http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1051024
ORIGINAL ARTICLE
Pregnancy outcome and placental pathology differences in term gestational diabetes with and without hypertensive disorders Michal Kovo1, Yoav Granot1, Letizia Schreiber2, Michael Divon3, Avi Ben-Haroush4, and Jacob Bar1 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
1
Department of Obstetrics & Gynecology and 2Department of Pathology, Edith Wolfson Medical Center, Holon, Israel, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 3Department of Obstetrics & Gynecology, New York University School of Medicine, Lenox Hill Hospital, New York, NY, USA, and 4Department of Obstetrics & Gynecology, Rabin Medical Center, Petah-Tikva, Israel Abstract
Keywords
Objective: To compare pregnancy outcome and placental pathology in pregnancies complicated by gestational diabetes mellitus (GDM A1 and A2), with and without hypertensive disorders. Methods: Pregnancy outcome and placental pathology from term deliveries of women complicated with GDM with (GDM + H) and without (GDM H) hypertensive disorders were compared. Results of the GDM + H group were compared also with the non-diabetic patients but with hypertensive disorders (non-GDM + H). Composite neonatal outcome was defined as one or more of early complications: respiratory distress or need of ventilation support, sepsis, phototherapy, transfusion, seizure, hypoxic-ischemic encephalopathy. Placental lesions were categorized to lesions related to maternal and fetal vascular supply abnormalities, and maternal and fetal inflammatory responses. Results: Of the 192 women with GDM, the GDM + H group (n ¼ 41) were more obese, p50.001, with higher rate of placental maternal and fetal vascular supply lesions, p ¼ 0.008, p ¼ 0.03, respectively, but similar neonatal outcome, compared to the GDM H (n ¼ 151) group. Compared to the non-GDM + H group (n ¼ 41), the GDM + H group had higher birth weights, similar neonatal outcome and similar rate of placental vascular lesions. Conclusions: Higher rate of placental maternal and fetal vascular supply lesions express underlying placental pathology in women with diabetes and hypertensive disorders, similar to women without DM and with hypertensive complications.
Gestational diabetes, hypertension, placental pathology
Introduction Diabetes mellitus (DM) is one of the major medical complications in pregnancy that affects both the mother and the fetus [1]. Increased maternal levels of glucose, insulin, angiogenic growth factors, cytokines and inflammatory mediators may impact on the maternal and fetal vascular systems in the placenta [2]. Since diabetes affects placental development, function abnormalities in placental development may contribute to the poor pregnancy outcome. There is a range of placental reaction patterns that can be developed in response to the chronic ischemic insult observed in diabetes during pregnancy. Compared to normo-glycemic controls, several studies reported of significant increase in fibrinoid necrosis, chorangiosis, ischemia and villous immaturity in placentas retrieved from women with gestational diabetes mellitus (GDM) [3]. Yet, existing placental
Address for correspondence: Michal Kovo, MD, PhD, Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, P.O. Box 5, Holon 58100, Israel. Tel: +972 3 5028329. Fax: +972 3 5028503. E-mail: [email protected]
History Received 7 April 2015 Revised 9 May 2015 Accepted 11 May 2015 Published online 5 June 2015
histomorphometric studies display varied and inconsistent findings regarding placental abnormalities in relation to GDM and pregestational diabetes as well [4]. Additionally, the degree to which maternal glycemic control contributes to the development and to the extent of the different placental lesions remains uncertain [3,5–7]. Hypertensive disorder is also a common complication in pregnancy, resulting in increased maternal and fetal/neonatal morbidity. Histological studies demonstrated that vascular lesions are more common in placentas from pregnancies complicated by the disorder [8]. Since hypertensive disorders and maternal GDM during pregnancy have been associated, it has been suggested that concomitant maternal conditions are likely to contribute to the placental pathological changes seen in women with diabetes. Most of the existing studies on placental pathology and GDM did not concentrate on GDM patients with and without additional hypertensive disorders. The aim of the present study was to compare the clinical characteristics and placental histopathology between pregnancies complicated by GDM A1 and A2, in the presence and absence of maternal hypertensive disorders. Placental lesions were classified into those consistent with maternal and fetal
2
M. Kovo et al.
vascular supply abnormalities, and with maternal and fetal inflammatory responses [9,10].
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Patients and methods For the present study, the medical records of all patients diagnosed with GDM, who gave birth at term, between January 2008 and December 2013 and their placentas underwent histopathology examination at the Edith Wolfson Medical Center were reviewed. Our department protocol includes placental analyses in all patients attending the department with a complicated pregnancy. GDM was diagnosed in the presence of abnormal 100 g oral glucose tolerance test (OGTT) at 24–32 weeks. For GDM diagnosis the American Diabetes Association (ADA) criteria were used [11]. GDMA1 included patients who were treated with diet only, and GDMA2 included those who were treated also with insulin. For the purpose of the study, women with GDM were divided to those with (GDM + H) and without (GDM H) hypertensive disorders. Hypertensive disorders included gestational hypertension, chronic hypertension and preeclampsia, defined according to the criteria of the American College of Obstetrics and Gynecology [12]. The GDM + H group was also compared to non-diabetic patients with hypertensive disorders (non-GDM + H), with a negative 50 g glucose challenge test (GCT) or normal OGTT, who delivered at term, and were matched to by mode of delivery [cesarean section (CS) versus vaginal delivery (ND)] on a 1:1 basis. Exclusion criteria were multiple pregnancies and preterm deliveries defined as labor 537 weeks of gestation. Gestational age was confirmed by first-trimester ultrasonography in all cases. The following data were collected from the medical files: maternal characteristics: age, gravidity, parity, body mass index, cigarettes smoked per day; known chronic disease: thrombophilia, epilepsy or asthma. Neonatal outcome parameters included mean cord pH, days of hospitalization and the rate of neonatal intensive care unit (NICU) admission. Early neonatal complications including: sepsis, blood transfusion, hypoglycemia, phototherapy, respiratory distress, mechanical ventilation, need of respiratory support, intra-ventricular hemorrhage, seizures, hypoxic-ischemic encephalopathy or death. Neonatal birth weight percentile in each case was assigned using the updated Israeli growth charts [13]. Macrosomia was defined as birth weight above the 90th percentile for age, and fetal growth restriction (FGR) was defined as a birth weight below the 10th percentile for age. Clinical and placental pathology findings were compared between the GDM + H and GDM H groups (diabetic patients without hypertensive disorders), and also between the GDM + H and non-GDM + H groups (non-diabetic patients but with hypertensive disorders). We also established a database of placental findings in women without any pregnancy complications for research purposes. We then identified those who delivered at term, and were matched by mode of delivery to the GDM + H group and the GDM H group on a 1:1 basis. Placental lesions were also compared between the three groups. The study was approved by the local Ethics Committee.
