diabetes mellitus: Glucose
management and maternal prognosis" and "Pregestational (preexisting) diabetes:
Preconception counseling, evaluation, and management".)
FETAL EFFECTS
Poor glycemic control in pregnant diabetic women leads to deleterious fetal effects
throughout pregnancy, as follows [1]:
● In the first trimester and time of conception, maternal hyperglycemia can cause
diabetic embryopathy, resulting in major birth defects and spontaneous abortions
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( table 1). This primarily occurs in pregnancies with pregestational diabetes [2]. The
risk for congenital malformations is only slightly increased with gestational diabetes
mellitus (GDM) compared with the general population (odds ratio [OR] 1.1-1.3). The risk
of malformations increases as maternal fasting blood glucose levels and body mass
index (BMI) increases when GDM is diagnosed early in pregnancy. These findings
suggest that some of these mothers are probably undiagnosed women with type 2
diabetes [3,4]. (See 'Congenital anomalies' below and "Pregestational (preexisting)
diabetes: Preconception counseling, evaluation, and management".)
● Diabetic fetopathy occurs in the second and third trimesters, resulting in fetal
hyperglycemia, hyperinsulinemia, and macrosomia.
• Animal studies have shown that chronic fetal hyperinsulinemia results in elevated
metabolic rates that lead to increased oxygen consumption and fetal hypoxemia, as
the placenta may be unable to meet the increased metabolic demands [5]. Fetal
hypoxemia contributes to increased mortality, metabolic acidosis, alterations in fetal
iron distribution, and increased erythropoiesis [6]. Increased synthesis of
erythropoietin leads to polycythemia [7,8]; promotes catecholamine production,
which can result in hypertension and cardiac hypertrophy; and may contribute to
the 20 to 30 percent rate of stillbirth seen in poorly controlled diabetic pregnancies
[9]. As the fetal red cell mass increases, iron redistribution results in iron deficiency
in developing organs, which may contribute to cardiomyopathy and altered
neurodevelopment [6]. Fetal hyperinsulinemia is also thought to contribute to
impaired or delayed lung maturation. (See 'Polycythemia and hyperviscosity
syndrome' below and 'Cardiomyopathy' below and 'Respiratory distress' below and
"Pregestational (preexisting) diabetes mellitus: Obstetric issues and management"
and "Gestational diabetes mellitus: Obstetric issues and management", section on
'Fetal surveillance' and "Pregestational (preexisting) diabetes mellitus: Obstetric
issues and management", section on 'Initiation and frequency of fetal surveillance'.)
• Oxidative stress may play a role in maternal and fetal complications of diabetic
pregnancies [10,11]. For example, increased generation of reactive oxygen species
with inadequate antioxidant defenses in the fetal heart might lead to abnormal
cardiac remodeling and hypertrophic cardiomyopathy [4,12]. In addition, increased
erythropoietin production with resultant polycythemia in the newborn infant of a
mother with diabetes was related to the degree of oxidative stress [12,13].
• Excessive nutrients delivered from the poorly controlled mother with diabetes cause
increased fetal growth, particularly of insulin-sensitive tissues (ie, liver, muscle,
cardiac muscle, and subcutaneous fat), resulting in macrosomia, defined as a birth
weight (BW) ≥4000 g or greater than the 90th percentile for gestational age (GA)
( picture 1). (See 'Macrosomia' below and "Pregestational (preexisting) diabetes:

Preconception counseling, evaluation, and management".)
• Maternal hyperglycemia leads to fetal hyperglycemia resulting in fetal

hyperinsulinemia and neonatal hypoglycemia. Fetal hyperinsulinemia also
stimulates storage of glycogen in the liver, increased activity of hepatic enzymes
involved in lipid synthesis, and accumulation of fat in adipose tissue. These
metabolic effects might contribute to long-term metabolic complications in the
offspring. (See 'Hypoglycemia' below and 'Metabolic risks' below.)
NEONATAL EFFECTS
Infants of mothers with diabetes are at increased risk for congenital anomalies, mortality
and morbidity compared with neonates born to a mother without diabetes ( table 2).
Neonatal complications in offspring of mothers with diabetes include [14]:
● Congenital anomalies
● Prematurity
● Perinatal asphyxia
● Macrosomia, which increases the risk of birth injury (eg, brachial plexus injury)
● Respiratory distress
● Metabolic complications including hypoglycemia and hypocalcemia
● Hematologic complications including polycythemia and hyperviscosity
● Low iron stores
● Hyperbilirubinemia
● Cardiomyopathy
Although insulin treatment and intensive prenatal and neonatal care have improved,
neonatal complications and congenital anomalies observed in diabetic pregnancies
contribute to a reported perinatal mortality rate that ranges from 0.6 to 4.8 percent.
Pregestational versus gestational diabetes — Infants born to mothers with pregestational

