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Prepregnancy Diabetes and Risk ofPlacental Vascular DiseaseTARYN
BECKER, MD, FRCPC 1
MARIAN J. VERMEULEN , BSCN, MHSC 2
PHILIP R. W YATT , MD, FRCPC, PHD 3CHRIS MEIER, BSC, MBA 4
JOEL G. RAY, MD, MSC, FRCPC 5
M aternal diabetes before pregnancyis associated with adverse
mater-nal and perinatal outcomes, in-cluding acquired hypertension
duringpregnancy (13). The maternal placentalsyndromes preeclampsia
and abruptionor infarction of the placenta (4) are alsomore
prevalent in women with insulin re-sistance, diabetes, and the
metabolic syn-drome (3,58). We evaluated the risk of placental
vascular disease in associationwith prepregnancy diabetes.
RESEARCH DESIGN ANDMETHODS We completed a retro-spective
population-based study of allwomen who underwent antenatal
mater-nal serum screening (MSS) in Ontario,Canada, between 1993 and
2000, as de-scribed elsewhere (9). Those with a mul-tiple gestation
pregnancy at the time of MSS were excluded.
Maternal characteristics (Table 1)were recorded on a
standardized form
and completed by the patients caregiversat the time of MSS. Data
on obstetricaloutcomes and the health status of eachnewborn were
also linked to the Dis-charge Abstract Database of the
CanadianInstitute for Health Information, provid-ing up to eight
ICD-9 diagnostic codes foreach woman and each newborn (see
theonline appendix [available at http://
dx.doi.org/10.2337/dc07-0364]).
The primary study outcome was a di-agnosis of eitherpreeclampsia
andabrup-tion or infarction, according to therelevant ICD-9 codes
recorded at the de-livery hospital (online appendix). Sec-ondary
study outcomes included anindividual diagnosis of preeclampsia
andabruption or infarction, maternal pre-eclampsia/eclampsia, and
poor fetalgrowth or fetal growth restriction.
Statistical analysisThe association between prepregnancydiabetes
and study outcomes was ana-lyzed using logistic regression
analysisand expressed as a crude odds ratio (OR)and 95% CI. The ORs
were further ad- justed for those variables listed in thefootnote
of Table 1. All statistical analyseswere done using SAS (version
9.1), andstatistical signicance was set at a two-sided P value
0.05.
Thestudy research protocol was orig-inally approved through the
Ministry of
Health and Longterm Care in Ontario,Canada, and by the research
ethics boardof St. Michaels Hospital.
RESULTS There were 386,323 sin-gleton pregnancies included
during theperiod of study, and 1,717 (0.44%)women had a diagnosis
of prepregnancydiabetes. Most maternal characteristicswere similar
among women with and
without prepregnancy diabetes (Table 1).Fewer women with
prepregnancy diabe-
tes were of nonwhite ethnicity (21.7 vs.27.4%); however, they
weighed more atthe time of MSS (74.6 vs. 66.9 kg).
The rate of preeclampsia was 12%in women with prepregnancy
diabetesand 3% in those without diabetes (ad- justed OR 3.4 [95% CI
2.94.0]) (Table1). Preeclampsia and abruption or infarc-tion was
diagnosed among 2.2% of women with prepregnancy diabetes and1.8% of
those without diabetes (1.1[0.791.5]) (Table 1).
CONCLUSIONS Despite having amore than three times greater risk
of pre-
eclampsia, women with prepregnancy di-abetesdid not appear
tobeat elevated riskfor preeclampsia and infarction or abrup-tion.
A nonsignicantlyhigherrisk of fetalgrowth restriction was seen
among thewomen with prepregnancy diabetes.
