Perinatal morbidities from maternal diabetes
Definition
Diabetes during pregnancy may have an adverse impact on the embryo and fetus and increase the rate of perinatal and long-term complications.
Type 1 diabetes is classified as a requirement for insulin supplementation to prevent ketoacidosis, or Type 2 diabetes is when hyperglycemia is caused by insulin resistance and is controlled by diet or oral hypoglycemics.
Diabetic mothers may suffer from pregestational diabetes (PGD) or develop glucose intolerance during pregnancy (gestational diabetes or GD) when carbohydrate intolerance is first diagnosed during pregnancy. GD is diagnosed according to biochemical parameters established to detect women whose offspring are at increased risk of adverse pregnancy outcome due to high glucose blood levels.
Since the associations between maternal glycemia and adverse outcomes are continuous across the range of glucose concentrations, the criteria were set in purpose to identify the infants at risk for birthweight above the 90th percentile. Criteria used by most centers suggest that all pregnant women should be screened and diagnosed by a 50-g glucose challenge test and those testing positive have a 3-hour 100-g oral glucose tolerance test (GTT) at 24 to 28 gestational weeks.
Criteria
50-g glucose challenge test: Two cutoffs levels are suggested:
(1) plasma glucose after 1 hour above 7.2 mmol/L (130 mg%)
(2) plasma glucose level above 7.8 mmol/L (140 mg%)
GTT: Normal values—0 min <5.3 mmol/L (95 mg%); 60 min <10 mmol/L (180 mg%); 120 min <8.6 mmol/L (155 mg%); 180 min <7.8 mmol/L (140 mg%). The American Congress of Obstetricians and Gynecologists (ACOG) in 2001 recommended the 50 g with a cutoff level of 7.2 mmol/L (130 mg%) and allows the GTT with two cutoffs: lower and higher.
Due to the increased rate of infants large for gestational age (LGA) with adverse outcome, more recent recommendations increased the number of women diagnosed as suffering from GD. According to the criteria set by the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) group in 2008, based on the International Association of the Diabetes and Pregnancy Study Groups all pregnant women without previous diagnosis of diabetes should be screened at 24 to 28 weeks by 75 g oral glucose challenge test. Levels exceeding 5.1 mmol/L (92 mg%) of fasting blood glucose, 10 mmol/L (180 mg%) 1 hour post-glucose load and 8.5 mmol/L (153 mg%) 2 hours post-glucose load are indicative for overt GD.
The ACOG recommends universal screening excluding women with all the specified criteria: under 25 years, no racial risk factors, BMI <25, no history of glucose intolerance, no history of adverse pregnancy outcome that may have been a result of glucose intolerance and no history of diabetes in first degree relatives.
Incidence/prevalence
In a meta-analysis of the literature, the prevalence of GD was found to be 1.7% to 11.6%.
The frequency of diabetes mellitus during pregnancy differs between countries. When using the new criteria established by the HAPO, it reaches 17.8% among their cohort with a median incidence of 5%.
The rate of PGD is estimated to be about 0.3%.
Pathophysiology
According to the Pederson hypothesis, maternal hyperglycemia during pregnancy leads to fetal hyperglycemia, which in turn causes an exaggerated response within the fetal pancreatic islet cells that produce large amounts of insulin. Pederson found that the higher the maternal blood glucose was during delivery, the higher it was in the infant and that the infant’s blood glucose was in negative correlation with their birthweight, and dropped to very low levels after delivery. Hence, the glucose concentration in maternal blood determines the insulin concentration in fetal blood because of the passive transfer of glucose by the fetus.
Additionally, the liver has a low threshold for glucose release, in negative correlation with insulin level. After delivery, when maternal glucose supply ceases, blood glucose is determined by the liver threshold for glucose release, which is abnormally low.
Thus, the infant’s blood sugar is in negative correlation with maternal pregnancy level due to the combination of high insulin level and low liver threshold.
