Pre-Gestational Diabetes:

A Public Health Growth Industry

Evan Klass, MD, FACP
Associate Dean, Statewide Initiatives
Director, Project ECHO-Nevada
 Goals for today
• 1) Recognize the importance of pre-gestational
Diabetes and its magnitude
• 2) Understand the difference between pre-
gestational and gestational Diabetes and the
implications of each
• 3) Consider opportunities for intervention to
reduce the health impact of pre-gestational
Diabetes
• I have no financial conflicts to report
 Definitions
• Gestational Diabetes (GDM)-Diabetes not
detected before pregnancy but discovered
during pregnancy. Nearly all (but not all)cases
are Type 2 Diabetes
• Pre-gestational Diabetes (PGDM)- Diabetes
diagnosed before conception. Includes
women with Type 1 and Type 2 Diabetes
 How big a problem is this?
• Women of child bearing age= 63M
• Prevalence of know Type 1 DM= 1%
– 630K women
• Prevalence of known Type 2 DM= 2.9%
– 1.8M women
• Prevalence of unknown Type 2 DM= 0.5%
– 314K women
SO: 2.7 million women with preconception
Diabetes!
 Rate of new cases of type 1 and type 2 diabetes among people
younger than 20 years, by age and race/ethnicity, 2008–2009

http://main.diabetes.org/site/R?
i=CcKLVT2ni5UsLHCbVf1bmw

<10 years 10–19 years

Source: SEARCH for Diabetes in Youth Study. NHW=non-Hispanic whites; NHB=non-Hispanic blacks; H=Hispanics;
API=Asians/Pacific Islanders; AIAN=American Indians/Alaska Natives.
*The American Indian/Alaska Native (AI/AN) youth who participated in the SEARCH study are not representative
of all AI/AN youth in the United States. Thus, these rates cannot be generalized to all AI/AN youth nationwide.
Prevalence of Type 2 Diabetes by
Age
Fig. 2. Age-adjusted incidence of pre-gestational diabetes and gestational diabetes over time.

Alex Fong, Allison Serra, Tiffany Herrero, Deyu Pan, Dotun Ogunyemi

Pre-gestational versus gestational diabetes: A population based study on clinical and demographic differences ☆

Journal of Diabetes and its Complications, Volume 28, Issue 1, 2014, 29–34

http://dx.doi.org/10.1016/j.jdiacomp.2013.08.009
Fig. 4. Age-adjusted prevalence of PGDM and GDM by race/ethnicity.

Alex Fong, Allison Serra, Tiffany Herrero, Deyu Pan, Dotun Ogunyemi

Pre-gestational versus gestational diabetes: A population based study on clinical and demographic differences ☆

Journal of Diabetes and its Complications, Volume 28, Issue 1, 2014, 29–34

http://dx.doi.org/10.1016/j.jdiacomp.2013.08.009
 Risk of birth defects associated with
pregestational diabetes
• Reviewed all pregnancies in Emilia-Romagna region between
1997-2010
• Malformations in 62/2269 diabetic pregnancies vs.
162/10,648 non-diabetic (1:5 cases/controls)
– Prevalence ratio of 1.79 (controls were age-matched)
– Prevalence ratio was 0.94 for probable type 1 patients and 4.89 for
Fig.
probable
42
Fig. Age-adjusted
Age-adjusted
Fig. 3 Prevalence type
prevalence
incidenceofof
of pre-gestational 2diabetes
PGDM
patients
and GDM bydiabetes
pre-gestational race/ethnicity.
and gestational diabetes over time.
compared to gestational diabetes in pregnancy by age range.

Alex Fong , Allison Serra , Tiffany Herrero , Deyu Pan , Dotun Ogunyemi
Alex Fong , Allison Serra , Tiffany Herrero , Deyu Pan , Dotun Ogunyemi
AlexPre-gestational
Fong , Allisonversus
Serragestational
, Tiffany Herrero
diabetes:,ADeyu Pan ,based
population Dotun Ogunyemi
study on clinical and demographic differences
Pre-gestational versus gestational diabetes: A population based study on clinical and demographic differences
Pre-gestational versus
Journal of Diabetes gestational
and its diabetes:
Complications, Volume 28,AIssue
population based
1, 2014, 29 - 34 study on clinical and demographic differences
Journal of Diabetes and its Complications, Volume 28, Issue 1, 2014, 29 - 34
http://dx.doi.org/10.1016/j.jdiacomp.2013.08.009
Journal of Diabetes and its Complications, Volume 28, Issue 1, 2014, 29 - 34
http://dx.doi.org/10.1016/j.jdiacomp.2013.08.009
Vinceti M et al. Risk of birth defects associated with maternal pregestational diabetes.
http://dx.doi.org/10.1016/j.jdiacomp.2013.08.009
Eur J Epidemiol 29:411-18
 A: Risk of a major or minor congenital anomaly according to the number of SDs of GHb above
normal, measured periconceptionally.