How do we explain the higher ob-served risk of preeclampsia but
not pre-eclampsia and abruption or infarction inassociation with
prepregnancy diabetes?The current study had 90% statisticalpower to
detect at least a 1.5 times higherrisk of preeclampsia and
abruption or in-farction between groups; thus, a type IIstatistical
error is unlikely. Poor codingand ascertainment of preeclampsia
andabruption or infarction in a database orig-inallydesigned to
focus on congenital andchromosomal anomalies may be one
ex-planation, and the ICD-9 codes for pre-eclampsia and abruption
and infarctionhave not been properly validated. TheOntario birth
record contains a manda-tory eld whereby the delivering physi-cian
or midwife describes the gross
appearance of the placenta and shouldtherefore record the
presence of pre-eclampsia and abruption or infarction.Because women
with prepregnancy dia-betes are more likely delivered electivelyby
Cesarean section (10), a factornotcon-trolled for herein, they
might be at lowerrisk of preeclampsia and abruption pre-cipitated
during labor (11). At the sametime, we did nd an association
betweenpreeclampsia and prepregnancy diabetes,as expected, and the
3% rate of pre-eclampsia and0.85% rate of preeclampsiaand abruption
among nondiabetic con-
From the 1 Division of Endocrinology and Metabolism,
Universityof Toronto, Toronto, Ontario, Canada; the2 Institute for
Clinical Evaluative Sciences, Sunnybrook and Womens College Health
Sciences Centre,
University of Toronto, Toronto, Ontario, Canada; the 3
Department of Genetics, York Central Hospital,Richmond Hill,
Ontario, Canada; 4 St. Michaels Hospital, University of Toronto,
Toronto, Ontario, Canada;and the 5 Divisions of Endocrinology and
Metabolism and General Internal Medicine, St. Michaels
Hospital,University of Toronto, Toronto, Ontario, Canada.
Address correspondence and reprint requests to Dr. Taryn Becker,
c/o Dr. Joel G. Ray, St. MichaelsHospital, University of Toronto,
30 Bond St., Toronto, Ontario, Canada M5B 1W8. E-mail:
[email protected].
Received for publication 24 February 2007 and accepted in
revised form 15 June 2007.Published ahead of print at
http://care.diabetesjournals.org on 22 June 2007. DOI:
10.2337/dc07-0364. Additional information for this article can be
found in an online appendix at http://dx.doi.org/10.2337/
dc07-0364.Abbreviations: MSS, maternal serum screening. A table
elsewhere in this issue shows conventional and Systeme
International (SI) units and conversion
factors for many substances. 2007 by the American Diabetes
Association.The costs of publication of this article were defrayed
in part by the payment of page charges. This article must therefore
be hereby
marked advertisement in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n
/ P s y c h o s o c i a l R e s e a r c hB R I E F R E P O R T
2496 D IABETES C ARE , VOLUME 30, NUMBER 10, O CTOBER 2007
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trol subjects are comparable with rates of other studies (5,11).
Thus, it appears thatthe current database may have capturedand
classied at least some study out-comes. This does not rule out an
associa-tion between prepregnancy diabetes andpreeclampsiaand
abruptionor infarction,however.
With respect to study strengths, thiswas a large cohort of
400,000 womenwho delivered over a 7-year period. Thes tudy
exposurethe presence of prepregnancy diabeteswas determinedbefore
all outcomes, and baseline mater-nal data were collected using a
standard-ized method, enabling us to adjust forseveral potential
confounding variables. Whereas we could not distinguish be-tween
women with type 1 and type 2 di-abetes, we did adjust for maternal
body
weight in early pregnancy, which is a ma- jor determinant of
type 2 diabetes (12).There is a direct relationship between
abnormal glucose metabolism before orin early pregnancy and the
developmentof preeclampsia (13), and the currentstudy conrms this.
Although hyperten-sive disorders of pregnancy are a majorrisk
factor for preeclampsia and abrup-tion or infarction (13,14), a
link betweenprepregnancy diabetes and preeclampsiaand abruption or
infartction was notfound in the original observation. It hasbeen
postulated that longer duration of
exposure of the placental vessels to a hy-perglycemic and
hypertensive environ-men t i s ha rmfu l (15 ,16 ) . I n
oneprospective study of 290 pregnantwomen with type 1 diabetes, an
elevated A1C at 24 weeks gestation was associatedwith a signicantly
higher risk of pre-eclampsia (17). However, as in our study,there
are no data on glycemic control inpregnancy and the risk of
preeclampsiaand abruption or infarction.
A prospective study can address theissue of maternal glycemic
control andtherisk of preeclampsia, preeclampsia andabruption, or
preeclampsia and infarc-tion. Both preeclampsia and abruptionand
infarction might be captured notonlyat delivery, with a systematic
examinationof the placenta, but also before deliveryusing
ultrasonography. The gestationalage at onset of the preeclampsia
and pre-eclampsia and abruption or preeclampsiaand infarction, as
well as the mode of de-livery, should also be documented.