Since insulin is a growth factor, the birthweight is increased in correlation to blood glucose.
Risk factors
Maternal risk factors for development of glucose intolerance during pregnancy
Women suffering from Type 1 and Type 2 PGD are prone to develop glucose intolerance during pregnancy.
Other risk factors include race: Women of Hispanic, Afro-Caribbean, south and east Asian origin have increased GD rate compared to Caucasians. Increase in pregestational BMI, higher maternal age, family history of diabetes mellitus, and previous pregnancy with glucose intolerance also increase the likelihood to develop glucose intolerance during pregnancy. Women suffering from preeclampsia also have higher percentage of GD.
Predictors of pregnancy outcome include low vitamin D, low adiponectin, oxidative stress, degree of maternal glycemic control, IGF, and chronic intrauterine acidosis.
Maternal risk factors for adverse perinatal outcome in infants of diabetic mothers (DM)
There is an increased rate of fetal death and perinatal complications associated with poor glycemic control.
Glycated or glycosylated hemoglobin (HbA1c) is an indicator of hyperglycemia that allows evaluation of maternal metabolic condition. It is related to higher complication rate; however, when adjusted for glucose levels there was no clear association between its levels and birthweight, sum of skinfolds, percent body fat >90th percentile, for fasting and 1-hour glucose and for cord C-peptide. There was also no correlation with cesarean section (CS) rate and neonatal hypoglycemia.
In other studies evaluating women with PGD HbA1c was associated with three- to fivefold increase in the rate of congenital malformations, mostly cardiovascular and genitourinary.
Ultrasonography is used to evaluate fetal growth. It is recommended (ACOG), that when there is a good glycemic control, to deliver at 40 weeks. When there is poor glycemic control, and before 39 weeks, induction of pulmonary maturity should be considered. Fetuses 4000 to 4500 g should be considered for cesarean delivery. When there are additional risk factors (delivery history, pelvimetry, no progress of labor), and over 4500 g, mothers should undergo surgical delivery.
Diabetic complications in the neonatal period
Clinical presentation, diagnosis, management, and prognosis: These will be discussed for each complication separately.
Overview
Diabetes in pregnancy increases the rate of perinatal complications. However, increased risk of congenital anomalies is mostly diagnosed among women with PGD. Perinatal stress, metabolic complications, and organs dysfunction occurs at increased rate among offspring of women with GD in correlation with maternal glycemic control.
Diabetes in pregnancy is associated with increased rate of polyhydramnios, delivery by CS, and shoulder dystocia.
Infants may present with abnormal body weight and proportions: SGA, LGA, and increased body adiposity.
The perinatal adaptation may be complicated by asphyxia, respiratory distress syndrome, cardiomyopathy, small left colon, and metabolic complications including hypoglycemia, hyperbilirubinemia, polycythemia, and hypocalcemia.
These morbidities are not unique for diabetes in pregnancy and may also complicate pregnancies with or without prior insult. The diagnosis and treatment are according to the situation as stated by the infant’s medical condition.
Shoulder dystocia
Clinical presentation
An increment in the rate of shoulder dystocia is associated in a linear manner with increased glucose levels.
Asymmetric macrosomia (excluding IDMs) with smaller head circumference than infants with a similar weight increased the rate of shoulder dystocia.
Diabetic asymmetric adiposity complicates the passage through the birth canal and raises the risk of brachial plexus injury, a flaccid paralysis of the arm that affects different nerves of the brachial plexus supplied by C5 to T1. In a meta-analysis of the literature until 2005 Andersen et al revealed that the odds ratio for brachial plexus injury among IDMs was 3.2. Macrosomia and assisted instrumental delivery further increased the risk for palsy.
Diagnosis
The diagnosis of brachial plexus paralysis is clinical.
The hand position depends on the affected nerve roots. High palsy (C5, C6) results in weakness of the shoulder, external rotation or abduction of arm, and elbow flexion/supination; middle (C5-7) is similar to high but also includes elbow flexion/supination paralysis and loss of wrist extension; low (C8, T1) result in a floppy hand with claw-like deformity; complete involvement of the brachial plexus result in a flail arm.