diabetes have a higher risk of mortality and morbidity compared with offspring from
mothers with gestational DM; these infants are more likely to be macrosomic, preterm, and
have congenital anomalies and respiratory distress [2,15-19]. For infants born to mothers
with gestational DM, the risk of adverse neonatal effects modestly increases when mothers
require insulin treatment during pregnancy compared with infants whose mothers are
managed by diet alone [20]. Strict glycemic control preconception and during pregnancy is
associated with lower perinatal mortality and morbidity. (See "Gestational diabetes mellitus:
Screening, diagnosis, and prevention" and "Gestational diabetes mellitus: Glucose
management and maternal prognosis", section on 'Rationale for treatment'.)
Infants of mothers who have insulin-treated DM are more likely to be preterm and
macrosomic than infants born to mothers with type 2 DM not treated with insulin as well as
infants of mothers with gestational diabetes. This was illustrated in a population study of all
live births in Finland between 2004 and 2014. Infants of women with any type of DM who
received insulin therapy were at highest risk for large for gestational age and preterm birth
(40 and 37 percent, odds ratio [adjusted OR] 43.8, 95% CI 40.88-46.93 and 11.17, 95% CI
10.46-11.93, respectively), infants of women with type 2 DM not receiving insulin were at
mild to moderately increased risk (12.8 and 10.1 percent, aOR 9.57, 95% CI 8.65-10.58 and
2.12, 95% CI 1.9-2.36, respectively), and infants of women with gestational DM not receiving
insulin were mildly or no increased risk (5 and 5 percent, aOR 3.8, 95% CI 3.66-3.96 and 1,
respectively) compared with women with no diabetes (2 and 5 percent) [18]. These data can
be useful for counseling women with diabetes about risks for LGA and PTB in offspring. (See
"Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and
management", section on 'Fetal and neonatal risks' and "Pregestational (preexisting)
diabetes mellitus: Obstetric issues and management".)
Congenital anomalies — Infants of mothers with diabetes are at significant risk for major
congenital anomalies due to maternal hyperglycemia at the time of conception and during
early gestation ( table 1) [6]. The overall reported risk for major malformations is
approximately 5 to 6 percent, with a higher prevalence rate of 10 to 12 percent when
mothers require insulin therapy [2,14,16,21]. In a study of 13,030 infants with congenital
anomalies and 4895 without birth defects, when compared with a reference group of
nondiabetic control mothers, the risk of isolated and multiple congenital anomalies was
highest in infants of mothers with pregestational diabetes (adjusted odd ratios [OR] 3.17,
95% CI 2.2-4.99 and adjusted OR 8.62, 95% CI 5.27-14.1, respectively) followed by infants
born to mothers with gestational diabetes (adjusted OR 1.42, 95% CI 1.17-1.73 and adjusted
OR 1.5, 95% CI 1.13-2.0) [22].
Congenital malformations account for approximately 50 percent of the perinatal deaths in

infants of mothers with diabetes [23]. This risk can be reduced by strict glycemic control
during the pre- and periconceptual (first eight weeks of pregnancy) periods. Two-thirds of
the anomalies in infants of mothers with diabetes involve either the cardiovascular system
(8.5 per 100 live births) or central nervous system (CNS; 5.3 per 100 live births) [21].
● Cardiac – Cardiovascular malformations occur in 3 to 9 percent of diabetic pregnancies

[21,24]. Cardiac defects that present more frequently in Infants of mothers with
diabetes than in the normal newborn population include transposition of the great
arteries (TGA), double outlet right ventricle (DORV), ventricular septal defect (VSD),
truncus arteriosus, tricuspid atresia, and patent ductus arteriosus (PDA) [14,21,24].
● CNS – Anencephaly and spina bifida are 13 and 20 times more frequent, respectively,
among Infants of mothers with diabetes compared with infants of mothers without
diabetes [21]. The majority of cases of caudal regression syndrome occur in Infants of
mothers with diabetes [25]. This syndrome consists of a spectrum of structural defects
of the caudal region, including incomplete development of the sacrum and, to a lesser
degree, the lumbar vertebrae ( picture 2), and occurs approximately 200 times more
frequently in Infants of mothers with diabetes than in other infants [26]. (See "Closed
spinal dysraphism: Pathogenesis and types", section on 'Risk factors'.)
● Other anomalies include [14,21]:
• Flexion contracture of the limbs.

• Vertebral anomalies.
• Cleft palate.
• Intestinal anomalies including small left colon syndrome, which occurs primarily in
infants of mothers with diabetes [27]. Small colon syndrome is a rare condition that
presents as a transient inability to pass meconium, which resolves spontaneously.
Preterm delivery — Spontaneous and medically indicated preterm delivery occur more

frequently in diabetic than nondiabetic pregnancies [2] ( table 2). Preterm labor and timing
of delivery in diabetic pregnancies are discussed separately. (See "Gestational diabetes
mellitus: Obstetric issues and management", section on 'Timing of birth' and "Pregestational
(preexisting) diabetes: Preconception counseling, evaluation, and management" and
"Pregestational (preexisting) diabetes mellitus: Obstetric issues and management", section
on 'Preterm birth'.)
Perinatal asphyxia — Infants of mothers with diabetes are at increased risk for intrauterine
or perinatal asphyxia due to macrosomia (failure to progress and shoulder dystocia) and
cardiomyopathy (fetal heart rate abnormalities), which often is defined broadly in the
literature to include fetal heart rate abnormalities during labor, low Apgar scores (calculator
1), and intrauterine death ( table 2).
In one study of 162 infants of mothers with diabetes, 27 percent had perinatal asphyxia [28].
Perinatal asphyxia correlated with hyperglycemia in labor, prematurity, and nephropathy.
Maternal vascular disease, manifested by nephropathy, may contribute to the development
of fetal hypoxia and subsequent perinatal asphyxia.
Macrosomia — Macrosomia, defined as birth weight (BW) greater than the 90th percentile
on a population-appropriate growth chart or above 4000 g, is a common complication and
can occur in all diabetic pregnancies. However, the incidence appears to be greater in infants
born to mothers with pregestational diabetes [2,29,30].
Macrosomia is associated with disproportionate growth, resulting in an increased ponderal

