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Brief Report—Endocrine Care

High Rate of Placental Infarcts in Type 2 Compared with Type 1 Diabetes

Catherine C. Beauharnais, Drucilla J. Roberts, and Deborah J. Wexler

Boston University School of Public Health (C.C.B.), Department of Pathology (D.J.R.), Massachusetts General Hospital, Massachusetts General Hospital Diabetes Center (D.J.W.), Boston, Massachusetts

02118; and Harvard Medical School (D.J.R., D.J.W.), Boston, Massachusetts 02114 Downloaded from https://academic.oup.com/jcem/article/97/7/E1160/2833356 by guest on 28 September 2021

Context: Timing and cause of pregnancy loss differ between type 1 (T1DM) and type 2 diabetes mellitus (T2DM).

Objective: The objective of the study was to determine whether placental histology corresponds to differing causes of pregnancy loss in T1DM and T2DM. We hypothesized that placentas from mothers with T2DM would be more likely to demonstrate vascular pathology than those from mothers with T1DM.

Research Design/Setting/Participants: We reviewed medical histories, pregnancy outcomes, and placental histology of women with pregestational T1DM and T2DM with singleton pregnancies between 2001 and 2009 at a single tertiary care medical center.

Main Outcome Measures: Placental weight, placental dysmaturity, villous maturation, villitis of unclear etiology, and histological evidence of placental infarction were measured.

Results: Ninety-eight placentas were available for review, 53 from T1DM mothers (56%) and 45 from T2DM mothers (46%). Mean age and glycemic control each trimester did not differ between diabetes types. T2DM placentas had a higher prevalence of placental infarcts (22 vs. 6%, P ϭ 0.02) and a lower prevalence of placental dysmaturity (12 vs. 29%, P ϭ 0.05) compared with T1DM; rates differed from those reported in the general population. There was no difference in placental weight, villous maturity, or villitis of unclear etiology between diabetes types.

Conclusions: There were many similarities in placental histological findings between diabetes types. Still, one in five T2DM placentas displayed histological infarcts, consistent with a vascular, rather than glycemic, etiology of pregnancy complications, whereas T1DM placentas showed signs of abnormal development. (J Clin Endocrinol Metab 97: E1160–E1164, 2012)

ypes 1 and type 2 diabetes mellitus (DM) increase the reasons for increased risk in type 2 diabetes relate to older T risk of pregnancy, with complications related to hy- maternal age, higher prevalence of obesity and other met- perglycemia as well as to comorbid conditions. As preges- abolic syndrome characteristics, and lower socioeconomic tational type 2 DM has become more common, there has status (5). been increasing recognition that risk may differ between In addition to differences in associated medical condi- diabetes types, irrespective of glycemia (1). Women with tions, placental structure differs between type 1 and type type 2 diabetes have similar or poorer pregnancy out- 2 diabetes. Factors other than glycemia, such as hyperten- comes, including later pregnancy loss, and high risk of sion (6) and inflammation (7), affect placental develop- neonatal complications despite better glycemic control, on ment in pregnancies complicated by pregestational type 2 average, than is seen in type 1 diabetes (2–4). Possible diabetes (8). The aim of this study was to compare the

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: CI, Confidence interval; DM, diabetes mellitus; GDM, gestational diabetes Printed in U.S.A. mellitus; HbA1c, hemoglobin A1c; OR, odds ratio; VUE, villitis of unknown etiology. Copyright © 2012 by The Endocrine Society doi: 10.1210/jc.2011-3326 Received December 9, 2011. Accepted March 20, 2012. First Published Online April 6, 2012

E1160 jcem.endojournals.org J Clin Endocrinol Metab, July 2012, 97(7):E1160–E1164 J Clin Endocrinol Metab, July 2012, 97(7):E1160–E1164 jcem.endojournals.org E1161 placental histology of type 1 and type 2 diabetes to provide knots, accelerated villous maturation, decidual vasculopathy, or insight into the differing causes of pregnancy outcomes atherosis. Background population rates of placental character- between diabetes types. We hypothesized that placentas istics were obtained from previously published reports. We compared continuous variables using Student’s t tests and from mothers with type 2 diabetes would have a higher categorical variables using the Fisher exact test for variables with rate of placental histology suggestive of vascular pathol- few outcomes. We ran multivariable logistic regression models ogy than placentas from mothers with type 1 diabetes. that were exploratory, given the limited number of outcome events. All analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, NC). A P Յ 0.05 was considered sta- tistically significant. The study was approved by the Partners Materials and Methods HealthCare Institutional Review Board.

