Placenta 49 (2017) 10e15

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Placenta
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Placental maternal vascular malperfusion and adverse pregnancy

outcomes in gestational diabetes mellitus
Christina M. Scifres a, c, *, W. Tony Parks b, Maisa Feghali c, Steve N. Caritis c,
Janet M. Catov c
a
Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine, 920 Stanton L. Young Blvd, WP 2410, Oklahoma City, OK 73104,
USA
b
Department of Pathology, University of Pittsburgh College of Medicine, S-417 BST 200 Lothrop Street, Pittsburgh, PA 15261, USA
c
Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, 300
Halket St., Pittsburgh, PA 15213, USA

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Maternal vascular malperfusion (MVM) lesions represent hypoxic-ischemic damage to the
Received 18 August 2016 placenta, and they are associated with adverse pregnancy outcomes. Women with gestational diabetes
Received in revised form (GDM) are at increased risk for pregnancy complications, so we set out to characterize the prevalence
10 October 2016
and clinical correlates of MVM lesions in this cohort.
Accepted 9 November 2016
Methods: This was a retrospective cohort study of 1187/1374 (86.4%) women with GDM delivered be-
tween 2009 and 2012 who had placental pathology available. Placental lesions of all types were tabu-
Keywords:
lated and grouped into constructs of related entities. MVM lesions specically included villous infarcts,
Gestational diabetes
Placenta
decidual vasculopathy, increased syncytial knots, perivillous brin, and brin deposition. We compared
Maternal vascular malperfusion lesions maternal characteristics between women with and without MVM lesions, and we also assessed the
Intrauterine growth restriction impact of these lesions on birth weight, preterm birth, and pre-eclampsia using multivariable logistic
Preterm birth regression analysis.
Hypertensive disorders of pregnancy Results: MVM lesions were the most common placental lesion type in women with GDM (n 362,
30.5%). Excess gestational weight gain was independently associated with MVM lesions (aOR 1.42, 95% CI
1.06e1.91, p 0.02) after adjusting for maternal characteristics. MVM lesions were associated with lower
birth weight (90.3 g, 95% CI -148.0 to 32.7, p 0.002), as well as a 2-fold increased risk for delivery of
a small for gestational age infant (10.8 vs 5.9%, p 0.01) in overweight and obese women. MVM lesions
were also associated with increased risk for preterm birth <34 weeks (adjusted OR 2.36, 95% CI 1.31
e4.23, p 0.004) and hypertensive disorders of pregnancy (HDP; adjusted OR 1.58, 95% CI 1.13e2.22,
p 0.02).
Discussion: Placental maternal vascular malperfusion lesions may be one pathway linking excess
gestational weight gain to adverse pregnancy outcomes in women with GDM, and future studies are
needed to identify metabolic factors that may explain this association.
2016 Elsevier Ltd. All rights reserved.

1. Introduction pregnancies [1], and it can result in adverse pregnancy outcomes

Gestational diabetes mellitus (GDM) affects approximately 7% of
* Corresponding author. Department of Obstetrics and Gynecology, University of
Oklahoma College of Medicine, 920 Stanton L. Young Blvd, WP 2410, Oklahoma City,
OK 73104, USA.
E-mail addresses: Christina-scifres@ouhsc.edu (C.M. Scifres), parkswa@upmc.
edu (W.T. Parks), feghalim@upmc.edu (M. Feghali), carisn@mail.magee.edu
(S.N. Caritis), catovjm@mail.magee.edu (J.M. Catov).
including fetal overgrowth [2] and pre-eclampsia [2,3]. In addition
to dysglycemia, gestational diabetes is associated with obesity and
excess gestational weight gain [4], both of which also increase the
risk for pregnancy complications. Although GDM is commonly
diagnosed in the late second and early third trimester, metabolic
perturbations including increased triglycerides [5] and alterations
in various inammatory cytokines and adipokines may occur much
earlier in gestation [6].
Less is known about the relationship between placental