Associated clavicular fracture may be clinically diagnosed or demonstrated by x-ray.
Management
Management may be conservative (PT/OT) or include brachial plexus surgical exploration.
Prognosis
Recovery may occur within 48 hours, but may take up to 6 months. Residual deficits may reach 20% to 30%.
Perinatal asphyxia
Clinical presentation
Infants born to mothers with PGD and GD had a fourfold increased risk of asphyxia among cases identified with encephalopathy associated with suboptimal care during the delivery.
On a meta-analysis of the literature from 2000 to 2010 an increased risk for asphyxia was found among mothers with PGD whose fetuses had fetal hypoxia, which caused an increase in fetal erythropoiesis and secondary polycythemia that led to abnormal fetal rhythm and cord blood acidosis. Despite lower oxygen content and higher lactate concentration in cord blood the infants had normal Apgar scores.
Other studies revealed increased placental size with an increase in degenerative lesions, villous immaturity, and an increase in nucleated fetal red blood cells, indicating chronic fetal hypoxia.
Perinatal death and asphyxia that were more common among untreated mothers with GD are sometimes the result of undiagnosed Type 2 diabetes, and are independently associated with maternal obesity and macrosomia.
Diagnosis
Low APGAR scores and the need for resuscitation at delivery are indicative of perinatal asphyxia
Management
Neonatal resuscitation and treatment include ventilation, chest compressions, medications, volume expansions, whole body hypothermia, etc (see Chapter 36).
Prognosis
The prognosis depends on the severity of the infant’s condition and subsequent management.
Cardiomyopathy
Clinical presentation
Hypertrophic cardiomyopathy is more common in IDMs even when good glycemic control is achieved. The thickening is more prominent in the ventricular septum than the free wall and may lead to functional subaortic stenosis.
The onset of hypertrophy is about 20 weeks of gestation. The rate of intrauterine hypertrophy was found up to 75% of the fetuses evaluated with an increase in both septum and cardiac dimension.
Usually the infants are asymptomatic and the hypertrophy resolves spontaneously; however, some may have clinical symptoms. Signs of hypertrophic cardiomyopathy in infants may include difficulty breathing, heart murmur, poor feeding or growth, excessive sweating, or signs of congestive heart failure.
Findings on echocardiography include reduced ejection time and reduced systolic anterior movement of the mitral valve.
Diagnosis
Diagnosis is by echocardiography both during pregnancy and after delivery.
Myocardial hypertrophy may result in decreased ventricular compliance.
Major septal hypertrophy can lead to functional subaortic stenosis and secondary mitral insufficiency.
Treatment
Most cases resolve spontaneously. Cardiac failure is treated as indicated from the clinical situation.
Prognosis
Most cases resolve spontaneously; however, death is reported among offspring of mothers with poor glycemic control.
Myocardial hypertrophy and functional subaortic stenosis usually improve within days. Complete resolution is usually seen within 6 months.
Small left colon
Clinical presentation
Small left colon is a rare functional low intestinal obst-ruction of an unknown cause associated with maternal diabetes.
In a retrospective analysis of offspring diabetic pregnancies from 2004 to 2008 in a tertiary medical center in Australia, six out of 105 infants admitted to the neonatal intensive care unit had the diagnosis of intestinal obstruction, five of them (PGD n = 3. GD n = 2) had small left colon. During the time evaluated there were no other cases of small left colon among other infants.
Diagnosis
Diagnosis is by contrast enema.
The typical picture is a narrowed left colon with an abrupt transition zone at the splenic flexure.
Management
Rectal enema and rectal washouts.
Prognosis
Good with no residual intestinal complications.
Hypoglycemia
Clinical presentation
Clinical symptoms of hypoglycemia include jitteriness, cyanosis, seizures, apneic episodes, tachypnea, weak or high-pitched cry, floppiness or lethargy, poor feeding, and eye rolling.
