AJCP / Original Article
Placental Histomorphometry in Gestational Diabetes
Mellitus
The Relationship Between Subsequent Type 2 Diabetes Mellitus
and Race/Ethnicity
Rhonda Bentley-Lewis, MD,1 Deanna L. Dawson,1 Julia B. Wenger, MPH,2 Ravi I. Thadhani,
MD,2 and Drucilla J. Roberts, MD3
From the 1Medicine/Diabetes Unit, Massachusetts General Hospital, Boston, MA; 2Medicine/Division of Nephrology, Massachusetts General Hospital,
Boston, MA; and 3Pathology, Massachusetts General Hospital, Boston, MA.
Key Words: Placental histomorphometry; Gestational diabetes mellitus; Type 2 diabetes mellitus; Race/ethnicity
DOI: 10.1309/AJCPX81AUNFPOTLL
ABSTRACT
Objectives: We examined placental histomorphometry in
gestational diabetes mellitus (GDM) for factors associated
with race/ethnicity and subsequent type 2 diabetes mellitus
(T2DM).
Methods: We identified 124 placentas from singleton, full-
term live births whose mothers had clinically defined GDM
and self-reported race/ethnicity. Clinical and placental
diagnoses were abstracted from medical records.
Results: Forty-eight white and 76 nonwhite women were
followed for 4.1 years (median, range 0.0-8.9 years). White
women developed less T2DM (12.5% vs 35.5%; P = .005)
but had higher systolic (mean ± SD, 116 ± 13 vs 109 ± 11
mm Hg; P < .001) and diastolic (71 ± 9 vs 68 ± 7 mm Hg;
P = .02) blood pressure, more smoking (35.4% vs 10.5%;
P = .004), and more chorangiosis (52.1% vs 30.3%; P = .02)
than nonwhite women.
Conclusions: Although more nonwhite women developed
T2DM, more white women had chorangiosis, possibly
secondary to the higher percentage of smokers among them.
Further study is necessary to elucidate the relationship
among chorangiosis, subsequent maternal T2DM, and race.
© American Society for Clinical Pathology
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CME/SAM
Upon completion of this activity you will be able to:
• define gestational diabetes mellitus (GDM).
• describe placental histomorphometry associated with a
normotensive pregnancy complicated by GDM.
• describe racial differences in placental histomorphometry
associated with GDM.
The ASCP is accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education for physicians.
The ASCP designates this journal-based CME activity for a maximum of
1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only
the credit commensurate with the extent of their participation in the activ-
ity. This activity qualifies as an American Board of Pathology Maintenance
of Certification Part II Self-Assessment Module.
The authors of this article and the planning committee members and staff
have no relevant financial relationships with commercial interests to disclose.
Questions appear on p 607. Exam is located at www.ascp.org/ajcpcme.
Gestational diabetes mellitus (GDM) affects approxi-
mately 7% of all pregnancies in the United States, but
prevalence estimates are as high as 18% among women of
nonwhite race/ethnicity.1 GDM increases the risk for type
2 diabetes mellitus (T2DM) and cardiovascular disease
subsequent to pregnancy2; therefore, early risk stratifica-
tion of women with GDM is critical to the development of
appropriate primary prevention strategies. Although several
risk factors have been identified as associated with progres-
sion to T2DM in women with GDM, including higher body
mass index, older age, and higher frequency of GDM in past
pregnancies,3 these factors incompletely identify the risk.
Because the placenta reflects the maternal metabolic milieu
during pregnancy, the use of placenta-derived data for sub-
sequent maternal disease is another opportunity to inform
risk stratification in this population.
Am J Clin Pathol 2014;141:587-592 587
587 DOI: 10.1309/AJCPX81AUNFPOTLL 587
Bentley-Lewis et al / Placental Histomorphometry in GDM
The placenta is the critical organ responsible for fetal
growth and development, as well as the transfer of blood, oxy-
gen, nutrients, and waste between the mother and the fetus.4
Normal placental anatomy comprises the lacuna, floating
and anchoring villi, villous and extravillous cytotrophoblasts,
syncytiotrophoblasts, uterine blood vessels, and uterine con-
nective tissue.5 Pathologic changes in placental structure
and function have been observed in type 1 diabetes mellitus
(T1DM)6 and T2DM.7 In addition, placental abnormalities in
GDM have been reported8 and have paralleled those associat-
ed with pregestational diabetes, including increased fetal and
placental weight, diameter, and thickness9; cytotrophoblastic
hyperplasia; villous edema and fibrin deposits; and choran-
giosis.8 However, placental abnormalities in GDM have not
been associated with subsequent maternal risk for T2DM. In
addition, the role of race/ethnicity in GDM placental pathol-
ogy has not been fully elucidated.
Therefore, we sought to compare placental histomor-