index that results in higher chest-to-head and shoulder-to-head ratio, higher body fat, and
thicker upper extremity skinfolds compared with nondiabetic control infants of similar
weight and length [29-32]. As a result, at birth, infants of mothers with diabetes typically
appear large and plethoric, with excessive fat accumulation in the abdominal and scapular
regions, and have visceromegaly ( picture 1).
Infants with macrosomia are more likely than those who are not macrosomic to have
hyperbilirubinemia, hypoglycemia, acidosis, respiratory distress, shoulder dystocia, and
brachial plexus injury [30,33]. Fetal macrosomia including risk factors and complications for
delivery and neonate are discussed separately. (See "Fetal macrosomia" and "Large for
gestational age newborn", section on 'Neonatal morbidity' and "Shoulder dystocia: Risk
factors and planning birth of high-risk pregnancies".)
Birth injury — Macrosomia predisposes to birth injury, especially shoulder dystocia.

Shoulder dystocia occurs in nearly one-third of infants of mothers with diabetes with
macrosomia [34] and is associated with increased risk of brachial plexus injury, clavicular or
humeral fractures, perinatal asphyxia, and, less often, cephalohematoma, subdural
hemorrhage, or facial palsy [14,15,35]. The risk of shoulder dystocia is also increased by the
disproportionate growth that occurs in macrosomic infants, resulting in a higher chest-to-
head and shoulder-to-head ratio than infants of mothers without diabetes [36].
The timing and route of delivery of infants of mothers with diabetes who are at risk for
shoulder dystocia are discussed separately. (See "Gestational diabetes mellitus: Obstetric
issues and management" and "Pregestational (preexisting) diabetes mellitus: Obstetric
issues and management", section on 'Route'.)
Respiratory distress — It has been commonly assumed that respiratory distress is a

frequent complication in infants of mothers with diabetes due to the increased risk of
neonatal respiratory distress syndrome (RDS) secondary to surfactant deficiency. However, a
secondary analysis of the Antenatal Late Preterm Delivery Steroids (ALPS) trial reported that
after adjusting for confounding variables (eg, age of the mother and gestational age [GA] at
delivery) neonates born to mothers with gestational diabetes had similar rates of respiratory
distress as those born to mothers without diabetes [37]. This report included only late
preterm births (GA between 34 0/7 and 36 5/7 weeks) and did not provide information about
each participant's glucose control and diabetes treatment. Therefore, good glycemic control
may have reduced the risk of respiratory problems in the infants of women with GDM. (See
"Gestational diabetes mellitus: Obstetric issues and management", section on
'Consequences of GDM'.)
Respiratory distress syndrome — RDS due to surfactant deficiency occurs more

frequently in infants of mothers with diabetes for the following two reasons [2,14,15,21,38]:
● Infants of mothers with diabetes are more likely to be delivered prematurely than
infants born to mothers without diabetes. (See 'Preterm delivery' above.)
● At a given gestational age, infants of mothers with diabetes are more likely to develop
RDS because maternal hyperglycemia appears to delay surfactant synthesis. The
proposed underlying mechanism is neonatal hyperinsulinemia, which interferes with
the induction of lung maturation by glucocorticoids [39-41]. The risk of RDS in preterm
infants of mothers whose diabetes is well-controlled approaches that of infants born to
mothers without diabetes at a similar gestational age [37,42,43].
The clinical manifestations, diagnosis, prevention, and management of RDS are discussed
separately. (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory
distress syndrome in the newborn" and "Management of respiratory distress syndrome in
preterm infants".)
Other causes of respiratory distress — In addition to RDS, other causes of respiratory

distress in infants of mothers with diabetes include transient tachypnea of the newborn
(TTN) and cardiomyopathy. (See 'Cardiomyopathy' below.)
TTN occurs two to three times more commonly in infants of mothers with diabetes than in
normal infants [14,44]. The mechanism may be related to reduced fluid clearance in the
diabetic fetal lung. Cesarean delivery, which is more frequently performed in diabetic versus
nondiabetic pregnancies, may be a contributing factor [2,45]. (See "Transient tachypnea of
the newborn".)
In infants born to mothers with gestational diabetes mellitus (GDM), the risk for respiratory
distress increases for those with BW >4000 g [3,33,46].
Metabolic complications — Infants of mothers with diabetes are at increased risk for

metabolic complications in the newborn period. The most common are hypoglycemia,
hypocalcemia, and hypomagnesemia.
Hypoglycemia — Hypoglycemia, defined as blood glucose levels below 40 mg/dL (2.2