This was a retrospective study performed at Massachusetts Gen- Downloaded from https://academic.oup.com/jcem/article/97/7/E1160/2833356 by guest on 28 September 2021 eral Hospital, an academic medical center in Boston, MA. We searched the pathology database for all placentas delivered at Results Massachusetts General Hospital between 2001 and 2009 using the terms “diabetes,” “IDDM,” “DM”, “GDM,” and “glu- We identified 765 placentas, most from pregnancies com- cose.” We retained the first placenta for each woman confirmed plicated by gestational diabetes mellitus (GDM). After ex- by chart review to have pregestational type 1 or type 2 diabetes cluding GDM, retaining the first placenta for each subject and singleton pregnancies. Standardized chart review was undertaken to determine di- and excluding one twin pregnancy and one with lost pla- abetes type, maternal age and race (self-reported), weight at first centa slides, 98 subjects remained in the sample, 53 with visit and at delivery, mean hemoglobin A1c (HbA1c) during each type 1 (56%) and 45 with type 2 diabetes (46%). trimester (mean of available HbA1c in each trimester if more There was no significant difference in age or glycemic than one was available, with date ranges for each trimester cal- control (HbA1c) between mothers with type 1 and type 2 culated from the gestational age at delivery), preeclampsia or diabetes. Other demographic and clinical characteristics eclampsia as noted in a physician’s note in the chart, family history of diabetes, smoking, and hypertension or gestational are shown in Table 1. Hypertension was nearly twice as hypertension. Diabetes type was determined by physician diag- common in women with type 2 diabetes (33 vs. 17% in nosis, medication prescriptions, medical history, and antibody type 1 DM, P ϭ 0.056), and women with type 2 diabetes and C-peptide levels, if available. Pregnancy-induced hyperten- had higher weight at first visit and before delivery than sion was defined as systolic blood pressure of 140 mm Hg or women with type 1 diabetes. Preeclampsia and eclampsia greater and/or diastolic blood pressure of 90 mm Hg or greater for 2 consecutive weeks during pregnancy with normal blood rates were not statistically significantly lower in type 2 ϭ pressure before gestation. Pregestational hypertension was de- than in type 1 diabetes (11 vs. 25%, P 0.09). Obstetric fined as prescription of hypertension drugs before pregnancy data, including gestational age at delivery, delivery by ce- and/or having hypertension listed in chart. Obstetric data re- sarean section, birth weight, Apgar scores, and rate of fetal corded were gestational age, parity, mode of delivery, Apgar demise did not differ between diabetes types, but women scores at 1 and 5 min, and fetal demise. with type 2 diabetes had higher parity. The blinded study pathologist re-reviewed the corresponding placenta slides to assure standard classification of placental his- Some, but not all, features of placental histology dif- tology. Parameters scored included placenta weight, villous mat- fered between diabetes types and appeared to differ from uration (9), villitis of unknown etiology [VUE; evidence of in- published population rates of placental pathology (Table flammatory pathology indicated by chronic villitis (10)], acute 2). Placental infarcts were significantly more common in chorioamnionitis (11), and evidence of hypertensive damage/ type 2 diabetes [odds ratio (OR) 4.7, 95% confidence in- ischemia [small placenta by weight, infarcts (12)]. The placental pathological diagnoses were diagnosed by a trained placental terval (CI) 1.22–18.6] than in type 1 diabetes and ap- pathologist. The placental weight was recorded trimmed of cord peared to be twice as high as the rate seen in the general and membranes. Villous maturation is based on the presence of population. This relationship was attenuated after adjust- well-defined and easily identified vasculosyncytial membranes in ing for hypertension (OR for type 2 DM relative to type 1 a background of mostly tertiary/terminal villi. The diagnosis of DM: 3.4, 95% CI 0.8–13.9; OR for hypertension: 4.4, VUE or chronic villitis is based on the presence of more than three 95% CI 1.2–16.2, P ϭ 0.03, data not shown). Villitis of villi affected by increased mononuclear cells within the villous stroma and often associated with intervillositis in more than unclear etiology appeared to be more prevalent in type 2 three locations. Plasma cells were noted but not required for the DM (20%) than in type 1 DM (13%) placentas, but this diagnosis. Placenta size was based on published percentiles by was not statistically significant. gestational age (13). Infarcts were defined by the presence of In contrast, placental dysmaturity (29 vs. 12%, P ϭ necrotic villi, collapsed maternal space, and grossly identified. 0.05) was more common in type 1 compared with type 2 We pooled some findings using composite diagnoses. For exam- ple, hypertensive damage was the presence of three of the fol- diabetes and with published population rates (Table 2). lowing pathologies: placentas less than the 10th percentile by Villous immaturity also appeared more common in type 1 weight, placental infarct, chronic abruption, large syncytial DM (26%) than type 2 DM (5%) placentas, but this did E1162 Beauharnais et al. Placental Histology and Diabetes Type J Clin Endocrinol Metab, July 2012, 97(7):E1160–E1164