Acknowledgments J.G.R. is supported bya Canadian Institutes of
Health Research NewInvestigator award.
We thank the Ontario Provincial Laborato-ries and Genetics
Clinics for contributing datato the Ontario MSS Database and the
womenof Ontario for supporting the MSS program.
References1. Khan KS, Daya S: Plasma glucose and pre-
eclampsia. Int J Gynecol Obstet 53:111116, 1996
2. Solomon CG, Graves SW, Greene MF,Seely EW: Gluocse
intolerance as a pre-dictor of hypertension in pregnancy. Hy-
pertension 23:717721, 1994
3. Innes KE, Wismatt JH, McDufe R: Rela-tive glucose tolerance
and subsequent de-velopment of hypertension in pregnancy.Obstet
Gynecol 97:905910, 2001
4. Ray JG, Vermeulen MJ, Schull MJ, Re-delmeier DA:
Cardiovascular health aftermaternal placental syndromes
(CHAMPS):population-based retrospective cohortstudy. Lancet
366:17971803, 2005
5. OBrien TE, Ray JG, Chan WS: Maternalbody mass index and the
risk of pre-eclampsia: a systematic overview. Epide-miology
14:368374, 2003
6. Roberts JM: Endothelial dysfunction inpreeclampsia. Semin
Reprod Endocrinol16:515, 1998
7. Chambers JD, Fusi I, Malik IS, HaskardDO, De Swiet M, Kooner
JS: Associationof maternal endothelial dysfunction
withpreeclampsia. JAMA 285:16071612,2001
8. Ray JG, Vermeulen MJ, Schull MJ, Mc-Donald S, Redelmeier DA:
Metabolicsyndrome and the risk of placentaldysfunction. J Obstet
Gynaecol Can 27:10951101, 2005
9. Ray JG, Vermeulen MJ, Meier C, WyattPR: Risk of congenital
anomalies detected
Table 1 Characteristics of women with and without prepregnancy
diabetes and risk of adverse placental and perinatal outcomes
Prepregnancy diabetes OR (95% CI)
Present (n 1,717) Absent (n 384,606) Crude Adjusted
Maternal characteristics Age (years) 30.0 5.1 29.7 5.0
Gestational age at the time of MSS (weeks) 16.5 1.1 16.7 1.1
Nonwhite ethnicity 362 (21.7) 101,670 (27.4) Median gravidity 2.0
2.0 Median parity 1.0 1.0 Weight at the time of MSS (kg) 74.6 17.6
66.9 14.4 Preeclampsia or eclampsia at delivery 205 (11.9) 11,410
(3.0) Gestational hypertension at delivery 117 (6.8) 7,071 (1.8)
Hypertension outside of pregnancy (coded at delivery) 8 (0.47) 148
(0.040) Tobacco use at delivery 1 (0.060) 951 (0.25) Drug
dependence at delivery 0 (0.00) 221 (0.060)
Study outcomesPlacental abruption or infarction 38 (2.2) 7,120
(1.8) 1.2 (0.871.7) 1.1 (0.791.5)*Placental infarction 19 (1.1)
3,998 (1.0) 1.4 (0.882.1) 1.2 (0.741.8)*Placental abruption 20
(1.2) 3,274 (0.85) 1.1 (0.681.7) 1.0 (0.661.6)*
Poor fetal growth or fetal growth restriction 17 (0.99) 2,000
(0.52) 1.9 (1.23.1) 1.5 (0.942.5)*Preeclampsia 205 (11.9) 11,410
(3.0) 4.4 (3.85.1) 3.4 (2.94.0)
Data are means SD or n (%) unless otherwise indicated. *Adjusted
for maternal age, nonwhite ethnicity, parity, and body weight at
the time of MSS, as well aspreeclampsia/eclampsia, gestational
hypertension, gestational diabetes, tobacco use, and drug
dependence at the time of delivery. Adjusted for maternal
age,nonwhite ethnicity, parity, and maternal body weight at the
time of MSS, as well as gestational diabetes and tobacco use at the
time of delivery.
Becker and Associates
D IABETES C ARE , VOLUME 30, NUMBER 10, O CTOBER 2007 2497
