Diabetes and Birth Defects

Adolfo Correa, MD, PhD

National Center on Birth Defects andDevelopmental Disabilities

Centers for Disease Control and Prevention

1st Central and Eastern European Summit on Preconception Health and Healthcare

August 2008, Budapest, Hungary

Outline

� Associations of diabetes with birth

defects

� Preconception care and the

prevention of birth defects

� Challenges and opportunities for

prevention of birth defects

Birth defects associated with pregestational diabetes

�Pregestational diabetes (PGDM) (type

1 or type 2) is a well known teratogen

�Across animal species

�Several organ systems susceptible• Some more susceptible than others

–Musculoskeletal• e.g., sacral agenesis

– CVM• e.g., conotruncal defects

– CNS• e.g., anencephaly

Rates of major defects by HbA1c at 1st prenatal visit among women with type 1 diabetes

0

5

10

15

20

25

30

7.7-8.6 8.7-9.9 10.-10.5 >10.6

HbA1c %

Percent of

infants

with

defects

Kitzmiller et al (1991)

Rates of major defects by initial fasting serum glucose among women with type 2 and gestational diabetes

Schaefer-Graf et al AJOG (2000)

Prevalence of preexisting diabetes per 100 births, age- and race/ethnicity adjusted, by

year, Kaiser Permanente Southern California

0

0.5

1

1.5

2

1999 2000 2001 2002 2003 2004 2005

Birth year

Prevalence %

Lawrence et al (2008)

0

10

20

30

40

50

60

2005 2010 2020 2030 2040 2050

Narayan KM et al. Diabetes Care, 2006

Projected increase in numbers (millions)

with diagnosed diabetes, USA, 2005-2050

Hossain et al. N Engl J Med 2007; 356:213-215

Can preconception care reduce the risk for birth defects associated with diabetes?

Rates of birth defects among offspring to women with PGDM by participation in preconception

care

7.5

1010.9

9

0.81.4 1.2

4.9

0

2

4

6

8

10

12

Furhman,'83

Steel, '90 Kitzmiller,'91

Mills, '88

Rate (%)No PCC

PCC

Preconception care for diabetes and risk of major defects

� Pooled analysis, 14 studies (Ray, 2001) of

pregnancies to women with type 1 diabetes

� 1459 offspring without preconception care – 6.5% major defects

� 1192 offspring with preconception care – 2.1% major defects

� Dutch study (Evers et al. 2004) of 323

pregnancies to women with type 1 diabetes

� Unplanned pregnancies – 12.1% defects

� Planned pregnancies – 4.2% defects

Glycemic control and risk for birth defects

�West Midlands study, 182 women with type 2 diabetes receiving early prenatal care, 1990-2002 (Dunne et al., 2003)� Rate of birth defects by first HbA1c

• Normal (33%) 3.3%• Moderately elevated (38%) 7.2%• Extremely elevated (29%) 20.7%

�Diabetes Complications Control Trial (DCCT) of 1441 adults with type 1 diabetes randomly assigned to conventional or intensive therapy (Loeken, 2005) � 180 women became pregnant

• 1 birth defect in intensive therapy group• 8 birth defects in conventional therapy group

Efficacy vs. effectiveness

� Efficacy

� the extent to which a specific intervention or service produces a beneficial result under ideal circumstances (i.e., controlled settings)

� Effectiveness

� the extent to which a specific intervention or service does what it is intended to do

To what extent is preconception care reaching women with

diabetes?

� Is diabetes continuing to be associated with

birth defects today?

The National Birth Defects Prevention Study (NDBPS)

�Case-control study of major birth defects

�Study subjects born Oct 1,1997-Dec 31,

2002

�Cases identified from 9 study centers

with population-based surveillance

systems

� AR, CA, GA, IA, MA, NC, NY, TX, UT

Centers Participating in the National Birth Defects Prevention Study

TX

CAUT

IA

ARGA

NC

NY MA

The National Birth Defects Prevention Study (NDBPS)

� Controls

� Liveborn infants without major birth defects randomly selected from birth cohorts from same region

• From birth certificates: GA, IA, MA

• From birth hospitals: AR, CA, GA, NC, NY, TX, UT

� Telephone interviews in English or Spanish

between 6 weeks and 2 years post-delivery

� Participation rate

� 70.5 percent (cases)

� 67.2 percent (controls)

Birth defects

� Neural tube defects� Anencephaly� Spina bifida

� Hydrocephalus� Cataract� Anotia/microtia� Cardiac defects� Oral clefts

� Cleft palate

� Cleft lip w/wo cleft palate

� Esophageal atresia� Intestinal atresias

� Ileal, Jejunal, Multiple� Duodenal

� Biliary atresia� Anorectal atresia� Hypospadias� Limb reduction defects� Craniosynostosis� Diaphragmatic hernia� Omphalocele� Gastroschisis� Sacral agenesis