TABLE 1. Baseline and pregnancy characteristics in women with pregestational type 1 and type 2 diabetes

P value (45 ؍ Type 2 (n (53 ؍ Type 1 (n Demographic data Age at delivery (yr), mean (SD) 31 (5.7) 32 (6.3) 0.37 Race/ethnicity Black, n (%) 3 (6) 8 (18) Ͻ0.0001a White, n (%) 41 (77) 13 (29) Hispanic, n (%) 7 (13) 20 (44) Other, n (%) 2 (4) 4 (9) Clinical data Weight at first visit (lb), mean (SD) 160.0 (32.5) 200.1 (43.3) Ͻ0.0001

Weight prior to delivery (lb), mean (SD) 190.2 (34.1) 218.7 (46.1) 0.002 Downloaded from https://academic.oup.com/jcem/article/97/7/E1160/2833356 by guest on 28 September 2021 First-trimester HbA1c (%), mean (SD) 7.4 (1.4) 7.5 (1.6) 0.9 Second-trimester HbA1c (%), mean (SD) 6.4 (1.0) 6.3 (1.0) 0.6 Third-trimester HbA1c (%), mean (SD) 6.5 (1.0) 6.4 (0.9) 0.6 Hypertension, n (%) 9 (17) 15 (33) 0.056 Preeclampsia or eclampsia, n (%) 13 (25) 5 (11) 0.09 Family history of diabetes mellitus, n (%) 31 (58) 28 (62) 0.5 Smoking, n (%) 2 (4) 5 (11) 0.2 Obstetric data Gestational age at delivery (wk), mean (SD) 37.0 (3.74) 37.5 (3.8) 0.6 Cesarean deliveries, n (%) 35 (67) 24 (53) 0.2 Birth weight (g), mean (SD) 3,309 (962) 3,372 (842) 0.7 One-minute Apgar score, mean (SD) 7.6 (2.2) 7.7 (1.9) 0.8 Five-minute Apgar score, mean (SD) 8.3 (2.1) 8.7 (0.6) 0.2 Parity, mean (SD) 1.9 (1.2) 2.8 (1.9) 0.004 Fetal demise 2 (4) 2 (4) 0.9 a P value for ␹2 test across all race/ethnicity groups. not reach statistical significance. In underpowered explor- and cesarean section rates, we observed significant differ- atory models adjusting for hypertension and glycemia, the ences in placental pathology. Consistent with previous increased rate of villous immaturity in type 1 DM became findings (14, 15), type 1 diabetes placentas had a higher ϭ significant (P 0.04). Placental weight and maternal prevalence of placental dysmaturity, indicating problems choriamnionitis did not differ by diabetes type. in placental development. In contrast, type 2 diabetes pla- centas had a 4-fold higher rate of placental infarction than type 1 diabetes, with infarcts found in one of five placentas Discussion from mothers with type 2 diabetes (and in one of the two Although there were many similar placental characteris- placentas associated with fetal demise); this relationship tics in type 1 and type 2 diabetes, it is notable that despite was attenuated after controlling for hypertension. Other equivalent glycemic control, gestational age at delivery, differences, such as those in villitis of unclear etiology and

TABLE 2. Placental weight and histology comparing type 1 with type 2 diabetes and background population