mmol/L) in the first 24 hours of life, occurs frequently in infants of mothers with diabetes [2],
even in mothers who receive intensive prenatal care [14,47]. The onset of hypoglycemia
typically occurs within the first few hours after birth. Thus, these infants require close blood
glucose monitoring after delivery and frequently need glucose supplementation, including
parenteral glucose infusion. In our experience, the hyperinsulinemic state typically lasts two
to four days. In neonates requiring glucose supplementation, the maintenance of normal
plasma glucose levels while supplemental glucose is being weaned is evidence of resolving
hyperinsulinism. Further testing should be undertaken to define the cause of persistent
hypoglycemia in infants who continue to require glucose infusions at rates exceeding 8 to 10
mg/kg per minute to maintain normal plasma glucose levels beyond the first week of life.
(See "Management and outcome of neonatal hypoglycemia", section on 'Evaluation of
infants with persistent hypoglycemia'.)
Hypoglycemia is likely caused by persistent hyperinsulinemia in the newborn after

interruption of the intrauterine glucose supply from the mother. In particular, macrosomic
infants with increased BW (>90th percentile or >4000 g) are more likely to develop
hyperinsulinemia and hypoglycemia [2,48,49]. Strict glycemic control during pregnancy
decreases, but does not abolish, the risk of neonatal hypoglycemia [50,51]. (See "Gestational
diabetes mellitus: Glucose management and maternal prognosis" and "Pregestational
(preexisting) diabetes mellitus: Antenatal glycemic control" and "Pregestational (preexisting)
and gestational diabetes: Intrapartum and postpartum glucose management" and
"Gestational diabetes mellitus: Obstetric issues and management".)
Infants of mothers with diabetes who are preterm or small for gestational age (SGA) are at
increased risk for persistent hypoglycemia because glycogen stores are reduced, and
hyperinsulinemia impairs the ability to mobilize hepatic glycogen [52]. In these infants,
hypoglycemia may last longer than two to four days and may require more prolonged and
higher rates of glucose infusion.
Although there are no data on the caloric needs of infants of mothers with diabetes once
glycemic control is established, it appears that the caloric needs of these infants are similar
to those of infants of mothers without diabetes, and that subsequent weight loss and gain is
self-regulated by the infant. However, offspring of diabetic pregnancies appear to be at risk
for excess weight gain during childhood. (See 'Obesity and glucose metabolism' below.)
The clinical manifestations, evaluation, and management of neonatal hypoglycemia are

discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal
hypoglycemia" and "Management and outcome of neonatal hypoglycemia".)
Hypocalcemia — The reported prevalence of hypocalcemia, defined as a total serum

calcium concentration less than 7 mg/dL (1.8 mmol/L) or an ionized calcium value less than 4
mg/dL (1 mmol/L), or in infants with BW less than 1500 g, an ionized calcium less than 3.2
mg/dL (0.8 mmol/L), ranges from at least 5 percent and up to 30 percent in infants of
mothers with diabetes ( table 2) [14,53]. Good glycemic control during pregnancy reduces
the risk of neonatal hypocalcemia [53].
The lowest serum calcium concentration typically occurs between 24 and 72 hours after
birth. Hypocalcemia usually is asymptomatic and resolves without treatment [14]. As a
result, routine screening is not recommended. However, the serum calcium concentration
should be measured in infants with jitteriness, lethargy, apnea, tachypnea, or seizures, and
in those with prematurity, asphyxia, respiratory distress, or suspected infection.
The clinical manifestations, evaluation, and management of neonatal hypocalcemia are

discussed separately. (See "Neonatal hypocalcemia".)
Hypomagnesemia — Hypomagnesemia, defined as serum magnesium concentration less

than 1.5 mg/dL (0.75 mmol/L), occurs in up to 40 percent of infants of mothers with diabetes
within the first three days after birth [54,55]. It has been proposed that low neonatal levels
are due to maternal hypomagnesemia caused by increased urinary loss secondary to
diabetes. Prematurity may be a contributing factor.
Hypomagnesemia usually is transient and asymptomatic and, thus, usually is not treated.
However, hypomagnesemia can reduce both parathyroid hormone (PTH) secretion and PTH
responsiveness [56,57]. As a result, in some neonates with hypocalcemia and
hypomagnesemia, the hypocalcemia may not respond to treatment until the
hypomagnesemia is corrected [58].
Polycythemia and hyperviscosity syndrome — Elevated hematocrits including

polycythemia, defined as a central venous hematocrit of more than 65 percent, are more
likely in infants of mothers with diabetes than in infants whose mothers are not diabetic [2].
In a large case series, of the 276 infants with measured hematocrits, 17 percent of infants of
mothers with diabetes had hematocrits above 60 percent, including 5 percent of infants with
polycythemia [14]. The underlying pathogenesis is due to increased erythropoietin
concentrations caused by chronic fetal hypoxemia [7,8]. Transfusion of placental blood to the
fetus associated with maternal or fetal distress also may contribute to a high hematocrit
[59]. Higher hemoglobin and hematocrit values in the newborn are associated with fetal
exposure to oxidative stress [12].
Polycythemia may lead to hyperviscosity syndrome, including vascular sludging, ischemia,

and infarction of vital organs. Hyperviscosity is thought to contribute to the increased
incidence of renal vein thrombosis seen in infants of mothers with diabetes [60]. To detect
polycythemia, the hematocrit should be measured within 12 hours of birth.
The clinical manifestations, management, and outcome of polycythemia are discussed