J Matern Fetal Neonatal Med, Early Online: 1–6
Placental examination Placental pathology examinations were performed using a standard protocol, described by us in previous studies [14,15]. Briefly, after fixation in formalin and removal of the membranes and cord, the placentas were weighed. For each placenta, at least five tissue samples were embedded in paraffin blocks for microscopic assessment. All examinations were done by a single pathologist (author LS). Placental lesions The placental lesions identified were classified by maternal or fetal origin according to the criteria that were adopted by the Society for Pediatric Pathology [9,10] and were described by us in previous studies [14,15]. Briefly, maternal vascular supply abnormalities included: lesions resulting from loss of integrity of the maternal circulation, i.e. placental, marginal and retro-placental hemorrhages, vascular lesions related to maternal underperfusion (acute atherosis and mural hypertrophy) and villous changes related to maternal underperfusion (increased syncytial knots, villous agglutination, increased intervillous fibrin deposition and villous infarcts). Fetal vascular supply abnormalities included findings consistent with fetal thrombo-occlusive disease: vascular lesions (thrombosis of the chorionic plate and stem villous vessels) and villous changes (hypovascular, fibrotic and avascular villi). Additionally, in this group we included lesions related to maldevelopment of the fetal vascular supply as distal villous immaturity. Placental findings consistent with chorioamnionitis were defined by the presence of an inflammatory neutrophil infiltrate at two or more sites on the chorionic plate and extraplacental membrane. The maternal inflammatory response (MIR) was divided into three stages: early, acute subchorionitis (stage 1); intermediate acute chorioamnionitis (stage 2) and late, severe chorioamnionitis (stage 3). The fetal inflammatory response (FIR) was also divided into three stages: early, umbilical phlebitis (stage 1); intermediate, umbilical arteritis (stage 2) and concentric umbilical perivasculitis (necrotizing funisitis, stage 3). Villitis of unknown etiology or chronic villitis, defined as lymphohistiocytic inflammation localized to the stroma of terminal villi but often extending to the small vessels of upstream villi, was recorded separately. Statistical analysis Data were analyzed with SPSS software, version 15.0 (Chicago, IL). Continuous variables were calculated as mean ± SD or median and range, as appropriate. Categorical variables were calculated as rate (%). Student’s t-test was used to compare continuous parameters between the GDM groups; analysis of variance (ANOVA) (where greater than two groups) and Mann–Whiney U-tests for non-normally distributed data, Chi-square test was used to analyze categorical variables. A p value of 50.05 was considered statistically significant. Composite neonatal outcome was defined as one or more of the following complications: sepsis, blood transfusion, phototherapy, hypoglycemia, respiratory distress, mechanical
Placental pathology in diabetes with and without hypertensive disorders
DOI: 10.3109/14767058.2015.1051024
ventilation, respiratory support, intra-ventricular hemorrhage, seizures, hypoxic-ischemic encephalopathy or death.
Results A total of 192 women diagnosed with diabetes during pregnancy were included in the study: 123 with GDMA1, 69 with GDMA2. Among them 151 were without hypertensive disorders (GDM H) and 41 (21.3%) had hypertensive disorders (GDM + H): 17 (41.4%) with preeclampsia, 13 (31.7%) with gestational hypertension and 11 (26.8%) with chronic hypertension.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Comparison between the GDM + H and GDM H groups Maternal characteristics of DM + H and DM H women are presented in Table 1. The GDM + H group had higher body mass index (BMI) (kg/m2) than the GDM H group, 33.2 ± 7.3 versus 27.88 ± 6.7, p50.001. There were no differences between the study groups in mean maternal age, gestational age at delivery, rates of smokers, IVF pregnancies and rate of induction of labor. Neonatal outcome of the GDM + H and GDM H is presented in Table 2. Table 1. Maternal characteristics of patients with gestational diabetes associated with (GDM+H) and without (GDM-H) hypertensive disorders.
Maternal age (years) Nulliparity BMI (kg/m2) Smokers (%) Gestational age at delivery (weeks) CS (%)
GDM + H n ¼ 41
GDM H n ¼ 151
p value
30.85 ± 5.1 10 (24.4) 31.9 ± 7 8 (19.5) 38.6 ± 0.94
32.5 ± 5 63 (41.7) 27.5 ± 6.43 21 (13.9) 38.7 ± 0.94
0.060 0.064 50.001 0.520 0.788
35 (85.3)
120 (79.5)
0.505
Birth weights, rate of macrosomia, mean length of hospitalization and composite neonatal outcome did not differ between the groups. Placental findings in the GDM + H versus GDM H groups (Table 3) revealed higher rate of vascular lesions related to maternal underperfusion in the GDM + H group compared to the GDM H group, 17% versus 4%, respectively, p50.001. Additionally, increased rate of vascular lesions related to fetal thrombo-occlusive disease (FTOD) was also found in the GDM + H compared to the GDM H group, 12.2% versus 3.3%, respectively, p ¼ 0.038. Distal villous immaturity was more common, with a borderline statistical significance, in the GDM H compared to the GDM + H group, 13.2% versus 2.4%, respectively, p ¼ 0.05. Comparison between the GDM + H and non-GDM + H groups Maternal characteristics and neonatal outcome of the GDM + H and the matched non-GDM + H are presented in Table 4. The GDM + H group compared to the non-GDM + H group had higher BMI (kg/m2), 31.9 ± 7 versus 27.8 ± 9, respectively, p ¼ 0.041, and lower rate of nulliparity, 24.4% versus 58.5%, respectively, p ¼ 0.003. There were no differences in mean maternal age, gestational age at delivery, rate of smokers, between the groups. The GDM + H group compared to the non-GDM + H group had higher birthweight 3416 ± 607 g versus 3129 ± 564 g, respectively, p ¼ 0.03, but with similar composite neonatal outcome. Placental findings in the GDM + H versus non-GDM + H groups are summarized in Table 5. Higher placental weights and lower fetal–placental ratio were observed in the GDM + H compared to the non-GDM H group, Table 3. Placental findings of patients with GDM associated with (GDM + H) and without (GDM H) hypertensive disorders.
