This is a newborn infant male delivered to a 25 year old primagravida mother with poorly controlled type 2 diabetes mellitus who has not been compliant with her insulin regimen. Her other prenatal labs are otherwise unremarkable. She presented in labor at 37 weeks gestational age and delivered vaginally. Delivery was complicated by shoulder dystocia. The large appearing infant male is brought to the warmer initially apneic and with poor tone but began to cry vigorously with tactile stimulation. He subsequently develops respiratory distress with retractions, tachypnea, and grunting. Pulse oximetry at 5 minutes of life is 80% on room air. He is placed on mask CPAP (continuous positive airway pressure) with 40% FiO2 oxygen which reduces his work of breathing. APGAR scores are 6 (-2 color, -1 tone, -1 respiratory effort) and 9 (-1 color) at one and five minutes, respectively.
Exam: Vital signs are remarkable for an increased respiratory rate of 80 and his oxygen saturation is 80% on room air, improving to 100% on 40% FiO2 mask CPAP. Weight is 4.2 kg (greater than 95th percentile for age). Breath sounds are clear bilaterally with equal aeration. Heart examination is notable for a grade 2 systolic murmur. Abdomen is soft, without masses. The skin color appears plethoric and ruddy. There is crepitus palpated over the right clavicle. The remainder of the initial examination is normal.
The infant is admitted to the neonatal intensive care unit (NICU) for respiratory support on CPAP. A chest x-ray (CXR) reveals a fractured right clavicle and bilateral pulmonary ground glass opacities suggestive of respiratory distress syndrome. A bedside point of care glucose test is <40 mg/dL and a confirmatory serum glucose sample results at 25 mg/dL. A peripheral IV is started and 2 mL/kg of 10% dextrose in water (D10W) bolus is given over a minute. A D10W infusion is started at 80 mL/kg/day, which gives a glucose infusion rate (GIR) of 5.6 mg/kg/min. A repeat glucose drawn 30 minutes later is improved to 50 mg/dL. Other labs are notable for polycythemia with an elevated hematocrit of 68%. Over the next three days, his respiratory status improves and he is gradually weaned to room air. He is able to take full formula feedings by a bottle and is weaned off his IV fluids with resolved hypoglycemia. He receives phototherapy for two days for hyperbilirubinemia. An echocardiogram is done due to the persistent cardiac murmur which reveals a small ventricular septal defect (VSD). He is discharged home on day 6 of life with outpatient cardiology follow up scheduled.
The infant of a diabetic mother (IDM) is born to a mother with type 1 diabetes mellitus, type 2 diabetes mellitus, or gestational diabetes. Studies estimate that 16% of babies born in 2015 were exposed to some form of hyperglycemia during pregnancy, with 85% due to gestational diabetes. Although strict blood glucose control during pregnancy can reduce the risk of neonatal complications, it does not entirely eliminate it (1). In one study, 36% of IDMs were born preterm and 47% required NICU admission for complications such as respiratory distress, preterm birth, or hypoglycemia (2). The neonatal mortality rate is five times higher in IDM versus infants of nondiabetic mothers, with even higher neonatal mortality rates associated with pregestational diabetes. Risk of intrauterine fetal demise also appears to increase with poor glucose control. Pathophysiology may be related to chronic hypoxia from increased oxygen consumption secondary to fetal hyperinsulinemia (3).
Hypoglycemia: Pathophysiology and Management
Maternal glucose is transported across the placenta to the fetus but larger maternal peptides such as insulin are not. When the fetus is exposed to hyperglycemia from a diabetic mother, it increases fetal pancreatic secretion of insulin, which results in fetal hyperinsulinemia and eventually hypertrophy and hyperplasia of fetal pancreatic islet beta cells. Prolonged exposure to fetal hyperglycemia and hyperinsulinemia leads to several pathological changes which can cause postnatal complications (4).
Hypoglycemia develops in 25% to 50% of infants of diabetic mothers and 15% to 25% of mothers with gestational diabetes. After birth and ligation of the umbilical cord, fetal glucose levels drop as maternal transfer of glucose ceases; however, hyperinsulinemia in the IDM persists, causing an impaired response to hypoglycemia by the counter regulatory hormones glucagon and catecholamines to stimulate hepatic glucose production and lipolysis, leading to hypoglycemia shortly after birth. Symptoms of hypoglycemia include irritability, apnea, jitteriness, tremors, feeding difficulty, lethargy, tachypnea, seizures, hypothermia, tachycardia or hypotonia (4).
IDMs are at higher risk of hypoglycemia and should undergo serial glucose monitoring and management (5). Most institutions have specific protocol for this. IV glucose therapy is recommended for: 1) symptomatic infants with a glucose level <40 mg/dL require IV glucose therapy; 2) asymptomatic infants, with a glucose level of <25 mg/dL within the first 4 hours of life, <35 mg/dL within the first 4 to 24 hours of life, or 3) an inability to tolerate feeds (5). For more about the management of neonatal hypoglycemia, refer to the chapter on Neonatal chapter.