separately. (See "Neonatal polycythemia".)
Low iron stores — The combined erythrocyte and storage iron pools are lower in infants of
mothers with diabetes. The degree of low iron stores at birth is inversely related to the
degree of polycythemia, suggesting a shunting of fetal iron into the red cell mass [61].
However, there are no data on iron supplementation therapy and it is not currently
recommended. It is thought that the excess iron in the polycythemic red cell mass will be
recirculated as the excess red blood cells break down.
Hyperbilirubinemia — Hyperbilirubinemia occurs in 11 to 29 percent of infants of mothers

with diabetes, especially in preterm infants [14]. In addition to prematurity, other factors
associated with neonatal jaundice include poor maternal glycemic control, macrosomia, and
polycythemia [54,62]. (See "Unconjugated hyperbilirubinemia in term and late preterm
infants: Screening" and "Unconjugated hyperbilirubinemia in term and late preterm infants:
Management".)
Cardiomyopathy — Infants of mothers with diabetes are at increased risk for transient

hypertrophic cardiomyopathy [2,63,64]. In this condition, the most prominent change is
thickening of the interventricular septum (IVS) with reduction in the size of the ventricular
chambers, resulting in potential obstruction of left ventricular outflow. Outflow obstruction
occasionally is aggravated by anterior systolic motion of the mitral valve.
Infants often are asymptomatic, but 5 to 10 percent have respiratory distress or signs of
poor cardiac output or heart failure. The chest radiograph may show cardiomegaly; but
hypertrophy is best detected by echocardiography. Cardiomyopathy is transient and resolves
as plasma insulin concentrations normalize. Symptomatic infants typically recover after two
to three weeks of supportive care, and echocardiographic findings resolve within 6 to 12
months [65]. Supportive care for symptomatic infants includes increased intravenous (IV)
fluid administration and propranolol. Inotropic agents are contraindicated because they may
decrease ventricular size and further obstruct cardiac outflow [66].
Cardiac hypertrophy is thought to be caused by fetal hyperinsulinemia, which increases the

synthesis and deposition of fat and glycogen in the myocardial cells [56]. It is most likely to
occur in mothers with poor glycemic control during pregnancy [67,68]. However, increased
cardiac muscle mass also occurs in fetuses of mothers with diabetes with good metabolic
control (mean glycated hemoglobin [HbA1c] 7.5 percent) [69]. One study suggests that there
is a correlation between high degrees of oxidative stress and the abnormal cardiac
remodeling resulting in selective morphologic hypertrophy [12].
Fetal echocardiography shows evidence of hypertrophy starting at the end of the second
and the beginning of the third trimester. Hypertrophy is characterized by marked thickening
of the IVS, and less of the left ventricular (LV) free walls [70]. Another study suggested that a
prenatal echocardiographic measurements (at 35 weeks or more) of IVS thickness ≥4.5 mm
and/or IVS/left myocardial wall thickness (LMWT) ratio ≤1.18 were not only predictive of
hypertrophic cardiomyopathy, but were also associated with increased risk for intrauterine
and perinatal mortality [71].
Some infants develop congestive cardiomyopathy, a more diffuse process of hypertrophy

and hyperplasia of the myocardial cells that frequently occurs in association with perinatal
asphyxia, hypoglycemia, or hypocalcemia [68]. Echocardiography shows a dilated and poorly
contractile heart. This condition usually is also reversible as the metabolic derangements are
corrected.
NEONATAL MANAGEMENT
The management of infants of women with diabetes needs to anticipate and treat any
complication associated with maternal hyperglycemia as well as provide routine neonatal
care. The risk of complications varies depending on the gestational age (GA), birth weight
(BW), and the degree and severity of maternal hyperglycemia as discussed above.
In our practice, we use the following approach:
● Prior to delivery, an assessment of the need for neonatal resuscitation is made based
on the GA, anticipated BW, presence of a congenital anomaly or labor complications,
and the mode of delivery (eg, cesarean delivery). (See "Neonatal resuscitation in the
delivery room", section on 'Anticipation of resuscitation need'.)
● Immediately after delivery, routine neonatal care is provided that includes drying,
clearing the airway of secretions, maintaining warmth, and a rapid assessment of the
infant's clinical status based on heart rate, respiratory effort, tone, and an examination
to identify any major congenital anomaly. The need for further intervention is based on
this initial evaluation. If the infant does not require additional resuscitation, the infant
should be given to the mother for skin-to-skin care and initiation of breastfeeding in
the delivery room. (See "Neonatal resuscitation in the delivery room", section on
'Resuscitation' and "Overview of the routine management of the healthy newborn
infant", section on 'Delivery room care'.)
● Further evaluation following transition from the delivery room includes a

comprehensive examination, and laboratory screening for hypoglycemia and
polycythemia.
• If cyanosis is detected, the infant should be assessed for cardiac and respiratory
disease including measurement of oxygen saturation by pulse oximetry. (See
"Overview of cyanosis in the newborn".)
• Glucose monitoring is performed within one to two hours after birth or whenever
symptoms consistent with hypoglycemia occur. Samples should be obtained before
feedings. Surveillance is performed for the first 12 to 24 hours of life. Monitoring is
continued after 24 hours of life, in infants with low plasma glucose concentrations
(less than 45 mg/dL, 2.5 mmol/L) until feedings are well established and glucose
values have normalized [72]. In our centers, intervention for hypoglycemia is
initiated at glucose levels <40 mg/dL (2.2 mmol/L) during the first 24 hours of life,
and <50 mg/dL (2.8 mmol/L) between 24 and 48 hours of life. (See 'Hypoglycemia'
above and "Management and outcome of neonatal hypoglycemia".)
• The hematocrit should be measured within the first few hours of delivery. (See
'Polycythemia and hyperviscosity syndrome' above and "Neonatal polycythemia".)
• Bilirubin levels should be measured if the infant appears to be jaundiced. (See