Continuous variables are presented as mean ± SD and categorical variables as n (%). BMI – body mass index; CS – cesarean section; IVF – in vitro fertilization.
Table 2. Neonatal outcome of patients with gestational diabetes associated with (GDM + H) and without (GDM H) hypertensive disorders.
Birth weight (BW) (g) Birth weight percentile Rate of macrosomia (%) Mean cord pH Hospitalization (days) NICU admission (%) Respiratory problems Sepsis (%) CNS abnormalities (%) Phototherapy (%) Hypoglycemia (%) Composite outcome (%)
GDM + H n ¼ 41
GDM H n ¼ 151
3416 ± 607 66 ± 32 14 (34.1) 7.26 ± 0.08 4.4 ± 2.3 17 (41.4) 2 (4.9) 1 (2.4) 0 2 (4.9) 5 (12.2) 9 (22)
3407 ± 582 63.7 ± 30.7 42 (27.8) 7.18 ± 0.95 4.55 ± 3.3 52 (34.4) 11 (7.3) 1 (0.6) 0 13 (8.6) 18 (12) 35 (23.1)
p value 0.936 0.665 0.550 0.633 0.707 0.517 0.846 1 0.644 0.961 0.868
Continuous variables are presented as mean ± SD and categorical variables as n (%). BW – birth weight; NICU – neonatal intensive care unit. Respiratory problems include respiratory distress, mechanical ventilation or the need of respiratory support; CNS abnormalities included: intra-ventricular hemorrhage, seizures or hypoxic-ischemic encephalopathy.
3
Placental weight (g) Fetal–placental ratio
GDM + H n ¼ 41
GDM H n ¼ 151
p value
575 ± 123 6 ± 0.7
536 ± 132 6.9 ± 5.1
0.09 0.279
1 (0.6) 6 (4)
1 0.008
67 (44.4)
0.596
5 (12.2)
5 (3.3)
0.038
Maternal vascular supply lesions Placental hemorrhage (%) 0 7 (17) Vascular lesions related to maternal under perfusion (%) 16 (39) Villous changes related to maternal under perfusion (%) Fetal vascular supply lesions Vascular lesions consistent with FTOD (%) Villous lesions consistent with FTOD (%) Villous immaturity (%)
6 (14.6)
13 (8.6)
0.248
1 (2.4)
20 (13.2)
0.05
Inflammatory lesions MIR (%) FIR (%) Chronic villitis
5 (12.2) 1 (2.4) 1 (2.4)
26 (17.2) 11 (7.3) 4 (2.6)
0.632 0.466 0.940
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, FTOD – fetal thrombo-occlusive disease, FIR – fetal inflammatory response, MIR – maternal inflammatory response.
4
M. Kovo et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
Table 4. Maternal characteristics and neonatal outcome of patients with GDM and hypertensive disorders (GDM + H) versus controls, nondiabetic with hypertensive disorders (non-GDM + H), matched by mode of labor.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Maternal age (yrs) Nulliparity (%) BMI (kg/m2) Smokers (%) Gestational age at delivery (wks) Neonatal outcome Birth weight (BW) (g) Birth weight percentile Rate of macrosomia (%) Mean cord pH Hospitalization (days) NICU admission (%) Respiratory problems Sepsis CNS abnormalities Phototherapy (%) Hypoglycemia (%) Composite outcome (%)
GDM + H n ¼ 41
Non-GDM + H n ¼ 41
p value
30.85 ± 5.1 10 (24.4) 31.9 ± 7 8 (19.5) 38.6 ± 0.94
31.44 ± 5.76 24 (58.5) 27.82 ± 9.12 5 (12.2) 38.9 ± 1.17
0.630 0.003 0.041 0.546 0.204
3416 ± 607 66 ± 32 14 (34.1) 7.26 ± 0.08 4.4 ± 2.3 17 (41.4) 2 (4.9) 1 (2.4) 0 2 (4.9) 5 (12.2) 9 (22)
3129 ± 564 48 ± 30 5 (12.2) 7.3 ± 0.05 4.48 ± 1.7 17 (41.4) 3 (7.3) 0 0 3 (7.3) 3 (7.3) 9 (22)
0.029 0.011 0.034 0.099 0.873 1 0.644 0.314 0.644 0.712 1
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, BW – birth weight; NICU – neonatal intensive care unit. Respiratory problems include respiratory distress, mechanical ventilation or the need of respiratory support; CNS abnormalities included: intra-ventricular hemorrhage, seizures or hypoxic-ischemic encephalopathy.
Table 5. Placental findings of patients with GDM and hypertensive disorders (GDM + H) versus controls with hypertensive disorders (nonGDM + H), matched by mode of labor.
Placental weight (g) Fetal–placental ratio
GDM + H n ¼ 41
Non-GDM + H n ¼ 41
p value
575 ± 123 6 ± 0.77
496 ± 112 6.4 ± 0.9
0.003 0.034
1 8 (19.5)
0.314 0.775
19 (46.3)
0.655
1(2.4)
0.203
Maternal vascular supply lesions Placental hemorrhage (%) 0 7 (17) Vascular lesions related to maternal under perfusion (%) 16 (39) Villous changes related to maternal under perfusion (%) Fetal vascular supply lesions Vascular lesions consistent with FTOD (%) Villous lesions consistent with FTOD (%) Villous immaturity Inflammatory lesions MIR FIR Chronic villitis
5 (12.2) 6 (14.6)
6 (14.6)
1
1 (2.4)
1(2.4)
1
5 (12.2) 1 (2.4) 1 (2.4)
10 (24.4) 2 (4.9) 1 (2.4)
0.253 0.556 1
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, FTOD – fetal thrombo-occlusive disease, FIR – fetal inflammatory response, MIR – maternal inflammatory response.