Prolonged hypoglycemia may lead to coma, seizures, and death.
Diagnosis
The definition of neonatal hypoglycemia is controversial.
Associated conditions including perinatal stress and infection may have an impact on glucose requirements.
Most neonates have decreased glucose levels after delivery that is mainly compensated by the use of ketone bodies as alternative fuel.
Prolonged hypoglycemia may have an adverse effect on the nervous system.
The recommended threshold of 47 mg/dL is offered by the American Academy of Pediatrics (AAP) as a representation of a glucose level that is safe in most infants.
Management
Breastfed neonates can tolerate lower glucose levels due to their high concentration of ketone bodies.
The target glucose recommended by the AAP is 45 mg/dL to prevent secondary hyperinsulinism.
The recommendations of the AAP for the diagnosis and treatment of hypoglycemia among IDMs are presented in Figure 40-1.
Plasma glucose levels are 10% to 18% higher than whole blood. Bedside reagent glucose strip is usually used.
Low blood levels should be treated by a bolus of 200 mg/kg followed by supplementation with IV D10%, 5 to 8 mg/kg/min.
At least three blood levels over 40 mg/dL should be recorded before discharge.
If hypoglycemia persists, hyperinsulinism should be ruled out and an endocrinologist consultation should be performed.
Prognosis
Hypoglycemia, if effectively treated immediately after birth, has no detrimental effect on the infant.
Extremely low or persistently low blood glucose levels can result in hypoglycemic brain injury: Boardman et al reviewed the literature and found that glucose levels under 1 mmol/L (18 mg/dL) lasting 1 to 2 hours and/or recurrent episodes complicated by neurological manifestations are associated with increased risk of brain injury.
Acute clinical manifestations of neurologic injury are nonspecific but include altered consciousness, high-pitched cry and tremor, sweating, poor feeding, hypotonia, apnea, and hypothermia, and there can be rapid progression to seizures and coma.
Increased rate of motor problems, visual, learning, and behavioral difficulties, poor head growth, and later seizures are reported.
Typical brain injuries are posterior white matter loss, abnormal gray/white matter differentiation in the posterior occipital lobes with involvement of the visual cortex, and cystic changes involving the optic radiation and visual areas.
Respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTNB)
Clinical presentation
Increased work of breathing, tachypnea, cyanosis.
Diagnosis
The effect of GD on fetal lung maturity is contradictory. Among low birthweight in an Israeli cohort, there was no higher rate of RDS. RDS was rare with similar rates among women suffering from GD and PGD when evaluated for the benefit of fetal lung maturity test in the amniotic fluid. Among term pregnancies RDS rates were 0.8% regardless of glycemic control. No difference from controls in fetal maturity testing was also found when infants with both GD and PGD were matched for the controls; however, respiratory complications were found in the diabetic group: RDS (2/45) and wet lung (5/45) and in none of the controls.
Good glycemic control decreases the rate of RDS to the expected rate; poor control with mean glucose levels >6.7 mmol/L (120.6 mg/dL) increases the rate of lung immaturity. When mean glucose levels were >6.7 mmol/L (120.6 mg/dL), the maturity at term was similar to late preterm. Maturity was evaluated by amniotic fluid analysis for Clements test (the ability of the pulmonary surfactant to form a stable foam in the presence of ethanol), optical density at 650 nm (OD650 nm) difference, and lamellar body count. Standard maturity values include lecithin/sphingomyelin ratio greater than or equal to 2.0, phosphatidylglycerol greater than 2% to 5%, and optical density at 650 nm greater than or equal to 0.150.
CXR finding of typical “ground-glass” appearance or retained fetal fluid.
Management
Oxygen, ventilatory support, surfactant supplementation, and cardiovascular stabilization are the main treatment modalities in RDS.
Maternal diabetes has no impact on the management and prognosis when controlling for other confounding variables.