http://dx.doi.org/10.1016/j.placenta.2016.11.004
0143-4004/ 2016 Elsevier Ltd. All rights reserved.
 C.M. Scifres et al. / Placenta 49 (2017) 10e15
pathology lesions and adverse pregnancy outcomes in women with
GDM. The placenta reects the metabolic milleu of both the mother
and fetus and it can shed light on the metabolic alterations that
occur during pregnancy. Oxygenated maternal blood ows through
remodeled spiral arteries that traverse the maternal myometrium
and decidua before emptying into the placental intervillous space.
A trophoblast layer separates this maternal compartment of the
placenta from the fetal vessels of the placental vasculature. The
maternal and placental circulations then exchange oxygen and
nutrients across this trophoblast barrier at the level of the terminal
villus. Consequently, placental dysfunction can lead to a number of
adverse pregnancy and neonatal outcomes [7,8].
Placental MVM lesions develop as a consequence of decient
trophoblastic invasion and remodeling of the spiral arterioles in
early pregnancy [9], and these lesions are a common pathologic
nding that may contribute to or represent damage from placental
hypoxia [10]. Maternal malperfusion is of clinical signicance,
because many aspects of this entity have been associated with se-
vere pregnancy-related complications [11]. Many MVM lesions
were originally described in the context of pre-eclampsia, and these
lesions were considered relatively specic for pre-eclampsia.
However, it is now known that these lesions can be found in sys-
temic lupus erythematosus, antiphospholipid antibody syndrome,
fetal growth restriction, preterm labor, preterm premature rupture
of membranes, placental abruption, and stillbirth [11], but the
maternal characteristics that are associated with the development
of these lesions are incompletely understood. Because women with
GDM are at increased risk for adverse outcomes, the goal of this
analysis was to characterize the prevalence of placental lesions in
women with GDM with a focus on maternal factors associated with
MVM lesions. We also sought to assess the impact of placental
MVM lesions on birth weight, preterm birth, and hypertensive
disorders of pregnancy in women with GDM.
2. Methods
This was a retrospective cohort study that included women with
singleton gestations and GDM who were delivered at Magee-
Womens Hospital (University of Pittsburgh, Pittsburgh, PA) from
January 2009 to October 2012 were included. Details of the cohort
derivation were presented previously [4], but in brief we identied
1374 women who were diagnosed with GDM using either a 50 g, 1 h
glucose challenge test (GCT) that exceeded 200 mg/dL, or if they
had two or more abnormal values on a 3 h, 100 g oral glucose
tolerance test (OGTT) as dened by the Carpenter-Coustan Criteria
[12]. Medical records were reviewed to conrm all diabetes di-
agnoses, and women who reported a diagnosis of diabetes at their
rst prenatal visit or those with a rst trimester HbA1c value > 6.5%
were considered to have pre-gestational diabetes and excluded.
Placentas from women with GDM were routinely sent for patho-
logic evaluation, and we included 1186/1374 (86.3%) of women with
GDM who had placental pathology available.
Placental pathology data were matched to patients with GDM
using the Magee Obstetric Medical and Infant (MOMI) database. All
placentas were examined for clinical indications, therefore a
limited amount of clinical history was available to the pathologist.
Our placenta pathology matching and extraction process has been
described previously. Briey, placental pathology reports were
reformatted into Extensible Markup Language (XML) using Java and
then A SQL Server Integration Services package (SSIS) extracted and
transformed this text information into SQL Server tables that were
then linked to the MOMI database. With the assistance of a
placental pathologist (WTP), lesions were then grouped into cate-
gories including maternal vascular malperfusion (MVM; decidual
vasculopathy, villous infarction, advanced villous maturation,
11
increased perivillous brin deposition, increased intervillous brin
deposition), ascending intrauterine infection (AIUI; acute cho-
rioamnionitis, acute funisitis, acute vasculitis, acute deciduitis),
villitis of unknown etiology (VUE; a chronic inammatory inltrate
in the villi), fetal thrombosis, or chorangiosis (Supplemental Table 1
contains denitions used for each lesion type) [13e15]. Because
lesions associated with ascending infection were unlikely to be
specically related to gestational diabetes, these lesions were
excluded from further analysis. A validation study demonstrated
excellent sensitivity and specicity for MVM lesions when auto-
mated abstraction was compared to manual record abstraction [13].
In addition, a number of cases (n 56 spontaneous PTBs, 19
medically indicated PTBs, and 50 term births) were reviewed by a
single pathologist blinded to all clinical information except gesta-
tional age (WTP). MVM lesions demonstrated good agreement