575 ± 123 g versus 496 ± 112 g, respectively, p ¼ 0.003 and 6.0 ± 0.7 versus 6.4 ± 0.9, respectively p ¼ 0.034. Rate of placental maternal and fetal vascular supply lesions and rate inflammatory lesions, did not differ between the groups. Comparison of placental findings between the GDM + H, GDM H and control groups Table 6 presents comparison of placental findings in three study groups, GDM + H, GDM H and healthy controls (n ¼ 192) matched by mode of delivery in a 1:1 basis. Placental weights of the GDM + H and GDM H were significantly higher than in the controls, p50.001. Vascular lesions related to maternal underperfusion were significantly more prevalent in the GDM + H than in the GDM H or the controls 17.1% versus 4% versus 2.1% respectively, p50.0001; Villous lesions related to maternal underperfusion were significantly less frequent in the controls than in either of the other two GDM groups (p50.0001). In relation to fetal vascular supply lesions, only distal villous immaturity was more common, in the GDM H than in either of the other two groups (p ¼ 0.022), but the difference between the controls and the GDM + H was not significant (p ¼ 0.17). Other placental lesions did not differ significantly between the three groups.
Discussion In the present study we analyzed pregnancy outcome and correlated results to placental pathological findings, in a cohort of women diagnosed with GDM, with and without hypertensive disorders. Those with GDM and hypertensive disorders were more obese and less nulliparous. Placentas from women with GDM and hypertension had more placental maternal vascular lesions and higher rate of placental fetal vascular lesions consistent with fetal thrombo-occlusive diseases, compared with women with GDM only. Such placental findings are well recognized, and known to be important contributors to adverse pregnancy outcome [16]. In contrast, placental villous immaturity was more common (though with borderline statistical significant) in GDM compared with those with hypertension. Different placental findings were observed in these two groups, yet, similar bad neonatal outcome was evident. More than a third of the neonates in both the groups were admitted to NICU and 22% of them had adverse composite outcome. Comparison between hypertensive GDM women versus hypertensive non-diabetic patients revealed similar high rate of composite neonatal outcome. Pregnancy outcome was associated with higher placental weight in the GDM group, but with similar high rate of maternal and fetal vascular placental lesions in both the groups. GDM during pregnancy is known to be associated with increased perinatal morbidity and mortality [17–19], and probably some of these pregnancy complications may arise from altered placental development and function. Placental lesions observed in GDM suggest that chronic insult occur in diabetic pregnancies. Specifically, the high rate of villous immaturity, as observed in the current study, and is in concordance with previous studies [3,5], may lead to chronic fetal hypoxemia due to increased diffusion distance between
DOI: 10.3109/14767058.2015.1051024
Placental pathology in diabetes with and without hypertensive disorders
5
Table 6. Comparison of placental findings of the three groups of patients: GDM + H, GDM H and normal healthy controls, matched by mode of labor.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Placental weight (g) Maternal vascular supply lesions Placental hemorrhage (%) Vascular lesions related to maternal under perfusion (%) Villous changes related to maternal under perfusion (%)
GDM + H n ¼ 41
GDM H n ¼ 151
Controls n ¼ 192
p value
575 ± 123
536 ± 132
492 ± 104
50.001
0 7 (17)
1 (0.6) 6 (4)
2 (1) 4 (2)
0.772 50.001
16 (39)
67 (44.4)
47 (24.5)
50.001
Fetal vascular supply lesions Vascular lesions consistent with FTOD (%) Villous lesions consistent with FTOD (%) Villous immaturity (%)
5 (12.2) 6 (14.6) 1 (2.4)
5 (3.3) 13 (8.6) 20 (13.2)
11 (5.7) 19 (10) 1 (0.5)
0.183 0.519 0.022
Inflammatory lesions MIR (%) FIR (%) Chronic villitis
5 (12.2) 1 (2.4) 1 (2.4)
26 (17.2) 11 (7.3) 4 (2.6)
38 (19.8) 10 (5.2) 12 (6.2)
NS NS NS
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, FTOD – fetal thrombo-occlusive disease, FIR – fetal inflammatory response, MIR – maternal inflammatory response.
inter-villous space and fetal capillaries [20]. This placental abnormality has been independently associated with an increased risk of perinatal mortality [21]. Our findings suggest that different placental pathology in women with GDM, with or without hypertension result in a common pathway to worse pregnancy outcome. The high rate of placental vascular lesions associated with GDM and hypertensive disorders may suggest that different mechanisms like vascular dysfunction versus placental dysmaturity lead to similar neonatal outcome. The present study is unique in several aspects. First, to the best of our knowledge, we are the first to compare between term pregnancies of GDM patients with and without hypertensive disorders, matched by mode of delivery, thus controlling confounding factors, such as preterm labor and mode of delivery, which may affect placental histopathology. Second, by applying placental histopathology criteria that were validated and adopted by the Society of Pediatrics Pathology [10], we were able to analyze placentas in terms of maternal and fetal vascular supply and maternal and fetal inflammatory responses, thereby separating the maternal and fetal placental compartments. Third, we compared placental pathology between GDM women, with and without hypertensive disorder and healthy controls, demonstrating the dominance of maternal vascular lesions in the GDM placentas. Our study has several limitations; first, there is the lack of information regarding maternal diabetic control, as the level of maternal HB A1C during pregnancy or the level of blood cord c-peptide. We are aware that maternal diabetic control could influence the degree and the rate of several placental lesions as well as on the rate of neonatal complications. However, placental vascular lesions, as observed by us, may also persist despite tight metabolic control [22], correlating with increased risk of fetal and neonatal complications. Second, other factors, such as maternal obesity or maternal weight gain, might also influence placental pathology. It has been proposed that maternal obesity cause an accumulation of
pro-inflammatory mediators in the placenta that lead to high cytokine content and increased markers of oxidative stress, that eventually cause placental dysfunction and altered placental development [23]. Moreover, maternal prepregnancy obesity was found to be associated with higher risk of maternal origin vascular lesions and inflammatory lesions [24]. Third, different maternal hypertensive disorders were included in the study. Yet, it has been demonstrated that although the clinical presentation of gestational hypertension is less severe, as compared to other hypertensive disorders, the placental pathology lesions in these disorders are similar [25]. In conclusion, the present study demonstrates that worse pregnancy outcome is the end result of various placental lesions in women with diabetes. In those without hypertensive disorders villous immaturity is dominant, and in those with hypertensive disorders placental maternal and fetal origin vascular lesions are dominant. Difference in placental pathology may reflect differences in pathophysiology among diabetic patients with and without hypertensive disorders.
