Infant of the Diabetic Mother

Sunhwa Kim, MD

Loma Linda University

Children Hospital

Diabetes … Obesity

Not every high blood sugar is

Diabetes

DiabetesObesity

Obesity…Diabetes

Metabolic abnormalities associated with obesity– Hyperglycemia, dyslipidemia, alterations in

growth factors, hyperinsulinism etc.

Excessive abdominal fat independently associated with diseases: cardiovascular, cancer, osteoarthritis, gall bladder, diabetes, etc

Excess body fat leads to type 2 diabetes within 20 years

Undiagnosed diabetes

Obesity… Pregnancy Complications

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Gestationaldiabetes

Preeclampsia Eclampsia

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Normal (BMI 20.0-24.9)

Overweight (BMI 25.0-29.9)

Obese (BMI >= 30.0)

*Adjusted for maternal age, smoking, education, marital status, trimester prenatal care began, payer, and weight gain during pregnancy; BMI<20.0 (lean) reference group. Baeten et al., Am J Public Health 91;436, 2001

Adjusted* Odds Ratios for Pregnancy Complications by Maternal BMI

Maternal Complications of Diabetes

Unstable maternal BG Cardiovascular

conditions Sepsis Birth Difficulties PP recovery issues Psychosocial issues

Delivering an affected infant

Infant of the Diabetic Mother

First described: 1880

Insulin isolated in 1921 maternal mortality decreased from 50 to 9 %

Stillbirhts decreased from >20% to 2% in the 1980’s

Perinatal mortality decreased after 1970NICU is still higher than controls (17 vs. 6/1000 in Europe

22 vs. 10/1000 in CA)

Congenital malformations remain high

IDM - Definitions

Any offspring of a gestational or insulin dependent diabetic woman– Type 1-insulin dependent– Type 2– Gestation Diabetes Mellitus– Impaired Glucose Tolerance

Diabetes complicating Pregnancy

0.5-1.0% of all pregnancies are complicated by pre-existing diabetes

0.1 % are insulin dependent diabetes

1-5% gestational diabetes

IDM -Incidence

50-150,000 IDMs born annually

Perinatal mortality: 20/1000 total births

5% of all NICU admissions

IDM - Outcome

Outcome is largely dependent on consistent blood glucose control from the preconception period through embryonic and fetal life.

Lack of control in early or late pregnancy leads to different problems in the offspring

IDM -IDM -EarlyEarly Pregnancy PregnancyDiabetic EmbryopathyDiabetic Embryopathy

Poor early control (Hyperglycemic embryo)

Risk for Congenital Malformations

Glucose Control and Malformations

MALFORMATION RATES BY LEVEL Of MATERNAL HEMOGLOBIN A1c

6.9 or less 0 % 7.0-8.5 5.1 % 8.6 or greater 22.4 %

Miller et al. N Engl J Med 304:1331-1333, 1988

Ylinen et al [89] 7.9 or less

3.2

8.0-9.9 8.1

10 or greater 23.5

Glucose Control and Malformations

HbA1c*% Malformations RR (95% CI)

<6 3.0% 1.06.1-9.0 5.2% 1.7 (0.4-1.7)9.1-12.0 4.3% 1.4 (0.3-8.3)12.1-15.0 38.9% 12.8 (4.7-35.0)>15.0 40.0% 13.2 (4.3-40.4)

*1st trimester HbA1c in 303 insulin-requiring diabetics

(Green et al. Teratology 39:224-231, 1989)

EmbryopathyEmbryopathy Gestational DiabeticGestational Diabetic Women’s Risk Women’s Risk

Becerra JE et al., 1990– Relative risk for major malformations among IDM was

7.9 compared to infants of non-diabetic mothers – Gestational diabetics who require insulin in 3rd trimester

were 20.6 times more likely to have a child with a cardiovascular defect

Kouseff BG, 1999– 152 infants of women with gestational DM, 87 had

anomalies compatible with diabetic embryopathy

Embryopathy Embryopathy Gestational DiabeticGestational Diabetic Women’s Risk Women’s Risk

Schaefer-Graf et al., Am J Obstet Gynecol 182:313-320, 2000– 4,180 consecutive pregnancies complicated by gestational diabetes (3,764) or type

2 diabetes (416) diagnosed after 20 weeks gestation (County USC).» Initial fasting glucose < 120 mg/dL 2.1% malfs» Initial fasting glucose 121-200 mg/dL 5.9% malfs» Initial fasting glucose > 200 mg/dL 12.9% malfs

Watkins et al., Pediatrics 111:1152-1158, 2003– Prepregnancy obesity (with no known diabetes) associated with increased risks for

spina bifida, omphalocele, heart defects, and multiple anomalies.