(62%) in preterm birth and excellent agreement among term births
(82%).
To assess maternal glycemic control, 7 days of consecutive blood
glucose values were obtained from the medical record at 4 week
intervals. Blood glucose data were available for 989/1186 women
(83.4%), and the mean fasting and postprandial blood glucose
values were calculated across gestation. Decisions regarding initi-
ation of glyburide or insulin were made by the treating physician,
and both dose at initiation of therapy and dose at delivery were
abstracted from the medical record. Pre-pregnancy BMI was
calculated using the patient-reported pre-pregnancy weight, and
gestational weight gain was categorized as insufcient, sufcient,
or excessive as dened in the Institute of Medicine 2009 guidelines
[16]. In women with preterm delivery (n 186) we estimated the
maximal recommended weight gain at the gestational age at which
they were delivered by multiplying the maximal weekly weight
gain in the second and third trimesters times the number of weeks
preterm the patient was delivered and subtracting this value from
the maximum recommended weight gain for each BMI category
[17].
The primary objectives of our study were to establish maternal
factors related to MVM lesions and to assess the relationship be-
tween these lesions and pregnancy outcomes. Our primary preg-
nancy outcomes included birth weight, preterm birth, and
hypertensive disorders of pregnancy. Birth weight categories
including large for gestational age (>90th percentile for gestational
age) or small for gestational age (<10th percentile for gestational
age) birth weight status based on US national birth weight data [18]
were compared between women with and without MVM lesions.
We also calculated the birthweight z-scores using population-
based birthweight data from our hospital over a 3 year period.
Preterm births (<37 or <34 weeks) were further characterized as
spontaneous (following the spontaneous onset of contractions or
premature rupture of membranes) or indicated preterm birth,
which encompassed all other preterm deliveries. Hypertensive
disorders of pregnancy were considered together as a single
outcome, and they were also individually dened as follows:
gestational hypertension consisted of blood pressures 140/
90 mmHg on two or more occasions 6 h apart after 20 weeks
gestation without proteinuria, while pre-eclampsia without severe
features was dened as the same blood pressure threshold
accompanied by detectable urinary protein (urinary protein:
creatinine ratio >0.3 or  0.3 g/24 h). Criteria for preeclampsia with
severe features included blood pressures 160/110 mmHg,
Eclampsia, pulmonary edema, oliguria (<500 ml/24 h), fetal growth
restriction, or symptoms suggestive of signicant end-organ
involvement (headache, visual disturbance, or epigastric or right
upper quadrant pain). Superimposed pre-eclampsia was diagnosed
in women with chronic hypertension who had blood pressure ex-
acerbations along with new-onset proteinuria (0.3 g/24 h).
12 C.M. Scifres et al. / Placenta 49 (2017) 10e15
Neonatal outcomes included neonatal intensive care unit (NICU)
admission, hypoglycemia (dened as a glucose value less than
35 mg/dL within the rst 24 h of life), hyperbilirubinemia requiring
phototherapy, respiratory distress syndrome, congenital anomalies,
and neonatal death. We also dened a composite neonatal
morbidity consisting of hypoglycemia, hyperbilirubinemia, or res-
piratory distress syndrome (RDS).
Statistical analyses were completed using Stata 13 software
package Special Edition (StataCorp LP, College Station, TX). Distri-
butions of variables were tested for normality using visual in-
spection of histograms and the Shapiro-Wilk W-test. Baseline
characteristics and pregnancy outcomes were compared between
women with and without MVM lesions using the chi-squared sta-
tistic, Fisher's exact test, or ANOVA as appropriate. Our primary
focus in modeling was to estimate the relationships between
baseline maternal characteristics and the presence of MVM lesions
as well as the relationship between MVM lesions and perinatal
outcomes including birth weight, preterm birth, and hypertensive
disorders of pregnancy. Potential predictor variables that showed
signicant relationships with each outcome of interest (p < 0.1)
were considered candidates for that outcome's multivariate
modeling and were retained using a backward-stepwise algorithm.
All potential combinations of predictors considered in multivariate
modeling were also tested for rst-order interactions. P-values less
than 0.05 were considered statistically signicant in all analyses.
Because of the hypothesis-generating nature of this study, all sta-
tistical analyses were conducted without adjustment for
multiplicity.
3. Results
MVM lesions were the most common pathologic nding,
affecting 362/1186 (30.5%) of women with GDM (Table 1). Women
with MVM lesions were similar to those without MVM with regards
to maternal age, race, education level, and mean pre-pregnancy
BMI. Women with MVM lesions were more likely to have chronic