Declaration of interest The authors report no conflict of interest.
References 1. Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med 2004;21:103–13. 2. Leach L. Placental vascular dysfunction in diabetic pregnancies: intimations of fetal cardiovascular disease? Microcirculation 2011; 18:263–9. 3. Daskalakis G, Marinopoulos S, Krielesi V, et al. Placental pathology in women with gestational diabetes. Acta Obstet Gynecol Scand 2008;87:403–7. 4. Huynh J, Dawson D, Roberts D, Bentley-Lewis R. A systematic review of placental pathology in maternal diabetes mellitus. Placenta 2015;36:101–14. 5. Madazli R, Tuten A, Calay Z, et al. The incidence of placental abnormalities, maternal and cord plasma malondialdehyde and
6
6. 7.
8.
9.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
10. 11. 12. 13. 14. 15.
M. Kovo et al. vascular endothelial growth factor levels in women with gestational diabetes mellitus and nondiabetic controls. Gynecol Obstet Invest 2008;65:227–32. al-Okail MS, al-Attas OS. Histological changes in placental syncytiotrophoblasts of poorly controlled gestational diabetic patients. Endocr J 1994;41:355–60. Bjork O, Persson B. Villous structure in different parts of the cotyledon in placentas of insulin-dependent diabetic women. A morphometric study. Acta Obstet Gynecol Scand 1984;63: 37–43. Kovo M, Schreiber L, Ben-Haroush A, et al. Placental vascular lesion differences in pregnancy-induced hypertension and normotensive fetal growth restriction. Am J Obstet Gynecol 2010;202:561 e561–5. Redline RW. Placental pathology: a systematic approach with clinical correlations. Placenta 2008;29:S86–91. Redline RW, Heller D, Keating S, Kingdom J. Placental diagnostic criteria and clinical correlation – a workshop report. Placenta 2005; 26:S114–17. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008;31:S55–60. Bulletins–Obstetrics ACoP. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99:159–67. Dollberg S, Haklai Z, Mimouni FB, et al. Birth weight standards in the live-born population in Israel. IMAJ 2005;7:311–14. Kovo M, Schreiber L, Ben-Haroush A, et al. Association of nonreassuring fetal heart rate and fetal acidosis with placental histopathology. Placenta 2011;32:450–3. Kovo M, Schreiber L, Ben-Haroush A, et al. The placental factor in spontaneous preterm labor with and without premature rupture of membranes. J Perinat Med 2011;39:423–9.
J Matern Fetal Neonatal Med, Early Online: 1–6
16. Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol 2005;192: 452–7. 17. Crowther CA, Hiller JE, Moss JR, et al., Australian Carbohydrate Intolerance Study in Pregnant Women Trial G. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–86. 18. Landon MB, Gabbe SG. Fetal surveillance in the pregnancy complicated by diabetes mellitus. Clin Perinatol 1993;20:549–60. 19. Kjos SL, Walther FJ, Montoro M, et al. Prevalence and etiology of respiratory distress in infants of diabetic mothers: predictive value of fetal lung maturation tests. Am J Obstet Gynecol 1990;163: 898–903. 20. Jauniaux E, Burton GJ. Villous histomorphometry and placental bed biopsy investigation in Type I diabetic pregnancies. Placenta 2006;27:468–74. 21. Higgins M, McAuliffe FM, Mooney EE. Clinical associations with a placental diagnosis of delayed villous maturation: a retrospective study. Pediatr Dev Pathol 2011;14:273–9. 22. Laurini RN, Visser GH, van Ballegooie E, Schoots CJ. Morphological findings in placentae of insulin-dependent diabetic patients treated with continuous subcutaneous insulin infusion (CSII). Placenta 1987;8:153–65. 23. Jeve YB, Konje JC, Doshani A. Placental dysfunction in obese women and antenatal surveillance strategies. Best Pract Res Clin Obstetr Gynaecol 2015;29:350–64. 24. Huang L, Liu J, Feng L, et al. Maternal prepregnancy obesity is associated with higher risk of placental pathological lesions. Placenta 2014;35:563–9. 25. Maloney KF, Heller D, Baergen RN. Types of maternal hypertensive disease and their association with pathologic lesions and clinical factors. Fetal Pediatr Pathol 2012;31:319–23.