� Cardiac defects� Heterotaxia� Conotruncal defects

• Tetralogy of Fallot• D-Transposition of the great arteries

� Atrioventricular septal defect� Total anomalous pulmonary venous return� Left ventricular outflow tract obstructions

• Hypoplastic left heart syndrome• Coarctation of the aorta• Aortic stenosis• LVOTO associations

– Coarctation + ASD– Coarctation + VSD– Coarctation + ASD + VSD

� Right ventricular outflow tract obstructions

• Pulmonary atresia• Pulmonic valve stenosis• RVOTO associations

– Pulmonic valve stenosis + VSD– Pulmonic valve stenosis + ASD

� Septal defects• Ventricular septal defect,

perimembranous• Ventricular septal defect, muscular• Atrial septal defect, secundum• Atrial septal defect, OS/NOS• Septal associations

– ASD + VSD

Diabetes definition

� Responses to two questions:

� 1: Were you ever told by a doctor that you had diabetes (including gestational diabetes), sometimes called sugar diabetes or diabetes mellitus?

� 2: What type of diabetes did you have? Was it:• Gestational, that is during pregnancy only• Insulin-dependent diabetes, also called Type 1 or Juvenile

• Non-insulin dependent diabetes, also called Type 2 or Adult-onset

• DK

� Analytic variables for pregestational diabetes (combination of Type 1 and Type 2) and gestational diabetes

Number exposed and crude odds ratios, by type of diabetes

Controls

(n=4086)

All cases

(n=9929)

All isolated cases

(n=8491)

All multiple cases

(n=1346)

No diabetes 3835 8994 7732 1177

Pregestational 21 209 141 65

ref 4.24 (2.70-6.64) 3.33 (2.10-5.27) 10.09 (6.14-16.57)

Type 1 9 106 71 34

ref 5.02 (2.54-9.93) 3.91 (1.95-7.83) 12.31 (5.89-25.74)

Type 2 12 103 70 31

ref 3.66 (2.01-6.66) 2.89 (1.57-5.34) 8.42 (4.31-16.44)

Gestational 230 726 618 104

ref 1.35 (1.15-1.57) 1.33 (1.14-1.56) 1.47 (1.16-1.87)