phometry from pregnancies complicated by GDM and exam-
ine factors that distinguished women from racially/ethnically
diverse populations compared with white populations. We
hypothesized that the placentas of women from racially/ethni-
cally diverse populations would have a higher prevalence of
vascular abnormalities given the higher prevalence of GDM
and concomitant cardiovascular disease risk among these
populations.2 Second, because women with GDM have simi-
lar placental pathology as women with T1DM and T2DM, we
hypothesized that placental pathology would provide insight
regarding the risk of subsequent T2DM postpartum.
Materials and Methods
Population Selection
Participants for this study were selected from placental
pathology specimens received in the Massachusetts General
Hospital (MGH) Pathology Department between January 1,
2001, and December 31, 2009 (n = 765). We then cross-ref-
erenced this population with a population of women who pre-
sented for prenatal care to the MGH Obstetrical Department
between September 1998 and January 2007 and were par-
ticipants in the MGH Obstetric Maternal Study (MOMS).10
These women, initially followed during pregnancy for the
development of preeclampsia, were subsequently observed
for a median of 11.1 years postpartum and had data on the
development of T2DM subsequent to pregnancy.
Of the population of women with pathology specimens
who also had longitudinal clinical data from the MOMS
data set (n = 178), we selected those categorized as having a
clinically confirmed diagnosis of GDM by Carpenter-Coustan
criteria.11 Women were diagnosed if they had two or more
588 Am J Clin Pathol 2014;141:587-592
588 DOI: 10.1309/AJCPX81AUNFPOTLL
venous plasma glucose values greater than or equal to the
defined threshold levels (fasting, ≥95 mg/dL; 1 hour, ≥180
mg/dL; 2 hours, ≥155 mg/dL; and 3 hours, ≥140 mg/dL) on
a 100-g oral glucose tolerance test. Among the women who
met the GDM criteria (n = 157), only those who delivered full-
term, singleton live births were selected for the study (n = 129).
Race and ethnicity were self-reported, and the women
identified themselves as black, white, Asian, Hispanic, or
“other.” Those who did not self-identify race/ethnicity were
categorized as “unknown” (n = 5) and were not included in the
population of women examined by race/ethnicity (n = 124). All
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participants completed informed written consent to encompass
this study, and the study protocol was approved by the Partners
Human Research Committee Institutional Review Board.
Placenta Specimen Examination
The pathologic specimens previously had been processed
by gross and histologic examinations. A standard gross tem-
plate was followed, and at least three sections of placenta were
sampled for histology (cord, membranes, and parenchyma).
One of four perinatal pathology experts rotating on service
(including D.J.R.) performed the initial diagnostic examina-
tion and reported the findings. All placental specimens select-
ed for our database were reexamined by two authors (D.J.R.
and D.L.D.), who were both blinded to clinical history.
The gross parameters examined included placental
weight, cord weight, cord length, and cord insertion site.
Samples were also coded for villous maturation, categorized
as mature, slightly immature, or immature. Mature villi had
at least a minimum of one vasculosyncytial membrane and
one syncytiotrophoblastic knot per two terminal villi. Slightly
immature villi were coded for villi bordering the two other
classifications but not meeting criteria for villous maturational
arrest.12 Immature villi were coded when the villi were large
without vasculosyncytial membranes and with a prominent
cytotrophoblastic layer.
On histologic examination, we scored and diagnosed vil-
lous maturational arrest; dysmorphic villi, defined as villi with
prominent trophoblastic layers without knots, irregular villous
contours, open villous stroma, and hypovascularization; and
chorangiosis, defined as 20 or more capillaries in a cluster of
villi in three ×40 fields.13 We captured maternal inflamma-
tion as an aggregate of the measures of villitis of unclear or
unknown etiology14; interface inflammation, confluent basal
plate chronic villitis with deciduitis, and/or confluent chronic
inflammation on the fetal side of the chorionic plate; and
plasma cell deciduitis. Maternal and fetal evidence of acute
chorioamnionitis was classified using the Redline nosology.15
Measures of fetal stress identified included the presence of
an increased number of circulating fetal nucleated RBCs
and multifocal or diffuse acute villous edema. Measures of
placental perfusion pathologies included placental infarcts,
© American Society for Clinical Pathology
 AJCP / Original Article