ORIGINAL ARTICLE
Pregnancy outcome and placental pathology differences in term gestational diabetes with and without hypertensive disorders Michal Kovo1, Yoav Granot1, Letizia Schreiber2, Michael Divon3, Avi Ben-Haroush4, and Jacob Bar1 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
1
Department of Obstetrics & Gynecology and 2Department of Pathology, Edith Wolfson Medical Center, Holon, Israel, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 3Department of Obstetrics & Gynecology, New York University School of Medicine, Lenox Hill Hospital, New York, NY, USA, and 4Department of Obstetrics & Gynecology, Rabin Medical Center, Petah-Tikva, Israel Abstract
Keywords
Objective: To compare pregnancy outcome and placental pathology in pregnancies complicated by gestational diabetes mellitus (GDM A1 and A2), with and without hypertensive disorders. Methods: Pregnancy outcome and placental pathology from term deliveries of women complicated with GDM with (GDM + H) and without (GDM H) hypertensive disorders were compared. Results of the GDM + H group were compared also with the non-diabetic patients but with hypertensive disorders (non-GDM + H). Composite neonatal outcome was defined as one or more of early complications: respiratory distress or need of ventilation support, sepsis, phototherapy, transfusion, seizure, hypoxic-ischemic encephalopathy. Placental lesions were categorized to lesions related to maternal and fetal vascular supply abnormalities, and maternal and fetal inflammatory responses. Results: Of the 192 women with GDM, the GDM + H group (n ¼ 41) were more obese, p50.001, with higher rate of placental maternal and fetal vascular supply lesions, p ¼ 0.008, p ¼ 0.03, respectively, but similar neonatal outcome, compared to the GDM H (n ¼ 151) group. Compared to the non-GDM + H group (n ¼ 41), the GDM + H group had higher birth weights, similar neonatal outcome and similar rate of placental vascular lesions. Conclusions: Higher rate of placental maternal and fetal vascular supply lesions express underlying placental pathology in women with diabetes and hypertensive disorders, similar to women without DM and with hypertensive complications.
Gestational diabetes, hypertension, placental pathology
Introduction Diabetes mellitus (DM) is one of the major medical complications in pregnancy that affects both the mother and the fetus [1]. Increased maternal levels of glucose, insulin, angiogenic growth factors, cytokines and inflammatory mediators may impact on the maternal and fetal vascular systems in the placenta [2]. Since diabetes affects placental development, function abnormalities in placental development may contribute to the poor pregnancy outcome. There is a range of placental reaction patterns that can be developed in response to the chronic ischemic insult observed in diabetes during pregnancy. Compared to normo-glycemic controls, several studies reported of significant increase in fibrinoid necrosis, chorangiosis, ischemia and villous immaturity in placentas retrieved from women with gestational diabetes mellitus (GDM) [3]. Yet, existing placental
Address for correspondence: Michal Kovo, MD, PhD, Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, P.O. Box 5, Holon 58100, Israel. Tel: +972 3 5028329. Fax: +972 3 5028503. E-mail: [email protected]
History Received 7 April 2015 Revised 9 May 2015 Accepted 11 May 2015 Published online 5 June 2015
histomorphometric studies display varied and inconsistent findings regarding placental abnormalities in relation to GDM and pregestational diabetes as well [4]. Additionally, the degree to which maternal glycemic control contributes to the development and to the extent of the different placental lesions remains uncertain [3,5–7]. Hypertensive disorder is also a common complication in pregnancy, resulting in increased maternal and fetal/neonatal morbidity. Histological studies demonstrated that vascular lesions are more common in placentas from pregnancies complicated by the disorder [8]. Since hypertensive disorders and maternal GDM during pregnancy have been associated, it has been suggested that concomitant maternal conditions are likely to contribute to the placental pathological changes seen in women with diabetes. Most of the existing studies on placental pathology and GDM did not concentrate on GDM patients with and without additional hypertensive disorders. The aim of the present study was to compare the clinical characteristics and placental histopathology between pregnancies complicated by GDM A1 and A2, in the presence and absence of maternal hypertensive disorders. Placental lesions were classified into those consistent with maternal and fetal
2
M. Kovo et al.
vascular supply abnormalities, and with maternal and fetal inflammatory responses [9,10].
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Patients and methods For the present study, the medical records of all patients diagnosed with GDM, who gave birth at term, between January 2008 and December 2013 and their placentas underwent histopathology examination at the Edith Wolfson Medical Center were reviewed. Our department protocol includes placental analyses in all patients attending the department with a complicated pregnancy. GDM was diagnosed in the presence of abnormal 100 g oral glucose tolerance test (OGTT) at 24–32 weeks. For GDM diagnosis the American Diabetes Association (ADA) criteria were used [11]. GDMA1 included patients who were treated with diet only, and GDMA2 included those who were treated also with insulin. For the purpose of the study, women with GDM were divided to those with (GDM + H) and without (GDM H) hypertensive disorders. Hypertensive disorders included gestational hypertension, chronic hypertension and preeclampsia, defined according to the criteria of the American College of Obstetrics and Gynecology [12]. The GDM + H group was also compared to non-diabetic patients with hypertensive disorders (non-GDM + H), with a negative 50 g glucose challenge test (GCT) or normal OGTT, who delivered at term, and were matched to by mode of delivery [cesarean section (CS) versus vaginal delivery (ND)] on a 1:1 basis. Exclusion criteria were multiple pregnancies and preterm deliveries defined as labor 537 weeks of gestation. Gestational age was confirmed by first-trimester ultrasonography in all cases. The following data were collected from the medical files: maternal characteristics: age, gravidity, parity, body mass index, cigarettes smoked per day; known chronic disease: thrombophilia, epilepsy or asthma. Neonatal outcome parameters included mean cord pH, days of hospitalization and the rate of neonatal intensive care unit (NICU) admission. Early neonatal complications including: sepsis, blood transfusion, hypoglycemia, phototherapy, respiratory distress, mechanical ventilation, need of respiratory support, intra-ventricular hemorrhage, seizures, hypoxic-ischemic encephalopathy or death. Neonatal birth weight percentile in each case was assigned using the updated Israeli growth charts [13]. Macrosomia was defined as birth weight above the 90th percentile for age, and fetal growth restriction (FGR) was defined as a birth weight below the 10th percentile for age. Clinical and placental pathology findings were compared between the GDM + H and GDM H groups (diabetic patients without hypertensive disorders), and also between the GDM + H and non-GDM + H groups (non-diabetic patients but with hypertensive disorders). We also established a database of placental findings in women without any pregnancy complications for research purposes. We then identified those who delivered at term, and were matched by mode of delivery to the GDM + H group and the GDM H group on a 1:1 basis. Placental lesions were also compared between the three groups. The study was approved by the local Ethics Committee.