Andrea Guerin et al. Dia Care 2007;30:1920-1925

©2007 by American Diabetes Association

 Figure 1. Hyperglycemia-induced oxidative stressSustained generation of reactive oxygen species (ROS) by maternal diabetes-
related hyperglycemia activates p66shc by phosphorylation (+P), which further causes mitochondrial dysfunction, aggravating ROS
generatio...

Peixin Yang, E. Albert Reece, Fang Wang, Rinat Gabbay-Benziv

Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling

American Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579

http://dx.doi.org/10.1016/j.ajog.2014.11.036
 Figure 2. Oxidative stress-induced proapoptotic PKC signalingMaternal diabetes-induced oxidative stress activates PKC α, βII, δ,
while it inhibits PKCε, ξ. Activated PKCα induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
Figure 2. Oxidative stress-induced proapoptotic PKC signalingMaternal diabetes-induced oxidative stress activates PKC α, βII, δ,
while it inhibits PKCε, ξ. Activated PKCα induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
Figure 2. Oxidative stress-induced proapoptotic PKC signalingMaternal diabetes-induced oxidative stress activates PKC α, βII, δ,
Figure 2. Oxidative stress-induced proapoptotic PKC signalingMaternal diabetes-induced oxidative stress activates PKC α, βII, δ,
while it inhibits PKCε,Fangξ. Activated PKCαGabbay-Benziv
induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
while it inhibits PKCε, ξ. Activated PKCα induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
Peixin Yang, E. Albert Reece, Wang, Rinat
Figure 2. Oxidative stress-induced proapoptotic PKC signalingMaternal diabetes-induced oxidative stress activates PKC α, βII, δ,
while it inhibits PKCε, ξ. Activated PKCα
Peixin Yang, E. Albert Reece, Fang Wang, Rinat Gabbay-Benziv induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
Decoding the oxidative stress
Figure hypothesis
2. Oxidative in diabetic proapoptotic
stress-induced embryopathy through
PKC proapoptotic
signalingMaternal kinase signaling
diabetes-induced oxidative stress activates PKC α, βII, δ,
while it inhibits PKCε, ξ. Activated PKCα
Peixin Yang, E. Albert Reece, Fang Wang, Rinat Gabbay-Benziv induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
Decoding the oxidative stress
Figure 2. hypothesis
Oxidative in diabetic proapoptotic
stress-induced embryopathy PKCthrough proapoptotic
signalingMaternal kinase signaling
diabetes-induced oxidative stress activates PKC α, βII, δ,
American Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579
Peixin Yang, while it inhibits
E. Albert PKCε,Fang
Reece, ξ. Activated PKCαGabbay-Benziv
Wang, Rinat induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
Decoding the oxidative Figurestress
2. hypothesis
Oxidative in diabetic proapoptotic
stress-induced embryopathy PKCthrough proapoptotic
signalingMaternal kinase signaling
diabetes-induced oxidative stress activates PKC α, βII, δ,
American Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579
Peixin Yang, E. Albert Reece, Fang Wang, Rinat Gabbay-Benziv
http://dx.doi.org/10.1016/j.ajog.2014.11.036
Peixin Yang, while it inhibits
E. Albert PKCε,Fang
Reece, ξ. Activated PKCαGabbay-Benziv
Wang, Rinat induces lipid peroxidation, which in turn aggravates oxidative stress, and induces apopto...
Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling
American Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579
http://dx.doi.org/10.1016/j.ajog.2014.11.036
Peixin Yang, E. Albert Reece, Fang Wang, Rinat Gabbay-Benziv
Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling
American Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579
http://dx.doi.org/10.1016/j.ajog.2014.11.036
Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling
Peixin Yang, E. Albert Reece, Fang Wang, Rinat Gabbay-Benziv
Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling
American Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579
http://dx.doi.org/10.1016/j.ajog.2014.11.036
Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling
American Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579
http://dx.doi.org/10.1016/j.ajog.2014.11.036
American Journal of Obstetrics and Gynecology,American
Volume 212, Issue 5, 2015, 569–579
Journal of Obstetrics and Gynecology, Volume 212, Issue 5, 2015, 569–579
http://dx.doi.org/10.1016/j.ajog.2014.11.036

http://dx.doi.org/10.1016/j.ajog.2014.11.036
http://dx.doi.org/10.1016/j.ajog.2014.11.036
Risk of major congenital anomalies
• 3% of all births- leading cause of infant
mortality
• 5.7% of offspring of women with type 1 DM
(Norwegian study)
• 6.6% of offspring of women with type 2DM
(British study)
 Relative risk (RR) for major congenital abnormalities from 14 studies of women with diabetes
mellitus who did or did not receive preconception care (PCC).