distal villous hypoplasia, and fetal thrombotic vasculopa-
thy.16 Decidual vasculopathy was characterized by fibrinoid
necrosis with or without atherosis in the decidua capsularis,
decidual necrosis with atherosis in the decidua basalis, or
the presence of small muscularized arterioles in the decidua
basalis. Meconium, fibrin deposition, intervillous thrombi,
and calcification were also evaluated.
nonwhite population to the white population. The statistical
analyses were performed using the SAS for Windows version
9.1 statistical software package (SAS Institute, Cary, NC). A
P value less than .05 was considered statistically significant.
Results

Statistical Analysis Clinical Findings

The placental pathologic and clinical parameters were From the initial 765 specimens available, we identified
compared and used to evaluate the differences in placental the 129 women with biochemically defined GDM who had

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pathology and vasculature between the two populations.
Continuous variables were summarized using means and
standard deviations, while frequency distributions account-
ing for missing values were used for categorical variables.
Summary characteristics of white vs nonwhite subjects were
compared using Mann-Whitney tests and c2 tests where
appropriate. To complete our analysis of the placenta, clinical
and pathologic data were analyzed and compared to examine
the differences in placental vasculature in women from the
full-term, singleton live births. Among these 129 women, 5
women did not identify their race/ethnicity and were excluded
from the analysis population (n = 124). Maternal and neonatal
baseline characteristics for the study population are listed
in ❚Table 1❚. Of the 124 women who provided information
regarding their race, 48 were white, four were black, 14 were
Asian, 51 were Hispanic, one was Native American, and six
were “other” nonwhite but unspecified race/ethnicity. The
women were followed for a median of 4.1 (range, 0.0-8.9)

❚Table 1❚
Clinical Characteristics of the Study Population With Gestational Diabetes Mellitusa

Characteristic All White Nonwhiteb P Value

No. of patients 129 48 76

Age, y 32.4 ± 5.8 32.7 ± 5.6 32.0 ± 6.0 .71
Body mass index, kg/m 2 30.0 ± 6.7 30.5 ± 7.2 29.8 ± 6.4 .71
Systolic blood pressure, mm Hg 112 ± 12 116 ± 13 109 ± 11 .001c
Diastolic blood pressure, mm Hg 69 ± 8 71 ± 9 68 ± 7 .02c
Total cholesterol, mg/dL 195 ± 38 189 ± 41 199 ± 37 .52
High-density lipoprotein, mg/dL 53 ± 13 55 ± 14 51 ± 13 .44
Low-density lipoprotein, mg/dL 114 ± 28 109 ± 28 116 ± 29 .49
Triglycerides, mg/dL 172 ± 128 188 ± 174 163 ± 90 .75
Gestational age at prenatal visit, wk 12.1 ± 6.0 11.5 ± 5.2 12.2 ± 6.3 .88
No. of total pregnancies 2.7 ± 1.7 2.4 ± 1.4 2.7 ± 1.6 .44
No. of live births 1.0 ± 1.3 0.7 ± 0.8 1.1 ± 1.3 .19
Weight gain, lb 21.3 ± 12.7 21.9 ± 13.8 20.7 ± 12.1 .85
Preeclampsia 2 (1.6) 1 (2.1) 1 (1.3) .74
Gestational age at delivery, wk 39.5 ± 1.1 39.4 ± 1.1 39.4 ± 3.3 .53
Baby weight, g 3,670 ± 618 3,667 ± 505 3,676 ± 699 .66
Birth weight for gestational age percentile, % 62.9 ± 30.0 64.2 ± 29.0 61.7 ± 31.3 .64
Time from MGH delivery to follow-up, median (range), y 4.1 (0-8.9) 3.7 (0-8.5) 4.1 (0-8.9) .96
d
Essential hypertension 17 (13.2) 6 (12.5) 11 (14.5) .53
Diabetes mellitusd 34 (26.4) 6 (12.5) 27 (35.5) .005c
Smoking status .004c
Never 56 (43.4) 18 (37.5) 36 (47.4)
Past 18 (14.0) 17 (35.4)e 8 (10.5)e
Current 8 (6.2)
Race
White 48 (37.2)
Black 4 (3.1)
Asian 14 (10.9)
Hispanic 51 (39.5)
Native American 1 (0.8)
Other nonwhite 6 (4.7)
Unknown 5 (3.9)