P value Population prevalence (45 ؍ Type 2 (n (53 ؍ Type 1 (n Placental weight (g), mean (SD) 468 (161) 471 (143) 0.9 626 (133) Villous maturity 0.3 Hypermature, n (%) 6 (11) 6 (13) Immature, n (%) 14 (26) 5 (11) Mature, n (%) 32 (60) 33 (73) Other, n (%) 1 (2) 1 (2) VUE, n (%) 7 (13.2) 9 (20.0) 0.4 5–15%b Placental dysmaturity, n (%) 15 (29) 5 (12) 0.05 7.7%c Infarction, n (%) 3 (5.7) 10 (22.2) 0.02 12%d Maternal choriamnionitis, n (%) 7 (13) 6 (13) 0.9 1.5%c a See reference 19. Based on Norwegian 50th percentile for placental weight at 37 wk gestation, the mean gestational age in this study. b See Ref. 10. c See Ref. 15. d See Ref. 20. J Clin Endocrinol Metab, July 2012, 97(7):E1160–E1164 jcem.endojournals.org E1163 villous maturity, did not reach statistical significance. Pla- searched for placental vascular disease in association with cental weight did not differ between diabetes types but did pregestational diabetes did not find a higher risk of infarction appear to be lower than population reference ranges in between all pregestational diabetes pregnancies compared both diabetes groups. with normoglycemic pregnancies, but this study used Inter- These histological differences suggest that differing national Classification of Diseases, ninth revision, codes pathophysiology associated with type 1 or type 2 diabetes rather than histological review, which, as the authors ac- affects placentation despite similar medical care and gly- knowledged, was likely insensitive for this finding (18). cemic characteristics; other nonsignificant differences, in Although our single-center findings are additionally this small sample, favor this interpretation as well. The limited by the retrospective study design, failure to capture high rates of placental dysmaturity in type 1 diabetes and early pregnancy losses, and the small sample size, the de- placental infarcts in type 2 diabetes provide histological tailed review provides histological correlates for the dif- Downloaded from https://academic.oup.com/jcem/article/97/7/E1160/2833356 by guest on 28 September 2021 correlates of the prior observation that the cause and tim- fering causes and timing of pregnancy loss in pregesta- ing of pregnancy loss differ between diabetes types. Due to tional type 1 and type 2 diabetes. In addition, these the retrospective study design, this study failed to capture findings support the hypothesis that the complications as- first-trimester pregnancy losses and placental tissue. Con- sociated with type 2 diabetes in pregnancy are related to sequently, our findings are derived from surviving preg- vascular pathology in addition to hyperglycemia, analo- nancies that presumably had less severe abnormalities. Ex- gous to the relationship between type 2 diabetes and risk treme hyperglycemia in the first trimester, which is more of cardiovascular disease later in life. Future studies of common in type 1 than in type 2 diabetes, may have led to placental pathology should follow patients with diabetes increased first-trimester losses in that group, yielding a matched to controls without diabetes prospectively from somewhat healthier subset of type 1 diabetes pregnancies the beginning of pregnancy to capture all pregnancy losses in this study. Prior studies have shown that congenital and events and to allow comparison with normal placental anomaly and first-trimester losses are more common in pathology to determine whether these findings can eluci- type 1 and stillbirth more common in type 2 diabetes (3). date the etiology of pregnancy complications in pregesta- Diabetes is associated with a 2.5 increased odds of still- tional diabetes. birth (16). Even well-controlled diabetes (with pericon- ception HbA1c Ͻ 6.9%) is associated with perinatal mor- tality of 2.1% compared with 0.75% in an unaffected Acknowledgments population (17). Similarly, it appears that many of the rates of pathological characteristics of type 1 and type 2 We thank Bianca Porneala, M.S. (Massachusetts General Hos- diabetes pregnancies differ from those in background pital Division of General Internal Medicine, Boston, MA) for populations. assistance with statistical analyses. Author contributions include the following: D.J.W. conceived of the project and designed the There are few prior reports comparing placental his- study with assistance from C.C.B. and D.J.R., C.C.B. performed tology in type 1 with type 2 diabetes. Higgins compared the chart review. D.J.R. performed the histology review. D.J.W. placental structure by stereology in 10 nondiabetic, eight performed some of the statistical analyses. C.C.B. drafted the type 2 DM, and 10 type 1 DM women and found an manuscript. D.J.W. and D.J.R. reviewed and edited the manu- association between maternal diabetes, glycemia, and ter- script. D.J.W. had full access to all of the data in the study and minal villous volume and type 1 DM and increased cap- takes responsibility for the integrity of the data and the accuracy illary length (variables we were not able to assess in this of the data analysis. study) (8). In that study, there was no association between glycemia and stromal development, suggesting that non- Address all correspondence and requests for reprints to: Deb- orah J. Wexler, Massachusetts General Hospital Diabetes Unit, glycemic factors also influence placental development. In Bulfinch 408a, Massachusetts General Hospital, 55 Fruit Street, a Kuwaiti study of placental pathology in association with Boston, Massachusetts 02114. E-mail: [email protected]. White’s classification of diabetes, placental infarcts did D.J.W. is supported by National Institute of Diabetes and not differ by White class, but dysmaturity appeared to be Digestive and Kidney Diseases Career Development Award K23 more prevalent in White classes C/D (mostly type 1 DM, DK 080 228. n ϭ 7) compared with normal controls and white classes Disclosure Summary: The authors have nothing to disclose. A (GDM) or B (mostly type 2 DM) (15). 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