J Matern Fetal Neonatal Med, Early Online: 1–6
Placental examination Placental pathology examinations were performed using a standard protocol, described by us in previous studies [14,15]. Briefly, after fixation in formalin and removal of the membranes and cord, the placentas were weighed. For each placenta, at least five tissue samples were embedded in paraffin blocks for microscopic assessment. All examinations were done by a single pathologist (author LS). Placental lesions The placental lesions identified were classified by maternal or fetal origin according to the criteria that were adopted by the Society for Pediatric Pathology [9,10] and were described by us in previous studies [14,15]. Briefly, maternal vascular supply abnormalities included: lesions resulting from loss of integrity of the maternal circulation, i.e. placental, marginal and retro-placental hemorrhages, vascular lesions related to maternal underperfusion (acute atherosis and mural hypertrophy) and villous changes related to maternal underperfusion (increased syncytial knots, villous agglutination, increased intervillous fibrin deposition and villous infarcts). Fetal vascular supply abnormalities included findings consistent with fetal thrombo-occlusive disease: vascular lesions (thrombosis of the chorionic plate and stem villous vessels) and villous changes (hypovascular, fibrotic and avascular villi). Additionally, in this group we included lesions related to maldevelopment of the fetal vascular supply as distal villous immaturity. Placental findings consistent with chorioamnionitis were defined by the presence of an inflammatory neutrophil infiltrate at two or more sites on the chorionic plate and extraplacental membrane. The maternal inflammatory response (MIR) was divided into three stages: early, acute subchorionitis (stage 1); intermediate acute chorioamnionitis (stage 2) and late, severe chorioamnionitis (stage 3). The fetal inflammatory response (FIR) was also divided into three stages: early, umbilical phlebitis (stage 1); intermediate, umbilical arteritis (stage 2) and concentric umbilical perivasculitis (necrotizing funisitis, stage 3). Villitis of unknown etiology or chronic villitis, defined as lymphohistiocytic inflammation localized to the stroma of terminal villi but often extending to the small vessels of upstream villi, was recorded separately. Statistical analysis Data were analyzed with SPSS software, version 15.0 (Chicago, IL). Continuous variables were calculated as mean ± SD or median and range, as appropriate. Categorical variables were calculated as rate (%). Student’s t-test was used to compare continuous parameters between the GDM groups; analysis of variance (ANOVA) (where greater than two groups) and Mann–Whiney U-tests for non-normally distributed data, Chi-square test was used to analyze categorical variables. A p value of 50.05 was considered statistically significant. Composite neonatal outcome was defined as one or more of the following complications: sepsis, blood transfusion, phototherapy, hypoglycemia, respiratory distress, mechanical
Placental pathology in diabetes with and without hypertensive disorders
DOI: 10.3109/14767058.2015.1051024
ventilation, respiratory support, intra-ventricular hemorrhage, seizures, hypoxic-ischemic encephalopathy or death.
Results A total of 192 women diagnosed with diabetes during pregnancy were included in the study: 123 with GDMA1, 69 with GDMA2. Among them 151 were without hypertensive disorders (GDM H) and 41 (21.3%) had hypertensive disorders (GDM + H): 17 (41.4%) with preeclampsia, 13 (31.7%) with gestational hypertension and 11 (26.8%) with chronic hypertension.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Comparison between the GDM + H and GDM H groups Maternal characteristics of DM + H and DM H women are presented in Table 1. The GDM + H group had higher body mass index (BMI) (kg/m2) than the GDM H group, 33.2 ± 7.3 versus 27.88 ± 6.7, p50.001. There were no differences between the study groups in mean maternal age, gestational age at delivery, rates of smokers, IVF pregnancies and rate of induction of labor. Neonatal outcome of the GDM + H and GDM H is presented in Table 2. Table 1. Maternal characteristics of patients with gestational diabetes associated with (GDM+H) and without (GDM-H) hypertensive disorders.
Maternal age (years) Nulliparity BMI (kg/m2) Smokers (%) Gestational age at delivery (weeks) CS (%)
GDM + H n ¼ 41
GDM H n ¼ 151
p value
30.85 ± 5.1 10 (24.4) 31.9 ± 7 8 (19.5) 38.6 ± 0.94
32.5 ± 5 63 (41.7) 27.5 ± 6.43 21 (13.9) 38.7 ± 0.94
0.060 0.064 50.001 0.520 0.788
35 (85.3)
120 (79.5)
0.505
Birth weights, rate of macrosomia, mean length of hospitalization and composite neonatal outcome did not differ between the groups. Placental findings in the GDM + H versus GDM H groups (Table 3) revealed higher rate of vascular lesions related to maternal underperfusion in the GDM + H group compared to the GDM H group, 17% versus 4%, respectively, p50.001. Additionally, increased rate of vascular lesions related to fetal thrombo-occlusive disease (FTOD) was also found in the GDM + H compared to the GDM H group, 12.2% versus 3.3%, respectively, p ¼ 0.038. Distal villous immaturity was more common, with a borderline statistical significance, in the GDM H compared to the GDM + H group, 13.2% versus 2.4%, respectively, p ¼ 0.05. Comparison between the GDM + H and non-GDM + H groups Maternal characteristics and neonatal outcome of the GDM + H and the matched non-GDM + H are presented in Table 4. The GDM + H group compared to the non-GDM + H group had higher BMI (kg/m2), 31.9 ± 7 versus 27.8 ± 9, respectively, p ¼ 0.041, and lower rate of nulliparity, 24.4% versus 58.5%, respectively, p ¼ 0.003. There were no differences in mean maternal age, gestational age at delivery, rate of smokers, between the groups. The GDM + H group compared to the non-GDM + H group had higher birthweight 3416 ± 607 g versus 3129 ± 564 g, respectively, p ¼ 0.03, but with similar composite neonatal outcome. Placental findings in the GDM + H versus non-GDM + H groups are summarized in Table 5. Higher placental weights and lower fetal–placental ratio were observed in the GDM + H compared to the non-GDM H group, Table 3. Placental findings of patients with GDM associated with (GDM + H) and without (GDM H) hypertensive disorders.
Continuous variables are presented as mean ± SD and categorical variables as n (%). BMI – body mass index; CS – cesarean section; IVF – in vitro fertilization.
Table 2. Neonatal outcome of patients with gestational diabetes associated with (GDM + H) and without (GDM H) hypertensive disorders.