MGH, Massachusetts General Hospital.

a Values are presented as mean ± SD or number (%) unless otherwise indicated. Percentages that do not add up to 100% denote missing or unknown data.
b Nonwhite group includes all categories except white and “unknown.”
c Significant at P < .05.
d Percentage denotes development of disease following delivery.
e Numbers include past and current smokers.

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589 DOI: 10.1309/AJCPX81AUNFPOTLL 589
Bentley-Lewis et al / Placental Histomorphometry in GDM
years from delivery to last MGH encounter, and we observed
that the development of T2DM after pregnancy among the
nonwhite population was nearly three times more frequent
compared with the white population (35.5% vs 12.5%; P =
.005). White women also had higher systolic (mean ± SD, 116
± 13 vs 109 ± 11 mm Hg; P < .001) and diastolic (71 ± 9 vs
68 ± 7 mm Hg; P = .02) blood pressure compared with non-
white women. Notably, the number of past or current smokers
was significantly higher among the white compared with the
nonwhite women (35.4% vs 10.5%; P = .004). Otherwise,
both the white and nonwhite populations had similar clinical,
prenatal, and perinatal parameters.
❚Table 2❚
Placental Pathology Characteristics in the Study Population
With Gestational Diabetes Mellitusa
Characteristic All White Nonwhiteb P Value
Placental weight, g 536 ± 132 532 ± 108 540 ± 148 .88
Placental weight .95
 percentile
<10 24 (18.6) 9 (18.8) 14 (18.4) populations. To our knowledge, this is the first study that has
10-90 72 (55.8) 27 (56.3) 41 (54.0)
>90 33 (25.6) 12 (25.0) 21 (27.6) examined racial/ethnic differences in the placental pathology
Cord length, cm 36.1 ± 13.8 33.7 ± 14.8 37.2 ± 13.2 .19
Cord insertion 5.0 ± 2.4 4.7 ± 2.5 5.2 ± 2.3 .25
Cord insertion location .26
Membranous 2 (1.6) 0 2 (2.6) we observed that white women had higher blood pressure,
Maturation .92
Mature 9 (7.0) 3 (6.3) 6 (7.9)
Slightly immature 117 (90.7) 44 (91.7) 68 (89.5) develop subsequent T2DM than the nonwhite women. From
Immature 3 (2.3) 1 (2.1) 2 (2.6) a pathology perspective, we observed that placental pathology
Chorangiosis 49 (38.0) 25 (52.1) 23 (30.3) .02c
Chorangiosis— 7 (5.4) 4 (8.3) 3 (4.0) .30
  focal diffuse
Dysmorphic 16 (12.4) 5 (10.4) 11 (14.5) .51
Maturation arrest 0 0 0 NA
Inflammation 51 (39.5) 19 (39.6) 30 (39.5) .99
Acute chorioamnionitis 22 (17.1) 6 (12.5) 14 (18.4) .38
Villitis of unclear/ 26 (20.2) 11 (22.9) 14 (18.4) .54
  unknown etiology
Interface inflammation 4 (3.1) 2 (4.2) 2 (2.6) .64
Deciduitis 2 (1.6) 2 (4.2) 0 .07
Fetal acute 2 (1.6) 1 (2.1) 1 (1.3) .74
 chorioamnionitis
Vasculitis 6 (4.7) 2 (4.2) 3 (4.0) .74
Nucleated RBCs 6 (4.7) 3 (6.3) 3 (4.0) .54
Acute villous edema 14 (10.9) 5 (10.4) 9 (11.8) .81
Placental infarcts 20 (15.5) 8 (16.7) 12 (15.8) .90
Intervillous thrombi 26 (20.2) 9 (18.8) 16 (21.1) .76
Fetal thrombotic 9 (7.0) 1 (2.1) 8 (10.5) .07
 vasculopathy
Avascular villi 5 (3.9) 1 (2.1) 4 (5.3) .38
Edema 1 (0.8) 1 (2.1) 0 .21
Meconium 39 (30.2) 11 (22.9) 27 (35.5) .14
Extensive meconium 2 (1.6) 0 2 (2.6) .26