Odds ratios for pregestational diabetes

and non-cardiac defects

118.99

8.81 7.49 7.2 7.16 6.16 4.91 4.492.65 2.55 2.53 2.02 1.98 1.62 1.47

0.74

0.01

0.1

1

10

100

1000

Sacra

l Age

nesi

sH

ydro

ceph

aly

Anore

ctal

Atre

sia

Anotia

/Mic

rotia

Biliar

y Atre

sia

Lim

b R

educ

tion D

efec

tsO

mph

aloc

ele

Esoph

ageal

Atre

sia

Cle

ft Li

p w

ith o

r with

out C

left

Palate

Cle

ft Pal

ate

Hyp

ospa

dias

Dia

phra

gmat

ic H

erni

a

Cra

nios

ynos

tosi

sAne

ncep

haly

Spina

Bifid

aG

astro

schi

sis

Od

ds R

ati

o a

nd

95%

Co

nfi

den

ce In

terv

al

Odds ratios for pregestational diabetes and

cardiac defects

15.6213.11

10.07 8.87 8.61

5.73 5.6 5.54 5.474.16 4.07

3.46

1.93 1.8 1.62

0.1

1

10

100

AVSD

RVO

TO A

ssoc

iatio

nsH

eter

otax

iaAS

D S

ecun

dum

TAPVR

Septa

l Ass

ocia

tion

Tetra

logy

of F

allo

t

d-TG

AAS

D O

S/N

OS

VSD

Per

imem

bran

ous

LVO

TO A

ssoc

iatio

nsPul

mon

ary

Atresi

a

Coa

rcta

tion

of the

Aor

ta

HLH

S

Pulm

onic

Val

ve S

tenos

is

Od

ds R

ati

o a

nd

95%

Co

nfi

den

ce In

terv

al

Odds ratios for gestational diabetes and

non-cardiac defects

1.69 1.63 1.6 1.57 1.5 1.5 1.49 1.46 1.4 1.37 1.33

1.11 1.11 0.99 0.95

0.73

0.35

0.1

1

10

Od

ds R

ati

o a

nd

95%

Co

nfi

dence In

terv

al

Odds ratios for gestational diabetes and

cardiac defects

2.29 2.2 2.16

1.63 1.5 1.44 1.37 1.28 1.2 1.21.05 1.05 0.99 0.98

0.79 0.76

0.58

0.1

1

10

AVSD

Pulm

onic

Val

ve S

tenos

is

ASD

Sec

undu

m

Coa

rcta

tion

of the

Aor

ta

Tetra

logy

of F

allo

t

HLH

S

Septa

l Ass

ocia

tion

d-TG

AAS

D O

S/N

OS

VSD

Per

imem

bran

ous

Pulm

onar

y Atre

sia

VSD

Mus

cula

r

RVO

TO A

ssoc

iatio

ns

Aortic

Ste

nosi

sH

eter

otax

ia

TAPVR

LVO

TO A

ssoc

iatio

nsO

dd

s R

ati

o a

nd

95%

Co

nfi

den

ce In

terv

al

Odds ratios for pregestational diabetes and

birth defects, by pregravid obesity

3.234.21

2.78 3.22

6.869.13

1

10

100

obese not

obese

obese not

obese

obese not

obese

All defects All isolated defects All multiple defects

Od

ds

Ra

tio

an

d 9

5%

Co

nfi

de

nc

e

Inte

rva

l

Odds ratios for gestational diabetes and birth

defects, by pre-gravid obesity

1.61

1.2

1.6

1.23

1.76

1.1

0

0.5

1

1.5

2

2.5

3

obese not

obese

obese not

obese

obese not

obese

All defects All isolated defects All multiple defectsOd

ds

Ra

tio

an

d 9

5%

Co

nfi

de

nc

e

Inte

rva

l

Summary: Pregestational diabetes

� Associated with an increased risk

for a wider range of defects than

previously reported

�Associations moderate to strong

�Associations stronger for multiple than for isolated defects

�Effect not modified by maternal

pre-gravid obesity

Summary: Gestational diabetes

�Relatively fewer and weaker

associations

�No variation in effect between isolated and multiple defects

�Associations limited to offspring of

mothers with pre-gravid obesity

� suggesting associations might be with undiagnosed type 2 diabetes

What are the challenges and opportunities for prevention of birth defects associated with

diabetes?

� Among women with known pre-gestational

diabetes� > 50% do not plan their pregnancies � Many lack access to preconception care and educational services

� Even in managed care settings, preconception counseling for diabetic women is inadequate (Kim et al, 2005)

� Among women with gestational diabetes� post-partum screening for diabetes can be infrequent (Almario et al., 2007)

� Among women with undiagnosed diabetes� How to identify them?

Possible strategies for women with a history of pregestational diabetes

� Offer preconception care with a

multidisciplinary team to � Optimize general health and glycemic control

• Counsel re family planning

• Healthy lifestyle (weight loss/control, exercise)

� Review risks for birth defects� Promote use of folic acid� Define and maintain target glucose levels before and during pregnancy • Guidelines by ADA (Diabetes Care, 2008), ACOG (Obstet Gynecol, 2005)

� Monitor pregnancy for birth defects

Possible strategies for women with a history of gestational diabetes

� Conduct post-partum evaluations to

determine baseline glycemic status

� If type 2 diabetes, offer preconception counseling

� If normal,

• Counsel re family planning, healthy lifestyle

• Screen for GDM in subsequent pregnancies

� If prediabetes or overweight,

Possible strategies for women with prediabetes or

who are overweight

� Promote/enroll/offer

preconception care� Counsel re family planning� Promote healthy lifestyle (weight loss/control, exercise)

� Monitor glycemic status

Conclusions

� Pregestational diabetes is a teratogen of

public health importance today

� potency, range of effects, increasing

prevalence, and potential for prevention

� Although preconception care has the

potential of preventing birth defects

associated with diabetes,

� many offspring to women with pregestational

diabetes continue to be at increased risk for

birth defects

Conclusions� Most likely reason

� Many women with pregestational

diabetes have no access to quality

preconception care

� What is needed

� A concerted effort to eliminate barriers

to access to quality preconception care

for women with pregestational

diabetes

Maternal hyperglycemia in Maternal hyperglycemia in

pregnancy: Longpregnancy: Long--term implicationsterm implications

Maternal hyperglycemia in pregnancy:

Abnormal metabolic

environment

Childhood obesity

(insulin resistance, dyslipidemia, hypertension)

Fetal-Neonatal

obesityAdult obesity

Type 2 diabetes

Diet/Activity

Environment

Diet/Activity

Environment

Potential benefits of efforts of preventing preconception and

prenatal hyperglycemia

� Go beyond prevention of birth

defects

� obstetric complications

� fetal and neonetal complications

� childhood obesity and type 2 diabetes among the offspring

� Maternal risks for gestational and type 2 diabetes and complications

Dr.,

I just read the article about your study. My son was

born in 2000 with several heart defects. He had surgery

to correct them in 2002, and didn't make it. His mother

was diagnosed with diabetes while pregnant with him.

A year later, my daughter was born with truncus

arteriosus. She had surgery exactly one year after her

brother to the day. She's doing fine today. Your article

and study helped me understand a little better what I

have gone through. Anyway, I just wanted to thank

you for releasing this info, and helping me understand a

little more. Keep up the good work.

Thanks,

Epistemologist

"the Stone Age did not end for lack of stone."