"Unconjugated hyperbilirubinemia in term and late preterm infants: Screening" and
"Unconjugated hyperbilirubinemia in preterm infants <35 weeks gestation".)
• Calcium and magnesium levels should be obtained in any infant with symptoms
compatible with either hypocalcemia or hypomagnesemia (eg, seizure or
jitteriness). (See 'Hypocalcemia' above and 'Hypomagnesemia' above and "Neonatal
hypocalcemia".)
● If there are no significant complications that require further intervention, routine

newborn care should be provided. (See "Overview of the routine management of the
healthy newborn infant".)
LONG-TERM OUTCOME
Long-term outcome data show that prenatal exposure to hyperglycemia increases the risk of
postnatal metabolic complications and impacts neurodevelopmental outcome [73-76].
Metabolic risks
Diabetes — Infants of mothers with diabetes have an increased risk of developing

diabetes, which is, in part, genetically determined [77]. The lifelong risk of type 1 diabetes is
2 percent in offspring of a mother with type 1 diabetes, 6 percent in siblings, and 65 percent
by age 60 years in identical twins (versus 0.3 to 0.4 percent in subjects with no family history)
[78]. (See "Pathogenesis of type 1 diabetes mellitus".)
The development of type 2 diabetes also is influenced by genetic susceptibility. The lifetime
risk for a first-degree relative of a patient with type 2 diabetes is 5 to 10 times higher than
that of age- and weight-matched subjects without a family history. (See "Pathogenesis of
type 2 diabetes mellitus".)
The development of type 2 diabetes also may be affected by the abnormal intrauterine
metabolic environment of a diabetic pregnancy. Data from studies performed in Pima
Indians, who have the highest rates of gestational diabetes, demonstrate that 45 percent of
offspring of mothers with gestational diabetes develop type 2 diabetes between 20 and 24
years of age compared with offspring of prediabetic (9 percent) or women without diabetes
(1 percent) [79,80]. This increased risk persists despite accounting for paternal history of
diabetes, age of onset of diabetes in parents, and the child's body mass index (BMI),
suggesting that the intrauterine environment contributed to the development of diabetes, in
addition to genetic factors. In a follow-up study, more than two-thirds of offspring of
mothers with gestational diabetes developed type 2 diabetes by 34 years of age [81].
Obesity and glucose metabolism — Intrauterine exposure to hyperglycemia resulting in

fetal hyperinsulinemia may affect the development of adipose tissue and pancreatic beta
cells leading to increased BMI and impaired glucose metabolism, which may result in an
increased risk for obesity. This effect is seen in offspring as adults or older children for both
pregestational [82-84] and gestational diabetes [85-91].
Neurodevelopmental outcome — Data are limited regarding the effect of maternal

pregestational and gestational diabetes on the subsequent neurodevelopmental outcome of
offspring.
● A review of the literature reported that maternal gestational diabetes seems to be

negatively associated with offspring's childhood cognitive development, particularly
language development [92]. However, the quality of the evidence was poor, as most
studies did not adequately control for confounding factors such as pre-pregnancy
obesity or maternal socioeconomic status, and failed to provide or report adequate
blinding.
● In a subsequent report from the National Institute of Child Health and Human
Development (NICHD) Neonatal Research Network of extremely preterm infants
(gestational age [GA] from 22 to 28 weeks) born from 2006 to 2011, there was no
difference in neurodevelopmental outcome amongst the initial three study groups
(infants born to mothers using insulin before pregnancy, infants born to those starting
insulin during pregnancy, and infants born to maternal controls) at 18 to 22 months
corrected age [93].
● In a Danish cohort study, adolescents born to mothers with pregestational type 1

diabetes had lower scores on cognitive testing compared with controls after
adjustment for confounding factors [94]. Confounding factors based on parental
reporting by questionnaire included sex, age at follow-up, parity, parental educational
achievement, maternal age at delivery, presence of neonatal complications, maternal
complications, gestational age, and maternal socioeconomic status.
Other limited data suggest that poorly controlled maternal diabetes during pregnancy may
impact neurodevelopmental outcome [73,94,95]. However, evidence is circumstantial and of
poor quality.
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Care during pregnancy for people with type 1 or
type 2 diabetes (The Basics)")
● Beyond the Basics topics (see "Patient education: Care during pregnancy for patients
with type 1 or 2 diabetes (Beyond the Basics)" and "Patient education: Gestational
diabetes (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Diabetes in pregnancy is associated with an increased risk of fetal, neonatal, and long-term
complications in offspring.
● Adverse effects of diabetes during pregnancy that affect the fetus include spontaneous
abortions, major malformations, and stillbirths. In addition, maternal hyperglycemia
leads to increased fetal growth resulting in macrosomia and fetal hyperinsulinemia,
which increase the risk of neonatal hypoglycemia. (See 'Fetal effects' above.)
● Infants of mothers with diabetes are at increased risk for mortality and morbidity
compared with infants born to mothers without diabetes. The risk of neonatal
complications generally increases with poor maternal glycemic control. Potential
adverse effects include:
• Congenital anomalies, especially cardiovascular and central nervous system (CNS)