hypertension (9.1 vs 5.8%, p 0.04) (Table 2). Women with MVM
lesions also had slightly higher fasting glucose values on their 3 h
oral glucose tolerance test (OGTT), but there were no differences in
the remainder of their OGTT values.
Women with MVM were more likely to have weight gain in
excess of the IOM guidelines (Table 2). This was primarily limited to
overweight and obese women, and the increased mean weight gain
persisted when women with hypertensive disorders of pregnancy
were excluded in sensitivity analysis (data not shown). When
compared by trimester, mean weight gain in all women was
signicantly higher in the rst trimester with a trend towards
higher weight gain in the third trimester (Table 2). When we
compared women with weight loss in the rst trimester to those
with either weight gain of 0e5 lbs or 5 lbs in the rst trimester,
women with weight loss were less likely to have MVM lesions on
placental pathology (24.1 vs 32.0 vs 32.8%, p 0.04). Because the
maternal factors associated with MVM lesions are incompletely
understood, we next used multivariable logistic regression to
evaluate the maternal factors that were independently associated
with these lesions. After adjusting for pre-pregnancy BMI and
maternal chronic hypertension, excess weight gain remained
associated with an increased risk for MVM lesions (adjusted OR
1.42, 95% CI 1.10e1.91, p 0.02).
We next compared pregnancy outcomes in women with and
without MVM lesions. As shown in Table 3, mean birth weight was
lower in the women with MVM lesions as was the birth weight Z-
score, and there was a trend towards smaller placental weight
(Table 3). There were no overall differences in rates of small for
gestational age, appropriate for gestational age, and large for
gestational age fetal growth between women with and without
MVM lesions (Table 3). However, MVM lesions were associated
with small decreases in birth weight (90.3 g, 95% CI -148.0
to 32.7, p 0.002) after adjusting for gestational age at delivery,
pre-pregnancy BMI, weight gain, smoking, chronic hypertension,
nulliparity, and mean post-prandial blood glucose values. We
identied a signicant interaction between MVM lesions and BMI
as a continuous variable with regards to both birthweight
(p 0.04) and the risk for small for gestational age birth weight
(p 0.02). We therefore performed a stratied analysis and found
that there was a 2-fold increased risk in having a small for gesta-
tional age infant among overweight and obese women with MVM
lesions (10.8 vs 5.9%, p 0.01) (Fig. 1). Because excess weight gain is
associated with fetal overgrowth, we also compared mean birth
weight Z-scores in women with insufcient, sufcient, and excess
weight gain. We found that mean birth weight z-scores were lower
in those women with excess weight gain and MVM lesions (Fig. 2),
suggesting that these lesions may affect the risk for fetal over-
growth in subsets of women with excess gestational weight gain.
Women with MVM lesions were delivered at an earlier mean
gestational age, and rates of preterm birth <34 weeks were
signicantly higher in women with MVM lesions (7.2 vs 3.0%,
p 0.001). MVM lesions were seen in 23.4% of spontaneous pre-
term births, 40.2% of indicated preterm births, and 30.3% of term
births. After adjusting for maternal weight gain, pre-pregnancy
BMI, smoking, maternal race, and nulliparity, the presence of
MVM lesions was independently associated with an increased risk
for preterm birth <34 weeks (adjusted OR 2.36, 95% CI 1.31e4.23,
p 0.004). Likely as a result of the increased risk for preterm birth,
NICU admission was higher in the group with MVM lesions (17.5 vs
10.9%, p 0.002), but overall neonatal composite morbidity did not
differ between groups (21.8 vs 20.1%, p 0.47). Of the components
of the neonatal composite morbidity score only hyperbilirubinemia
was higher in the MVM group (10.6 vs 6.7%, p 0.02).
As expected, the prevalence of hypertensive disorders of preg-
nancy was higher in women with MVM lesions when compared to
those without (23.5 vs 14.4%, p < 0.001), and this included higher
rates of gestational hypertension, mild pre-eclampsia, severe pre-
eclampsia, and superimposed pre-eclampsia. MVM lesions were
associated with increased risk for hypertensive disorders of
Table 1
Frequency of placental lesions among women with gestational diabetes mellitus.
Lesion type Frequency
Any lesion 626 (52.8)
Maternal Vascular Malperfusion (MVM) 362 (30.6)
Infarct 138 (11.6)
Vasculopathy 70 (5.9)
Syncytial knots 124 (10.5)
Perivillous brin 117 (9.9)
Fibrin deposition 149 (12.6)
Distal villous hypoplasia 5 (0.4)
Fetal thrombosis 67 (5.6)
Thrombosis 30 (2.5)
Stromal vascular 2 (0.2)
Avascular villi 65 (5.5)
Villitus of unknown origin (VUE) 199 (16.8)
Fetal Hypoxia 144 (12.1)
Chorangiosis 142 (12.0)
Chorangiomatosis 12 (1.0)
Dysmaturity 3 (0.3)
Delayed maturity 72 (6.1)
Number of lesion types
0 560 (47.2)
1 444 (37.4)
2 182 (15.3)
The frequency of placental lesions are presented as n (%).
 C.M. Scifres et al. / Placenta 49 (2017) 10e15 13

