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Infants of women with diabetes

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
Literature review current through: Jun 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 (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", section on 'Scheduled cesarean birth for fetal weight ≥4500 grams' 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 the preterm infant (less than 35 weeks gestational age)".)

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.

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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.)

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Topic 5058 Version 30.0

References