Ray J et al. QJM 2001;94:435-444

© Association of Physicians
 Does preconception care matter?
• PGDM w/o PCC
– 41.4 % pre-term
– 7.3% with birth defects
– 4.4% perinatal death
• PGDM w/ universal PCC
– 8400 pre-term births avoided
– 3725 birth defects prevented
– 1900 perinatal deaths avoided
Preventable health and cost burden of adverse birth outcomes associate with PGDM
in the US
Peterson C, et al. Am J Obstet Gynecol 2015;212:74e1-9.

• PCC for known PGDM

– $770 M in direct medical costs
– $3.6B in lost productivity
• PCC for undiagnosed PGDM
– $207M in direct medical costs
– $960M in lost productivity

SO: approximately $5.5 billion in

preventable costs!
 Management goals
• Pregnancy outcomes no different from the
general population
– There is no more motivated patient with Diabetes than a
pregnant patient with Diabetes!
– Nearly all of the work in this area focused on Type 1
patients but the future is in women with pre-existing Type
II Diabetes
 Management goals
• No unplanned pregnancies (but
<50% are planned)
– Start discussions with teenage girls early and often
– Contraception-
• OCA’s acceptable but must monitor for BP changes
• IUD
• Barrier methods
• Abstinence?
• Plan B
 Management goals
• Pre-conception assessment- Pre-existing
Diabetes
– Complication status and stability
– Glycemic control
– Nutritional management awareness- CHO
counting skills
– Emotional readiness for pregnancy
– Start folic acid early
 Management goals
(Pre-gestational pre-diabetes)
• Pre-conception evaluation of at risk women
– Previous GDM
– Pre-Diabetes (A1C≥5.7%), HTN, ASCVD
– Family history
– PCOS or other insulin resistance states
– Acanthosis nigricans
– Overweight (BMI>25!)
 ADA Guidelines- 2016
• New recommendation
– Counsel all women of child-bearing age about the
importance of “near-normal” glycemia prior to
conception
– Major malformations directly proportional to
HgbA1C levels in the first 10 weeks of pregnancy
– Discuss family planning and effective
contraception until the woman is prepared and
ready
 Pre-pregnancy evaluation:
2016 ADA Recommendations
• HgbA1C • Medication review
• Serum creatinine for possible
• Urine teratogens inc. ACE-i
albumin/creatinine and statins
• TSH
• Comprehensive eye
evaluation
 Management goals
• Consider modifying medical regimen
if pregnancy is anticipated or if
unintended pregnancy likely
– Intensify insulin regimen/pump therapy
– Statins, TZD’s, ACE’s and ARB’s are contraindicated in
pregnancy!
– Metformin and glyburide may be continued if achieving
adequate glycemic control
 The National Agenda for Public Health Action
(ADA, APHA, CDC and P…)
• 10 priority recommendations including:
– Encourage and support state programs to develop
prevention programs
– Expand community based health promotion
– Strengthen advocacy
– Expand population based surveillance
– Educate community leaders about Diabetes
– Encourage healthcare providers to promote risk
assessment…
– Encourage access to trained professionals
– Conduct public health research
 Impediments to PCC
• General health status-women with chronic illness
are more likely to have unplanned pregnancy
• Socioeconomic status including health insurance
• Co-existent tobacco and/or alcohol use
• Contraceptive use- ½ of women with unplanned
pregnancy were not using contraception. Low
rates of use in Diabetic women
 Health Literacy and Pregnancy
Preparedness
• Lower health literacy linked to:
– Lack of high school diploma
– Lower socioeconomic status
– Unplanned pregnancy
– Lower probability of pre-conception discussion with endocrinologist or
obstetrician
– Lower probability of pre-conception folic acid ingestion
– Greater probability of hospitalization during pregnancy

Endres LK et al. Diabetes Care: 27; 331-4.

 And then what?
• Encourage lifestyle modification to reduce risk
of persistent dysglycemia and overweight
– 30-50% of women with GDM will develop Type 2
DM
• Encourage nursing
– Reduction of risk by up to 50%
• Counsel on the importance of planning future
pregnancies and offer birth control
 Thank you!

eklass@medicine.nevada.edu