defects. (See 'Congenital anomalies' above.)
• Preterm birth. (See 'Preterm delivery' above.)
• Perinatal asphyxia. (See 'Perinatal asphyxia' above.)
• Macrosomia, defined as a birth weight (BW) greater than the 90th percentile or
greater than 4000 g. In infants of mothers with diabetes, macrosomia is associated
with disproportionate growth that results in high chest-to-head and shoulder-to-
head ratios that predispose to birth injury, especially shoulder dystocia
( picture 1). (See 'Macrosomia' above.)
• Respiratory distress is a common complication primarily due to the increased risk of

respiratory distress syndrome (RDS). (See 'Respiratory distress' above.)
• Hypoglycemia that generally occurs within the first few hours after birth. (See
'Hypoglycemia' above.)
• Hypocalcemia is commonly observed but generally is asymptomatic. (See

'Hypocalcemia' above.)
• Polycythemia and hyperviscosity. (See 'Polycythemia and hyperviscosity syndrome'

above.)
• Low iron stores.
• Hyperbilirubinemia. (See 'Hyperbilirubinemia' above.)
• Transient hypertrophic cardiomyopathy that is generally asymptomatic. However, a

subset of affected infants (5 to 10 percent) may present with respiratory distress,
poor cardiac output, or heart failure. (See 'Cardiomyopathy' above.)
● The management of infants of women with diabetes needs to anticipate and treat any
complication associated with maternal hyperglycemia and also provides routine
neonatal care. It includes a physical examination that focuses on the respiratory and
cardiac status of the infant and identifies any major congenital anomaly. One hour
after delivery, laboratory evaluation includes measurement of the infant's blood
glucose and hematocrit to screen for hypoglycemia and polycythemia. (See 'Neonatal
management' above.)
● Long-term outcome data suggest that prenatal exposure to hyperglycemia increases

the risk of postnatal metabolic complications (eg, diabetes, increased body mass index
[BMI], and impaired glucose metabolism) and may also negatively impact
neurodevelopmental outcome. (See 'Long-term outcome' above.)
Use of UpToDate is subject to the Terms of Use.
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Topic 5058 Version 30.0
GRAPHICS
Common congenital anomalies in infants of diabetic mothers
System Manifestations
Neurologic Anencephaly with or without herniation of neural elements, arrhinencephaly,

microcephaly, holoprosencephaly, neural tube defects (meningomyelocele and
other variants).
Cardiovascular Transposition of the great vessels with or without ventricular septal defect
(VSD), VSD, coarctation of the aorta with or without VSD or patent ductus
arteriosus, atrial septal defect, single ventricle, hypoplastic left ventricle,
pulmonic stenosis, pulmonary valve atresia, double outlet right ventricle
truncus arteriosus.
Gastrointestinal Duodenal atresia, imperforate anus, anorectal atresia, small left colon
syndrome, situs inversus.
Genitourinary Ureteral duplication, renal agenesis, hydronephrosis.
Skeletal Caudal regression syndrome (sacral agenesis), hemivertebrae.
Other Single umbilical artery.
Adapted from Tyrala EE. Obstet Gynecol Clin North Am 1996; 23:221; and Reece EA, Homko CJ. Semin Perinatol 1994;
18:459.
Graphic 62158 Version 2.0
Macrosomic infant of diabetic mother
A newborn macrosomic infant of a diabetic mother. The main abnormalities

are disproportionate growth with a plethoric appearance and excessive fat
accumulation.
Courtesy of G Cabrera- Mesa, MD.
Perinatal mortality and neonatal morbidity in infants of diabetic mothers
Rate,
Condition Comments
percent
Perinatal mortality 0.6 to 4.8 Lowest rates reflect very good prenatal
care and strict glycemic control
Cesarean delivery 32 to 45 Highest rates are associated with lowest

perinatal mortality
Prematurity
<37 weeks gestation 24 to 36
<34 weeks gestation 14 to 16
Congenital anomalies 1.7 to 9.4 Lowest rates are associated with strict
glycemic control preconception and in
early pregnancy
Perinatal asphyxia, including fetal 9 to 27 Lowest rates are seen with close
distress during labor, low 1-minute Apgar monitoring during labor and appropriate
score, and intrauterine death intervention
Macrosomia 9 to 47 Lowest rates are seen with strict glycemic

control during pregnancy; strong
association with neonatal hypoglycemia
Intrauterine growth restriction 2 to 8
Respiratory distress syndrome 2 to 6 Lower rates seen with strict glycemic

control during pregnancy
Hypoglycemia 5 to 25 Strong correlation with macrosomia,