Prognosis
Prognosis is good and according to the associated complications.
Hyperbilirubinemia
(see Chapter 19)
Clinical presentation
Typical jaundice appearance
Diagnosis
High bilirubin levels can be measured in the infants’ blood or be evaluated by noninvasive bilirubin skin analyzers.
The rate of significant hyperbilirubinemia (over 95%, at the high-risk zone) increased from 6.4% among controls to 13.1% among offspring of women with diabetes in pregnancy. Women with GD were two times more likely to have infants with bilirubin ≥20 mg/dL (342 mmol/L).
It seems that fetal hyperinsulinemia increases fetal oxygen uptake, leading to increased erythropoiesis and neonatal hyperbilirubinemia.
Management
Appropriate feeding, phototherapy, and exchange transfusions, when severe, are according to the indications in other infants with hyperbilirubinemia.
Prognosis
Does not differ from other infants with hyperbilirubinemia.
Polycythemia
Clinical presentation
Increase in red blood cell mass is associated with maternal diabetes. Among infants who had partial exchange transfusion due to hyperviscosity syndrome, diabetic pregnancy was the main risk factor.
The increase in blood viscosity decreases oxygen delivery due to high resistance to blood flow.
An increase in erythropoietin cord blood was found in PGD and GD. The increase in erythropoiesis results from fetal hypoxia. An increase in glycosylated hemoglobin that reduces oxygen transport through the placenta, hyperinsulinism that increases oxygen consumption, and maternal ketosis with increased β-hydroxybutyrate levels were described in PGD and GD.
Infant is usually ruddy in appearance. May also show signs of respiratory distress, dehydration, hypoglycemia, or heart failure.
Diagnosis
Diagnosis is confirmed by central hematocrit >65%.
Management
Treatment is usually based on whether or not the infant is symptomatic; otherwise supportive treatment (hydration, phototherapy) may be instituted.
Partial exchange transfusion with either plasmanate, normal saline, or 5% albumin solution is the main treatment modality, though controversial. The Cochrane analysis found no change in the rate of neurodevelopmental delay comparing infants with partial exchange transfusion to controls.
Prognosis
Polycythemia is mostly self-resolving.
Polycythemic infants are at greater risk for developmental delays, lower IQ scores, and lower achievement.
Hypocalcemia
Clinical presentation
Infants of diabetic mothers have an increased rate of hypo-calcemia in the first few days of life. Increased rate of maternal diabetes was also found among infants presented with moderate to severe late onset symptomatic hypocalcemia.
A corresponding increase in parathyroid hormone in the cord blood and first day blood has been shown.
Low maternal vitamin D levels were inversely correlated with HbA1c and glucose blood levels. Low vitamin D in pregnancy increases the rate of hypocalcemia; however, the effect of vitamin D supplementation during pregnancy on neonatal calcium levels is unclear with contradictive results.
Clinical symptoms may include signs of neuromuscular irritability such as myoclonic jerks and/or seizures, apnea, cyanosis, and cardiac rhythm disturbances.
Other symptoms are vomiting, laryngospasm, tachycardia, heart failure, and prolongation of the QTc interval on the electrocardiogram.
Diagnosis
Confirmed by total serum calcium level <8 mg/dL or <2 mmol/L (symptomatic term infant) or <7 mg/dL or <1.75 mmol/L (asymptomatic).
Ionized fraction of calcium may be considered more significant and a level <4 mg/dL is generally accepted as hypocalcemic.
Management
Most of the infants of diabetic mothers have asymptomatic hypocalcemia.
Infants who have clinical symptoms or QTc prolongation should be treated with oral or intravenous calcium.
If magnesium concentration is low, treatment with intravenous or intramuscular magnesium sulfate is essential for correction of the hypocalcemia.
Treatment in cases of hypocalcemic seizures is by calcium replacement without need for anticonvulsants.
Prognosis
The hypocalcemia in IDMs is transitory and the prognosis depends on the infant’s medical condition.
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