Other Concerns for Infants of Diabetics Mothers
36% to 45% of IDM’s may present as large for gestational age (LGA, birth weight greater than the 90th percentile) or macrosomic (weight greater than 4kg) (2). Fetal hyperinsulinemia causes increased hepatic glucose uptake, glycogen synthesis, and lipogenesis which leads to increased body fat, enlarged viscera, myocardial hypertrophy, and plethoric facies. This increased adiposity leads to macrosomia and a birth weight that is large for gestational age, which places the infant at high risk for birth injuries related to shoulder dystocia, brachial plexus injury, clavicular fracture, and increases the need for caesarian section by three time (2). The risk of perinatal asphyxia is also increased (3). In pregestational diabetic mothers with associated cardiovascular disease, such as chronic hypertension, the resulting uteroplacental insufficiency can cause intrauterine growth restriction and small for gestational age infants (SGA, birthweight less than 10th percentile) are observed in 2% of IDMs (2).
Respiratory distress after birth is more likely to occur in IDMs. Fetal hyperinsulinemia impairs surfactant production by disrupting cortisol’s stimulation of surfactant synthesis, resulting in an increased risk for surfactant deficiency and respiratory distress syndrome (RDS) (6). The IDM is also at increased risk for developing transient tachypnea of the newborn (TTN) (1,3). In managing IDMs with respiratory symptoms, CXR and echocardiogram can be considered to evaluate underlying pathologies. The management of RDS includes surfactant therapy and respiratory support. Blood cultures should be obtained and antibiotics started if infection is suspected based on other perinatal infection related risk factors.
There is a four-fold increase in the incidence of congenital anomalies in the IDM, though the risk varies with hemoglobin A1c (HbA1c) during the time of organogenesis (first trimester). The risk of malformation increases drastically once maternal HbA1c levels are sustained at more than 7% (3). These include: cardiac anomalies (ventricular or atrial septal defect, transposition of the great vessels, truncus arteriosus, double outlet right ventricle, tricuspid atresia, coarctation of the aorta), spinal agenesis-caudal regression (agenesis or hypoplasia of the femurs in conjunction with agenesis of the lower vertebrae and sacrum), neural tube defects, holoprosencephaly, gastrointestinal anomalies (duodenal or anorectal atresia), and renal anomalies (hydronephrosis, renal agenesis and dysplasia, cystic kidneys) (3). Cardiac and central nervous system abnormalities are involved in two-thirds of IDM-related anomalies. The pathogenesis of these congenital anomalies is unclear, although proposed mechanisms include teratogenic effects of hyperglycemia, hypoglycemia, fetal hyperinsulinemia, uteroplacental vascular disease, and genetic predisposition. Neonatal small left colon syndrome is a transient condition characterized by impaired intestinal motility that can occur in 5% of IDMs and presents as intestinal obstruction mimicking Hirschsprung disease, although normal bowel innervation is present (3). Hormone imbalance affecting the autonomic nervous system or increased amylin peptide, an inhibitor of gastric motility that is co-secreted with insulin, has been proposed as a mechanism for this transient condition (6).
Hypertrophy of the interventricular septum and walls of the right and left ventricles (septal hypertrophy) due to fetal hyperinsulinemia occurs in 30% of IDMs (3) and can lead to obstructive cardiomyopathy and heart failure in 5% to 10%. Studies show that cardiac hypertrophy can develop in late gestation even with strict glucose control. In general, this condition resolves spontaneously within the first six to 12 months of life (6). Symptomatic neonates should be managed with beta-blockers, such as propranolol.
Approximately 50% of IDMs develop transient hypocalcemia (serum calcium less than 7mg/dl) during the first 3 days after birth, due to suppression of the neonatal parathyroid hormone response. The risk is increased if there is birth asphyxia or prematurity. Hypomagnesemia (serum magnesium less than 1.5 mg/dl) occurs in 33% of IDMs, which may be related to increased urinary losses and can exacerbate hypocalcemia (6). Hypocalcemia and hypomagnesemia in IDMs is usually transient but may require supplementation if symptomatic.
Polycythemia (hematocrit greater than 65%) is seen in 20% to 40% of IDMs. Chronic fetal hyperinsulinemia results in an increase in metabolic rate and oxygen consumption, leading to relative hypoxemia which causes increased synthesis of erythropoietin and polycythemia. Polycythemia, in conjunction with immature liver metabolism, leads to increased risk for hyperbilirubinemia, which occurs in 25% of IDMs. Hyperviscosity resulting from polycythemia can lead to renal vein thrombosis, stroke, and other ischemic vascular related injury (6). Symptomatic neonates may be treated with IV fluid hydration or partial exchange transfusion.