Table 2 Table 3
Maternal factors associated with MVM lesions in women with gestational diabetes Maternal and neonatal outcomes associated with MVM lesions in women with
mellitus. gestational diabetes mellitus.

MVM No MVM P MVM No MVM P

N 362 N 824 N 362 N 824

Maternal age (years) 31.0 (5.7) 31.4 (5.3) 0.21 Gestational age (weeks) 38.1 (2.1) 38.4 (1.8) 0.04
Race Preterm birth (<37 weeks) 59 (16.3) 127 (15.4) 0.71
White 273 (75.4) 623 (75.6) Preterm birth (<34 weeks) 26 (7.2) 25 (3.0) 0.001
Black 59 (16.3) 111 (13.5) 0.21 Birth weight (grams) 3203 (648) 3310 (544) 0.003
Other 30 (8.3) 90 (10.9) Birth weight z-score 0.09 (1.0) 0.24 (0.99) 0.02
Nulliparity 186 (51.4) 420 (51.0) 0.90 Placental weight (grams) 460 (117) 474 (107) 0.06
Some College Education 238 (65.8) 563 (68.3) 0.28 Birth weight category
Pre-pregnancy BMI 30.6 (8.0) 30.0 (8.0) 0.25 SGA 38 (10.5) 61 (7.4)
Pre-pregnancy BMI Category AGA 290 (80.1) 680 (82.6)
Underweight 3 (0.8) 23 (2.8) LGA 34 (9.4) 82 (10.0) 0.21
Normal weight 90 (25.1) 242 (30.2) Macrosomia 28 (7.7) 63 (7.7) 0.96
Overweight 94 (26.2) 170 (21.2) 0.02 Cesarean delivery 156 (43.1) 309 (37.5) 0.07
Obese 175 (48.8) 389 (48.6) Hypertensive disorders of pregnancy
Weight gain category None 277 (76.5) 705 (85.6)
Under 67 (19.0) 199 (24.8) Gestational HTN 21 (5.8) 38 (4.6)
At 102 (28.9) 269 (33.5) 0.004 Mild Pre-eclampsia 33 (9.1) 44 (5.3)
Over 184 (52.1) 334 (41.7) Severe Pre-eclampsia 16 (4.3) 25 (3.0)
Total weight gain (lbs) 27.8 (15.7) 25.0 (15.1) 0.003 Superimposed pre-eclampsia 15 (4.2) 12 (1.5) 0.003
Weight gain (lbs) by pre-pregnancy BMI category NICU admission 63 (17.5) 89 (10.9) 0.002
Normal weight 30.5 (11.6) 30.3 (12.4) 0.88 Neonatal composite 79 (21.8) 165 (20.1) 0.49
Overweight 33.3 (16.0) 27.9 (12.6) 0.003 Hypoglycemia 40 (11.1) 109 (13.1) 0.30
Obese 23.2 (16.3) 20.1 (16.4) 0.04 RDS 20 (5.6) 35 (4.3) 0.34
Weight gain (lbs) (all women) Hyperbilirubinemia 38 (10.6) 55 (6.7) 0.02
1st trimester 5.4 (7.0) 4.3 (6.8) 0.01
2nd trimester 14.1 (8.4) 13.6 (8.6) 0.40
3rd trimester 8.1 (8.4) 7.1 (8.2) 0.08
Tobacco Use 41 (11.3) 84 (10.2) 0.56 associated with nausea and vomiting, mitigating the early weight
Chronic hypertension 33 (9.1) 48 (5.8) 0.04 gain. Dietary factors in early pregnancy may also affect placental
50 g GCT 169 (27.9) 172.5 (32.1) 0.11 implantation. Conversely, inadequate placental implantation could
100 g OGTT
alter production of hormones such as leptin that are produced in
Fasting 93.9 (15.9) 91.6 (15.5) 0.03
1h 196.3 (28.3) 196.2 (27.0) 0.98 the placenta and that may affect maternal metabolism. Our current
2h 178.8 (30.1) 177.1 (28.5) 0.45 understanding of the relationship between maternal metabolism
3h 128.0 (39.5) 128.1 (36.6) 0.96 and placental pathology is limited, with much work still to be done
GDM diagnosis (wks) 27.5 (4.9) 27.0 (5.4) 0.18
in this area.
Blood glucose values
Fasting 89.4 (10.9) 88.8 (11.2) 0.47
MVM lesions are associated with subtle but potentially impor-
Mean post-prandial 124.7 (14.8) 123.9 (14.3) 0.39 tant effects on birth weight. Observational studies have demon-