Decidual vasculopathy 2 (1.6) 1 (2.1) 1 (1.3) NA
Calcification 14 (10.9) 4 (8.3) 9 (11.8) .53
Fibrin 11 (8.5) 2 (4.2) 8 (10.5) .21
Atherosis 1 (0.8) 0 1 (1.3) .42
NA, not applicable.
a Values are presented as mean ± SD or number (%). Percentages that do not add up
to 100% denote missing or unknown data.
b Nonwhite group includes all categories except white and “unknown.”
c Significant at P < .05.
590 Am J Clin Pathol 2014;141:587-592
590 DOI: 10.1309/AJCPX81AUNFPOTLL
Pathologic Findings
Gross and histomorphometric examinations were per-
formed on all 129 placentas in the study cohort, and the
findings are listed in ❚Table 2❚. Placental weight (mean ± SD,
532 ± 108 vs 540 ± 148 g; P = .88) and gestational age at
delivery (39.4 ± 1.1 vs 39.4 ± 3.3 weeks; P = .53) were similar
between the white and nonwhite populations. We observed
a larger number of slightly immature placentas in the white
population compared with the nonwhite population (91.7% vs
89.5%), but this difference did not achieve statistical signifi-
cance in the overall maturation category. Chorangiosis was
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significantly higher in placentas from the white population
compared with the nonwhite population (52.1% vs 30.3%, P =
.02) ❚Image 1❚. Excluding chorangiosis, the placental pathol-
ogy parameters were not statistically significantly different
between the white and nonwhite populations (Table 2).
Discussion
In our study, we analyzed the placental histomorphom-
etry of GDM among women from white and nonwhite
of women with GDM with a consideration of the clinical
implications during and subsequent to pregnancy. Clinically,
were more likely to be smokers, and were less likely to
was largely similar between the white and nonwhite popula-
tions. However, we did observe that white women with GDM
had a greater percentage of chorangiosis than was evident
among nonwhite women with GDM, a finding worthy of
further consideration.
Chorangiosis refers to the presence of excess blood ves-
sels in the placental villi. Ogino and Redline13 observed that
chorangiosis is significantly associated with having enlarged
placenta, immature villi, and maternal diabetes. In addi-
tion, they observed in the literature that chorangiosis is also
associated with maternal anemia, smoking, twin gestations,
and delivery at high altitudes. In our study, all women were
healthy, and none were reported to have anemia or cardiovas-
cular disease. In addition, all pregnancies in our study cohort
were singleton and delivered at MGH, so ambient altitude
was not a factor. However, a significantly greater number,
35.4%, of the white women identified as past or current
smokers compared with 10.5% of the nonwhite population
(P = .004). Therefore, it is possible that the relatively high
proportion of past or current smokers in the white population
contributed to the greater degree of chorangiosis in that popu-
lation, although both populations’ insulin dependence during
pregnancy should also be considered.
© American Society for Clinical Pathology