The prognosis of long term outcomes of IDMs remains controversial. A long term follow up study showed that the increased fetal adiposity seen at birth normalized over infancy and there was no increased risk for obesity or diabetes in IDMs in childhood at 5 years of age (7). However, several subsequent studies have shown an increased risk of childhood obesity, diabetes mellitus, or metabolic syndrome (obesity, hypertension, dyslipidemia, and glucose intolerance) in IDMs (3,8-12). Evaluating neurodevelopmental outcomes of IDMs is difficult due to the higher incidence of confounding factors such as birth asphyxia, metabolic acidosis, concomitant hypoglycemia, and congenital malformations in this population. While some meta-analyses show associations between maternal diabetes and deficits in mental and psychomotor development, attention span, and overall intellectual function, other studies demonstrate no relationship between maternal diabetes and neurodevelopmental impairment (13). Some studies have shown that maternal acetonuria, a marker for poor diabetic control during pregnancy, is associated with lower IQ and mental developmental indices (14,15). Furthermore, there remains no definitive level of neonatal hypoglycemia that correlates consistently with adverse outcomes in the short or long-term. Overall, long-term outcomes for IDMs are still being investigated.
Questions
1. Infants of diabetic mothers are at the greatest risk for which of these conditions in the first day of life?
a. Hypercalcemia
b. Hypermagnesemia
c. Hyperglycemia
d. Hypoglycemia
2. Infants of diabetic mothers are at increased risk for being
a. Large for gestational age
b. Small for gestational age
c. Either
3. IV glucose therapy is required immediately for:
a. Symptomatic infant with a glucose level of 39
b. Asymptomatic infant with a glucose level of 35
c. Both
d. Neither
4. Infants who are large for gestational age have a birth weight greater than
a. 50th percentile
b. 75th percentile
c. 90th percentile
d. 98th percentile
5. Which of the following substances can cross the placenta to the fetus?
a. Maternal insulin
b. Maternal glucose
c. Neither
References
1. Adamkin DH. Neonatal hypoglycemia. Semin Fetal Neonatal Med. 2017;22(1):36-41. doi:10.1016/j.siny.2016.08.007
2. Committee on Fetus and Newborn, Adamkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics. 2011;127(3):575-579. doi:10.1542/peds.2010-3851
3. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005;115(3):e290-e296. doi:10.1542/peds.2004-1808
4. Burguet A. Long-term outcome in children of mothers with gestational diabetes. Diabetes Metab. 2010;36(6 Pt 2):682-694. doi:10.1016/j.diabet.2010.11.018
5. Camprubi Robles M, Campoy C, Garcia Fernandez L, Lopez-Pedrosa JM, Rueda R, Martin MJ. Maternal Diabetes and Cognitive Performance in the Offspring: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(11):e0142583. Published 2015 Nov 13. doi:10.1371/journal.pone.0142583
6. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics. 2000;105(5):1141-1145. doi:10.1542/peds.105.5.1141
7. el-Hashimy M, Angelico MC, Martin BC, Krolewski AS, Warram JH. Factors modifying the risk of IDDM in offspring of an IDDM parent. Diabetes. 1995;44(3):295-299. doi:10.2337/diab.44.3.295
8. Hay WW Jr. Care of the infant of the diabetic mother. Curr Diab Rep. 2012;12(1):4-15. doi:10.1007/s11892-011-0243-6
9. Kallem VR, Pandita A, Pillai A. Infant of diabetic mother: what one needs to know?. J Matern Fetal Neonatal Med. 2020;33(3):482-492. doi:10.1080/14767058.2018.1494710
10. Edward S. Ogata; Problems of the Infant of the Diabetic Mother. Neoreviews November 2010; 11 (11): e627–e631. https://doi.org/10.1542/neo.11-11-e627
11. Persson B, Gentz J. Follow-up of children of insulin-dependent and gestational diabetic mothers. Neuropsychological outcome. Acta Paediatr Scand. 1984;73(3):349-358. doi:10.1111/j.1651-2227.1994.tb17747.x
12. Pribylová H, Dvoráková L. Long-term prognosis of infants of diabetic mothers. Relationship between metabolic disorders in newborns and adult offspring. Acta Diabetol. 1996;33(1):30-34. doi:10.1007/BF00571937
13. Warram JH, Krolewski AS, Gottlieb MS, Kahn CR. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med. 1984;311(3):149-152. doi:10.1056/NEJM198407193110304
14. Rizzo T, Metzger BE, Burns WJ, Burns K. Correlations between antepartum maternal metabolism and intelligence of offspring. N Engl J Med. 1991;325(13):911-916. doi:10.1056/NEJM199109263251303
15. Sugar J, Lum TG, Fertel S, et al. Long-term neurodevelopmental outcomes among preterm infants born to mothers with diabetes mellitus. J Perinatol. 2022;42(4):499-502. doi:10.1038/s41372-021-01255-8
Answers to questions
1. d, 2.c, 3.a, 4.c, 5.b