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TRANSCRIPT
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."