Therapy at delivery strated strong evidence of an association between gestational
None 122 (33.7) 292 (35.4) weight gain and birth weight, with excess gestational weight gain
Glyburide 190 (52.5) 438 (53.2) 0.65
leading to higher birth weight predominantly in underweight and
Insulin 49 (13.5) 93 (11.3)
normal weight women [20]. Our ndings of lower birth weight z-
scores in women with MVM lesions and excess weight gain, as well
as the 2-fold increase in small for gestational age infants in over-
pregnancy (adjusted OR 1.58, 95% CI 1.13e2.22, p 0.007) after
weight and obese women with MVM lesions, suggests that the
adjustment for pre-pregnancy BMI, maternal race, weight gain,
presence of MVM lesions in overweight and obese women with
chronic hypertension, nulliparity, and systolic blood pressure in the
excess gestational weight gain may counteract fetal overgrowth.
rst trimester.
MVM lesions were also associated with preterm birth before 34
weeks. In a systematic review of 150 studies that examined the
4. Discussion inuences of gestational weight gain on various pregnancy out-
comes [20], the majority of studies found that low gestational
MVM lesions were the most common type of placental lesion in weight gain was associated with increased preterm birth but a less
this cohort of women with GDM. When compared to a cohort study consistent association between high gestational weight gain and
of 124 women with GDM, the prevalence of decidual vasculopathy preterm birth. However, MVM lesions could provide a link between
identied in our cohort was higher (5.9 vs 1.6%), whereas the excess gestational weight gain and preterm birth in select women.
prevalence of placental infarct was lower (11.6 vs 16.1%) than pre- MVM lesions have been linked to hypertensive disorders of
viously reported [19]. The prevalence of other lesions characterized pregnancy, but the mechanisms leading to this association are still
as MVM lesions in our study were not reported in the study by unclear. The damage to the placenta represented by these lesions
Huynh et al., and our data provide a baseline estimate of a broad has traditionally been ascribed to vascular underperfusion with
array of placental pathology lesions in a well-characterized group resulting hypoxia-ischemia [10], and placentas from pregnancies
of women with GDM. complicated by pre-eclampsia may also display substantial oxida-
Excess gestational weight gain as early as the rst trimester is tive damage, as might be expected from hypoxia/reperfusion in-
associated with MVM lesions in women with GDM. However, the juries [21]. While still incompletely understood, it is possible that
reasons for the increased weight gain in the rst trimester are metabolic disturbances associated with obesity play a role in
unclear. It is possible that, as compared with the diminished early inadequate vascular remodeling. Some studies have suggested that
placentation seen with MVM, the more robust early placentation of normal glucose levels are associated with normal-appearing
normal pregnancies leads to higher levels of hormones that are
14 C.M. Scifres et al. / Placenta 49 (2017) 10e15