A B
❚Image 1❚ Mature placentas at ×20. A, Chorangiosis. Multiple capillaries are in all villi with villous expansion (H&E). B, Normal
nonchorangiotic placenta showing normal number of capillaries in villi (H&E).
Several studies have considered glycemic control during
pregnancy when investigating placental pathology associated
with diabetes. Calderon et al17 found that abnormal glycemic
levels could contribute to morphometric abnormalities observed
in the GDM placenta. Gauster et al8 supported these findings,
concluding that poorly controlled GDM could result in villous
edema and increased fibrin in the placenta. While GDM has
numerous implications for the vasculature and gross charac-
teristics of the placenta, it has also been shown to contribute
to impaired placental function, including reduced glucose
metabolism and the ability to metabolize other substrates.18,19
Alternatively, good glycemic control during pregnancy
reduces adverse clinical pregnancy outcomes associated with
GDM,20 but normoglycemia does not mediate all the patho-
logic characteristics associated with GDM.21-23 In our popula-
tion, the only pathologic difference was that chorangiosis was
significantly more prevalent among the white compared with
the nonwhite women with GDM. Because we do not know the
degree of insulin use or glycemic control of these women, we
do not know if the greater incidence of chorangiosis among
white women resulted from greater intrapartum insulin use,
presumably leading to improved intrapartum glycemic control
and consequently less T2DM development subsequent to preg-
nancy. Conversely, more intrapartum insulin use among non-
white women with GDM would be consistent with data sug-
gesting an increased rate of subsequent development of T2DM
in this setting.24 Nonetheless, we require the data regarding
insulin use and glycemic control to clarify this relationship.
Accordingly, one limitation of our study is the lack of
information on glucose control or insulin use during pregnan-
cy. These data would facilitate the elucidation of the etiology
© American Society for Clinical Pathology
AJCP / Original Article
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of chorangiosis in our population. In addition, to elucidate the
observed racial difference in the degree of chorangiosis, it
would be beneficial to examine a population of white women
without GDM to distinguish this association with chorangio-
sis as race mediated or GDM associated. Furthermore, we had
limited racial/ethnic diversity within our nonwhite population.
This could have limited the differences between the white and
nonwhite populations.
In summary, we identified that chorangiosis was more
prevalent among white compared with nonwhite women with
GDM. Excluding chorangiosis, we found that the placental
pathology of the white and nonwhite women did not differ
significantly. This finding is clinically relevant for at least two
reasons. First, the placentas of women with GDM may not
undergo routine pathologic examination depending on institu-
tional practice. However, our findings suggest that placental
pathologic examination may demonstrate changes with impli-
cations for maternal postpartum cardiometabolic disease risk
surveillance. Second, the identification of placental pathology
may serve as an indicator of underlying maternal disease. For
example, in our study, we identified a racial/ethnic differ-
ence in the presence of chorangiosis, which has been directly
linked to clinical parameters such as maternal dysglycemia
and anemia.13 Consequently, this may be correlated with the
prenatal measurements of these parameters and potentially
lead to the consideration of additional prenatal intervention in
certain populations.
Further study is warranted to determine the cause of
greater chorangiosis in our white population and examine
whether this observation is related to smoking, insulin use,
glycemic control, or specifically race. We also found that
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591 DOI: 10.1309/AJCPX81AUNFPOTLL 591
Bentley-Lewis et al / Placental Histomorphometry in GDM
more nonwhite women developed T2DM after pregnancy
than white women in our GDM population. However, fur-
ther research is necessary to determine if the higher rate of
subsequent T2DM in nonwhite populations is associated with
differences in placental pathology. This may provide another
opportunity for risk stratification in GDM populations to
inform evidence-based interventions to alleviate racial/ethnic
disparities in GDM and T2DM.
Address reprint requests to Dr Bentley-Lewis, Massachusetts
General Hospital, 55 Fruit St, Bulfinch 4-415, Boston, MA 02114;
e-mail: Bentley-Lewis.Rhonda@mgh.harvard.edu.
   This study was supported by grant 1R03DK096152 from
the National Institutes of Health (NIH) and the Robert Wood
Johnson Foundation Harold Amos Medical Faculty Development
Program (R.B.-L.); Harvard Catalyst Summer Clinical and
Translational Research Program (D.L.D.); K24 DK094872 from
the NIH (R.I.T.); and the Massachusetts General Hospital (MGH)
Pathology Department (D.J.R.).
   These data were presented in part as an abstract poster
presentation at the Endocrine Society’s 95th Annual Meeting;
June 15, 2013; San Francisco, CA.
   Acknowledgments: We thank Kaitlyn Barnes, Stella St.
Hubert, Grace Xiong, Melissa Ong, Annie Yang, and Jennifer
Huynh of the MGH Diabetes Research Center for their assistance
with data compilation and manuscript preparation.
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