Diabetic Embryopathy -IncidenceDiabetic Embryopathy -Incidence

2 to 4-fold Increased Risk for Malformations (4-8%)

7 to 10-fold Increased Risk for Major Anomalies that are fatal or require surgery

Central nervous system Cardiac malformations Renal / urinary and GI tract anomalies Skeletal anomalies

Diabetic Embryopathy -Diabetic Embryopathy -CNS anomaliesCNS anomalies

Central nervous system

Neural tube defects– Anencephaly– Meningomyelocele

Hydrocephaly

Holoprosencephaly

Diabetic EmbryopathyDiabetic Embryopathy

Midline facial defects

Facial microsomia and microtia/anotia:

Diabetes in 10.3% of 155 case mothers versus 1.4% of 854 control mothers

Multivariate-adjusted odds ratios (CI):

Diabetes 6.3 (2.7 -1 4.9)(Werler et al., Birth Defects Research 70:258, 2004)

Diabetic Embryopathy – Cardiac anomaliesDiabetic Embryopathy – Cardiac anomalies

Transposition of great vessels Coarctation of the aorta Atrial & Ventricular septal defects Dextrocardia Single ventricle, hypoplastic right

heart Patent ductus arteriosus Pulmonary hypoplasia / atresia DiGeorge sequence

Diabetic Embryopathy, Diabetic Embryopathy, GI anomaliesGI anomalies

GI: Small Left Colon Syndrome

Bowel atresia

Bowel dysmotility (feeding intolerance)

Diabetic Embryopathy – Diabetic Embryopathy – Skeletal AnomaliesSkeletal Anomalies

Caudal Dysplasia or Regression SD– Rare disorder (1/25000)

– The most specific malformation related to diabetes 200-400 times more often in IDMs

– Sacral agenesis with hypoplastic pelvis and spinopelvic instability

– Usually with other malformations like: femoral hypoplasia, extrophy of the bladder, and club foot

Diabetic Embryopathy -Diabetic Embryopathy -PathophysiologyPathophysiology

Hyperglycemia + Genetic background Teratogenic period (3-6 weeks) Disturbances in maternal-fetal circulatory transport

systems Concentrations of metabolites

– Hyperglycemia

– Hyperketonemia

– Elevated intracellular levels of free oxygen radicals

– Disturbances in arachadonic acid and prostaglandin/prostacyclin metabolism affecting intracellular signaling and circulation

– Somatomedin inhibitors

– Genotoxicity as a result of aberrant fuels

(Reece et al., Teratology 54:171-182, 1997)

Diabetic EmbryopathyDiabetic Embryopathy

PREVENTION BEFORE CONCEPTION

Good Glycemic control Folic Acid/ Vitamin intake

IDM - IDM - LateLate Pregnancy PregnancyFetal and Neonatal ComplicationsFetal and Neonatal Complications

Poor late control (Hyperglycemic fetus)

Risk for Hyperinsulinemia (growth factor)

IDM -IDM -LateLate Pregnancy Pregnancy

Fetal and Neonatal Complications of Fetal and Neonatal Complications of HyperinsulinemiaHyperinsulinemia– Macrosomia growth of insulin-sensitive tissues plus

glycogen and fat deposition

– Hypoglycemia– Polycythemia/hyperbilirubinemia – Renal vein thrombosis– Cardiomyopathy– RDS

Fetal & Neonatal Complications

LGA– Birth weight > 4 kg or

above the 90th percentile for gestational age

Occurs in 20-60% IDM Physical findings

– Increased adipose tissue– Disproportionate

head/shoulder ratio– Plethoric– Large placenta & cord

IDM may also be SGA

in advanced diabetes complicated

with renal and cardiac disease

Macrosomia

Fetal & Neonatal Complications Macrosomia

Complications associated with delivery Birth trauma

– Shoulder dystocia – Brachial plexus injury– Fractured clavicle– Visceral hemorrhage

CPD– Risks associated with C/Section and

operative vaginal deliveries (vacuum extraction, forceps, etc.)

– Fetal distress– Meconium aspiration– Birth Asphyxia

Hypoglycemia

Symptoms

Jitteriness 81% Seizures 58% Apnea/cyanosis 47% Irritability 41 % Hypotonia 26% Poor feeding Hypothermia None

Defintition: Blood glucose <40 mg/dLUsually presents at ½-2 hours of life

Incidence: up to 40% of IDM

HypoglycemiaTreatment

If stable give early feedings

If not able to feed:

D10%W 2mL/kg (slow IVP) plus

Continuous IV infusion of D10%W at 80-100 mL/kg/day

Use glucagon in extreme cases

Follow blood glucose with

frequent Chemstrips

Hyperbilirubinemia Definitions: Elevated indirect

(unconjugated) bilirubin >10mg/dL in term infant, lower levels for preterms Incidence in IDM 20-40%

Pathophysiology

– Increased bilirubin production

» Polycythemia

» Heme turnover (ineffective erythropoeitin. and trauma)

– Decrease in bilirubin binding and excretion

» Liver immaturity

Hyperbilirubinemia Prevention

– Early, adequate breastfeeding– Good hydration and stooling

Diagnosis– Transcutaneous or serum bilirubin

at 24 hours of age, and at signs of increasing jaundice

Treatment:

– Adequate hydration and nutrition– Phototherapy– Exchange transfusion– Medications (agar)– Family teaching– Appropriate follow-up after

discharge

Polycythemia

Due to bone marrow stimulation (high erythropoietin levels) Elevated venous hematocrit of > 65% Caused by chronic hypoxia and increased O2 requirements in utero Placental insufficiency during fetal life May be worsened by placental transfusion at birth Incidence in IDM 35%

Signs and symptoms – Plethora– Jitteriness– Tachypnea– Cyanosis (general or circumoral)– Oliguria– Poor feeding– Lethargy/seizures

Screening: obtain hematocrit at 24 hrs of life or if symptoms noted

Polycythemia

Treatment – Treat underlying symptoms– Hydration– Hyperbilirubinemia treatment– Partial exchange transfusion

Common complications

– Respiratory Distress– Hyperbilirubinemia– Respiratory distress– Renal vein thrombosis– Hypertension

IDM -Cardiomyopathy

Cardiomegaly present in 30% Septal hypertrophy Myocardial dysfunction

– Glycogen stores– Hypoxia

CHF in 5%– Treatment: supportive therapy and beta blockers

Other Fetal & Neonatal Complications

Perinatal hypoxia/asphyxia

Respiratory Distress

Metabolic abnormalities:– Hypocalcemia– Hypomagnesemia

Small left colon Syn.

Neurologic dysfunction

Perinatal Hypoxia May lead to fetal demise or neonatal asphyxia May result from complicated labor and delivery

– Placental insufficiency (vascular disease, pre eclampsia)– Maternal ketoacidosis– CPD/ Prolonged labor due to Macrosomia– Meconium Aspiration – Intra-abdominal hematoma/hemorrhage– Polycythemia– Increased oxygen utilization from hyperinsulinism and increased metabolism

TTNB (delayed lung fluid clearance)

Respiratory Distress Transient Tachypnea of Newborn (delayed lung fluid

clearance) Aspiration of meconium or amniotic fluid Prematurity

Diagnosis Tachypnea/Retractions Grunting Cyanosis Apnea Hypoxemia Chest X-Ray

Respiratory Distress SyndromeRDS (delayed lung maturity), higher risk than non IDMs.

Respiratory Distress Syndrome

surfactant from

decreased steroids due to

insulin

Prevention: Check for lung maturity with presence of PG and L:S ratio >2

Treatment: – Surfactant

– Assisted support and ventilation

– Supplemental oxygen

Hypocalcemia/Hypomagnesemia

Incidence: 25%

Secondary to hypoparathyroid function due to maternal-fetal hypomagnesemia

Related to severity of maternal diabetes

Develops in first 3 days

Hypocalcemia/Hypomagnesemia

Symptoms:– Irritability– Jitteriness– Apnea– Lip smacking– Tongue thrusting

Laboratory Tests– Calcium– Ionized CA– Magnesium

Treatment– Transfer to Neonatal Intensive Care Unit– Calcium gluconate– Magnesium sulfate

IDM - Neurologic Dysfunction

Jitteriness Irritability Increased or Decreased

tone Seizures

Due to:– Chronic and/or acute

hypoxia

– Immaturity

– Hypoglycemia

– Hypocalcemia

– Polycythemia/strokes

– Delivery trauma

– Iron deficiency

Oral Feedings

Significant feeding difficulties Severe uncoordination

Assess oral-motor coordination Assess adequacy of feeding

Monitor pre feeding blood glucose

IDM and Breastfeeding

Offer breast as soon as possible within 1 hour of delivery

Encourage feedings whenever oral cues noted or at least every 3 hours

Formulas: only when medically indicated or mother has given informed consent

Keep mother and infant together continuously

Support mothers to nurse often (10-12 times per day)

IDM- Long Term Prognosis

Metabolic SyndromeMetabolic Syndrome (identifiable early precursor to adult chronic (identifiable early precursor to adult chronic diseases including diabetes, heart disease, diseases including diabetes, heart disease, certain cancers, and others)certain cancers, and others)

• ObesityObesity• Glucose IntoleranceGlucose Intolerance• DyslipidemiaDyslipidemia• HypertensionHypertension

Predisposing factorsPredisposing factors . . Infant of a diabetic motherInfant of a diabetic mother . Infant of an obese mother. Infant of an obese mother . Large for gestational age infant. Large for gestational age infant

Long Term Prognosis

Growth / DevelopmentGrowth / Development

Childhood obesity Childhood obesity (50%, 5 fold higher at adolescence)(50%, 5 fold higher at adolescence)

Risk of Developing Insulin Dependent DMRisk of Developing Insulin Dependent DM . Diabetic mother 2%. Diabetic mother 2% . Diabetic father 7%. Diabetic father 7%

Risk for delayed motor and cognitive developmentRisk for delayed motor and cognitive development Neurological development indefiniteNeurological development indefinite

IDM Neurodevelopmental Outcome

The IDM needs to be supported since conception

If we are to help the mothers to achieve