Fig. 1. Birth weight category by MVM lesions in normal weight (Panel A) and over-
weight or obese women (Panel B).
Legend: Birth weight category compared between women with and without MVM
lesions among A) normal weight and B) overweight and obese women using the chi-
square statistic.

placentas [22], while other have identied placental abnormalities

among women with well-controlled gestational diabetes [23,24].
We did not identify differences in glycemic control between
women with and without MVM lesions.
There are several limitations to these data. Diabetes is one of the
few indications where placentas are sent for pathologic exam
regardless of pregnancy outcome, so we were unable to compare
rates of placental lesions between women with and without dia-
betes. Pathologists were not blinded to clinical diagnoses, and
clinical knowledge could have inuenced their ndings. While the
sensitivity of pathologic evaluation for MVM lesions is modest, the
most severe lesions, such as decidual vasculopathy and villous in- Fig. 2. Birth weight Z scores by MVM lesion in women with insufcient (Panel A),
farcts, are highly reproducible [25,26]. The overall impression of a sufcient (Panel B), and excess weight gain (Panel C).
placental pathologist is superior to the detection of particular le- Legend: Birth weight z-score compared between women with and without MVM le-
sions in those with A) insufcient, B) appropriate, and C) excessive weight gain using
sions for the diagnosis of malperfusion [9], yet efforts to improve
the t-test.
the diagnostic accuracy of MVM lesions are needed [26]. One sig-
nicant strength is that this is one of the few cohort studies of
placental pathology in women with gestational diabetes, and this to identify links between maternal metabolic states and adverse
allows us to ll important gaps regarding the prevalence of various outcomes directly related to abnormal placentation such as pre-
lesions in women with GDM [27]. In addition, our well- term birth, growth restriction, and pre-eclampsia. We are currently
characterized cohort and large sample size allowed us to examine unable to assess placental function in vitro, but it is plausible that
both maternal characteristics associated with MVM lesions as well factors such as weight gain recommendations should be tailored
as the clinical implications of these lesions in this population. not only by maternal pre-pregnancy BMI [16] but also by measures
Finally, we utilized the recently published Amsterdam Placental of placental function. The Human Placenta Project strives to
Workshop Consensus Criteria to dene and group placental lesions, develop new methods and technologies for real-time assessment of
which will facilitate comparison of our ndings to other studies placental development across pregnancy [29], and our ndings
[28]. highlight several areas where improved understanding of placental
Large, cohort studies of placental pathology studies are essential function could be used to individualize maternal recommendations
 C.M. Scifres et al. / Placenta 49 (2017) 10e15
and optimize perinatal outcomes.
Funding
This work did not receive any specic grant from funding
agencies in the public, commercial, or not-for-prot sectors.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.placenta.2016.11.004.
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