Diabetic Embryopathy - University of Utah

Diabetic Embryopathy:A most important human teratogen

Janice L.B. Byrne, M.D., FACMG,FACOGUniversity of Utah

Maternal-Fetal Medicine / Clinical GeneticsThe Utah Fetal Center at Primary Children’s Hospital

Dr. Byrne has no conflict of interest related to the content of this presentation.

Potential benefits of prenatal diagnosis

Search for other structural abnormalities that may impact on diagnosis, survival, prognosis

Determination of fetal karyotype, other testing

Genetic counseling Discussion of reproductive options

(termination vs. continuation of pregnancy)

Diabetes and pregnancy

Definitions Pregestational diabetes (type I or II):

○ Diabetes predates pregnancy Gestational diabetes (GDM):

○ Any degree of glucose intolerance initially diagnosed during pregnancy

○ Diagnosis by oral glucose tolerance test from 24-28 weeks gestation

Diabetes and pregnancy

By definition, GDM resolves following pregnancy Recurrence in subsequent pregnancies is

common Increased risk of developing type II diabetes (40-

50% within 10 years) Controversy exists regarding risk of

anomalies in GDM Anomalies in GDM may reflect an undiagnosed

type II diabetic

Epidemiology of Diabetes in Pregnancy

Pregestational 25.3 per 1,000 pregnant women 13% of all diabetes in pregnancy Prevalence increasing in USA, in parallel with

increasing obesity rate Rate varies with ethnic group and age

Epidemiology of Diabetes in Pregnancy

Gestational Estimated to affect 1-14% of pregnancies in US,

depending upon population studied and diagnostic test used

Risk factors○ Older age○ Multiple gestation○ Previous GDM ○ Previous macrosomic infant

Malformations and diabetes

Major malformations in 6-10% of infants born to diabetic mothers 2-4x higher rate than in nondiabetics Poor metabolic control, especially in 1st trimester,

increases risk of malformations Structural anomalies, especially cardiac, account

for 50% of perinatal deaths According to the data from Utah Birth Defects

Network, maternal diabetes is the most common teratogen in our birth cohort


Glycosylated hemoglobin (HbA₁C) provides retrospective index of glycemic status over preceding 8-12 weeks

Correlates with risk of malformations < 6.9% → minimal increased risk over baseline 7-8.5% → 5% anomalies > 10% → 22% anomalies


Even with excellent diabetic control, risk of malformations greater than that of a non-diabetic

Overt diabetic first recognized during pregnancy has similar risk for embryopathy as a known pregestational diabetic

Cystic fibrosis-related diabetes (CFRD) Uncertain malformation risk due to rarity of

pregnancy in this condition

Etiology of diabetic embryopathy

Metabolic derangements associated with hyperglycemia may contribute to teratogenesis Exact mechanism uncertain but likely multifactorial

Many theories center on role of hyperglycemia in increasing oxidative stress

Etiology of diabetic embryopathy

Hyperglycemia triggers apoptotic signaling pathways Inhibition of cell survival pathways leads to

embryonic malformations Caspases (cysteine proteases active in the

cascade of apoptosis) currently under investigation for their role in pathogenesis of diabetic embryopathy

Inhibitors of caspase activation may have protective effect against high glucose induced NTDs

Imaging in diabetic embryopathy

Best diagnostic clue Abnormal growth + structural anomalies in fetus of

diabetic mother○ May be macrosomic (> 90th%tile), large for

gestational age (LGA), or growth restricted (IUGR)○ Most common anomalies include: Cardiac Central nervous system Renal Skeletal

Imaging in diabetes

GDM- fetus often macrosomic Accelerated growth apparent by late 2nd trimester

○ Disproportionate increase in abdominal and head circumferences

○ Increased skin, subcutaneous tissue (trunk, head)

○ Polyhydramnios common IUGR more common in pregestational

diabetes, although macrosomia can also occur

Macrosomia in diabetes

Gestational diabetes5200g at 32 wk. gestation

Pregestational diabetes6670g at term


Caudal dysplasia/ regression sequence Malformation complex characterized by

varying degrees of developmental failure involving legs, lumbar, sacral and coccygeal vertebrae and corresponding segments of the spinal cord

Lower extremity malposition (“tailor’s posture” or “Buddha pose”)

16% of cases due to maternal diabetes


Caudal dysplasia/ regression


Central nervous system (CNS) anomalies: 3-20x increase over non-diabetic Anencephaly Spina bifida Holoprosencephaly


VentriculomegalyHoloprosencephaly

Myelomeningocele


Cardiac anomalies: 5x increase over non-diabetic Transposition of great arteries Heterotaxy Cardiomyopathy (may be transient)

○ May be seen in poorly controlled gestational diabetic


Cardiomyopathy with thick interventricular septum


Extremities Preaxial polydactyly of feet and hands- very

specific for diabetic embryopathy Syndactyly- may be complex Femoral hypoplasia Angulated bones, especially of legs


Femoral hypoplasia/Complex tib-fib

Preaxial polydactyly


Genitourinary (GU) Renal agenesis Multicystic dysplastic kidneys

Gastrointestinal (GI) Anorectal malformation/ atresia

Non-specific Single umbilical artery Polyhydramnios Oligohydramnios Microtia


Potter’s faciesBilateral renal agenesis

Multicystic dysplastickidneys

Unilateral renal agenesis

Anal Atresia

Microtia


Imaging challenges in diabetes Maternal obesity! Maternal obesity! Maternal obesity! Too much amniotic fluid Too little amniotic fluid Late diagnoses

Multidisciplinary team approach to management

Optimize timing/ mode/ location of delivery Provide appropriate care to families and their

children with congenital malformations Coordination of care with primary provider, other

specialties, other services (SW, hospice etc.) Availability of fetal treatment when indicated Recurrence risk assessment with

recommendations for future pregnancy management

Questions?

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Diabetic Embryopathy - University of Utah