lower rates seen with strict glycemic
control during pregnancy
Hypocalcemia 4 Mostly asymptomatic
Polycythemia (hematocrit >65 percent) 5
Hyperbilirubinemia 11 to 29
Cardiomyopathy
Symptomatic 5 to 10
Asymptomatic 30 to 50
Note: The wide range cited for some complications is due to the inclusion of several studies,
which were performed at different times, places in the world, and in different study groups
(infants of all diabetic mothers, or those of gestational diabetic mothers or pregestational type 1
or 2 diabetic mothers). In many cases, different definitions of symptoms or findings were also
used. In general, the lowest rates of complications are associated with improved obstetric care
that resulted in better maternal glycemic control and neonatal management.
Caudal regression syndrome
Infant of a diabetic mother with caudal regression syndrome. Top

panel shows decreased growth of the left leg. In the bottom panel, a
plain radiograph reveals absence of the sacrum.
Courtesy of G Cabrera-Mesa, MD.
Contributor Disclosures
Arieh Riskin, MD, MHA, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Joseph A Garcia-Prats, MD No relevant financial relationship(s) with ineligible companies to
disclose. Leonard E Weisman, MD Equity Ownership/Stock Options: Vax-Immune [Ureaplasma
diagnosis, vaccines, antibodies, other medical diagnostics and pre-analytical devices].
Patent Holder:
Baylor College of Medicine [Ureaplasma diagnosis, vaccines, antibodies, process for preparing
biological samples].
All of the relevant financial relationships listed have been mitigated. Joseph I
Wolfsdorf, MD, BCh No relevant financial relationship(s) with ineligible companies to disclose. Laurie
Wilkie, MD, MS No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
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( picture 1). (See 'Macrosomia' below and "Pregestational (preexisting) diabetes:

• Maternal hyperglycemia leads to fetal hyperglycemia resulting in fetal

Pregestational versus gestational diabetes — Infants born to mothers with pregestational

Congenital malformations account for approximately 50 percent of the perinatal deaths in

● Cardiac – Cardiovascular malformations occur in 3 to 9 percent of diabetic pregnancies

● Other anomalies include [14,21]:

• Flexion contracture of the limbs.

Preterm delivery — Spontaneous and medically indicated preterm delivery occur more

Macrosomia is associated with disproportionate growth, resulting in an increased ponderal

Birth injury — Macrosomia predisposes to birth injury, especially shoulder dystocia.

Respiratory distress — It has been commonly assumed that respiratory distress is a

Respiratory distress syndrome — RDS due to surfactant deficiency occurs more

Other causes of respiratory distress — In addition to RDS, other causes of respiratory

Metabolic complications — Infants of mothers with diabetes are at increased risk for

Hypoglycemia — Hypoglycemia, defined as blood glucose levels below 40 mg/dL (2.2

Hypoglycemia is likely caused by persistent hyperinsulinemia in the newborn after

The clinical manifestations, evaluation, and management of neonatal hypoglycemia are

Hypocalcemia — The reported prevalence of hypocalcemia, defined as a total serum

The clinical manifestations, evaluation, and management of neonatal hypocalcemia are

Hypomagnesemia — Hypomagnesemia, defined as serum magnesium concentration less

Polycythemia and hyperviscosity syndrome — Elevated hematocrits including

Polycythemia may lead to hyperviscosity syndrome, including vascular sludging, ischemia,

The clinical manifestations, management, and outcome of polycythemia are discussed

Hyperbilirubinemia — Hyperbilirubinemia occurs in 11 to 29 percent of infants of mothers

Cardiomyopathy — Infants of mothers with diabetes are at increased risk for transient

Cardiac hypertrophy is thought to be caused by fetal hyperinsulinemia, which increases the

Some infants develop congestive cardiomyopathy, a more diffuse process of hypertrophy

In our practice, we use the following approach:

● Further evaluation following transition from the delivery room includes a

• Bilirubin levels should be measured if the infant appears to be jaundiced. (See

● If there are no significant complications that require further intervention, routine

Diabetes — Infants of mothers with diabetes have an increased risk of developing

Obesity and glucose metabolism — Intrauterine exposure to hyperglycemia resulting in

Neurodevelopmental outcome — Data are limited regarding the effect of maternal

● A review of the literature reported that maternal gestational diabetes seems to be

● In a Danish cohort study, adolescents born to mothers with pregestational type 1

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

• Congenital anomalies, especially cardiovascular and central nervous system (CNS)

• Preterm birth. (See 'Preterm delivery' above.)

• Perinatal asphyxia. (See 'Perinatal asphyxia' above.)

• Respiratory distress is a common complication primarily due to the increased risk of

• Hypocalcemia is commonly observed but generally is asymptomatic. (See

• Polycythemia and hyperviscosity. (See 'Polycythemia and hyperviscosity syndrome'

• Low iron stores.

• Hyperbilirubinemia. (See 'Hyperbilirubinemia' above.)

• Transient hypertrophic cardiomyopathy that is generally asymptomatic. However, a

● Long-term outcome data suggest that prenatal exposure to hyperglycemia increases

Use of UpToDate is subject to the Terms of Use.

3. Mitanchez D, Burguet A, Simeoni U. Infants born to mothers with gestational diabetes

4. Mitanchez D, Yzydorczyk C, Siddeek B, et al. The offspring of the diabetic mother--short-

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