Birth weight (BW) (g) Birth weight percentile Rate of macrosomia (%) Mean cord pH Hospitalization (days) NICU admission (%) Respiratory problems Sepsis (%) CNS abnormalities (%) Phototherapy (%) Hypoglycemia (%) Composite outcome (%)
GDM + H n ¼ 41
GDM H n ¼ 151
3416 ± 607 66 ± 32 14 (34.1) 7.26 ± 0.08 4.4 ± 2.3 17 (41.4) 2 (4.9) 1 (2.4) 0 2 (4.9) 5 (12.2) 9 (22)
3407 ± 582 63.7 ± 30.7 42 (27.8) 7.18 ± 0.95 4.55 ± 3.3 52 (34.4) 11 (7.3) 1 (0.6) 0 13 (8.6) 18 (12) 35 (23.1)
p value 0.936 0.665 0.550 0.633 0.707 0.517 0.846 1 0.644 0.961 0.868
Continuous variables are presented as mean ± SD and categorical variables as n (%). BW – birth weight; NICU – neonatal intensive care unit. Respiratory problems include respiratory distress, mechanical ventilation or the need of respiratory support; CNS abnormalities included: intra-ventricular hemorrhage, seizures or hypoxic-ischemic encephalopathy.
3
Placental weight (g) Fetal–placental ratio
GDM + H n ¼ 41
GDM H n ¼ 151
p value
575 ± 123 6 ± 0.7
536 ± 132 6.9 ± 5.1
0.09 0.279
1 (0.6) 6 (4)
1 0.008
67 (44.4)
0.596
5 (12.2)
5 (3.3)
0.038
Maternal vascular supply lesions Placental hemorrhage (%) 0 7 (17) Vascular lesions related to maternal under perfusion (%) 16 (39) Villous changes related to maternal under perfusion (%) Fetal vascular supply lesions Vascular lesions consistent with FTOD (%) Villous lesions consistent with FTOD (%) Villous immaturity (%)
6 (14.6)
13 (8.6)
0.248
1 (2.4)
20 (13.2)
0.05
Inflammatory lesions MIR (%) FIR (%) Chronic villitis
5 (12.2) 1 (2.4) 1 (2.4)
26 (17.2) 11 (7.3) 4 (2.6)
0.632 0.466 0.940
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, FTOD – fetal thrombo-occlusive disease, FIR – fetal inflammatory response, MIR – maternal inflammatory response.
4
M. Kovo et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
Table 4. Maternal characteristics and neonatal outcome of patients with GDM and hypertensive disorders (GDM + H) versus controls, nondiabetic with hypertensive disorders (non-GDM + H), matched by mode of labor.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Maternal age (yrs) Nulliparity (%) BMI (kg/m2) Smokers (%) Gestational age at delivery (wks) Neonatal outcome Birth weight (BW) (g) Birth weight percentile Rate of macrosomia (%) Mean cord pH Hospitalization (days) NICU admission (%) Respiratory problems Sepsis CNS abnormalities Phototherapy (%) Hypoglycemia (%) Composite outcome (%)
GDM + H n ¼ 41
Non-GDM + H n ¼ 41
p value
30.85 ± 5.1 10 (24.4) 31.9 ± 7 8 (19.5) 38.6 ± 0.94
31.44 ± 5.76 24 (58.5) 27.82 ± 9.12 5 (12.2) 38.9 ± 1.17
0.630 0.003 0.041 0.546 0.204
3416 ± 607 66 ± 32 14 (34.1) 7.26 ± 0.08 4.4 ± 2.3 17 (41.4) 2 (4.9) 1 (2.4) 0 2 (4.9) 5 (12.2) 9 (22)
3129 ± 564 48 ± 30 5 (12.2) 7.3 ± 0.05 4.48 ± 1.7 17 (41.4) 3 (7.3) 0 0 3 (7.3) 3 (7.3) 9 (22)
0.029 0.011 0.034 0.099 0.873 1 0.644 0.314 0.644 0.712 1
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, BW – birth weight; NICU – neonatal intensive care unit. Respiratory problems include respiratory distress, mechanical ventilation or the need of respiratory support; CNS abnormalities included: intra-ventricular hemorrhage, seizures or hypoxic-ischemic encephalopathy.
Table 5. Placental findings of patients with GDM and hypertensive disorders (GDM + H) versus controls with hypertensive disorders (nonGDM + H), matched by mode of labor.
Placental weight (g) Fetal–placental ratio
GDM + H n ¼ 41
Non-GDM + H n ¼ 41
p value
575 ± 123 6 ± 0.77
496 ± 112 6.4 ± 0.9
0.003 0.034
1 8 (19.5)
0.314 0.775
19 (46.3)
0.655
1(2.4)
0.203
Maternal vascular supply lesions Placental hemorrhage (%) 0 7 (17) Vascular lesions related to maternal under perfusion (%) 16 (39) Villous changes related to maternal under perfusion (%) Fetal vascular supply lesions Vascular lesions consistent with FTOD (%) Villous lesions consistent with FTOD (%) Villous immaturity Inflammatory lesions MIR FIR Chronic villitis
5 (12.2) 6 (14.6)
6 (14.6)
1
1 (2.4)
1(2.4)
1
5 (12.2) 1 (2.4) 1 (2.4)
10 (24.4) 2 (4.9) 1 (2.4)
0.253 0.556 1
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, FTOD – fetal thrombo-occlusive disease, FIR – fetal inflammatory response, MIR – maternal inflammatory response.
575 ± 123 g versus 496 ± 112 g, respectively, p ¼ 0.003 and 6.0 ± 0.7 versus 6.4 ± 0.9, respectively p ¼ 0.034. Rate of placental maternal and fetal vascular supply lesions and rate inflammatory lesions, did not differ between the groups. Comparison of placental findings between the GDM + H, GDM H and control groups Table 6 presents comparison of placental findings in three study groups, GDM + H, GDM H and healthy controls (n ¼ 192) matched by mode of delivery in a 1:1 basis. Placental weights of the GDM + H and GDM H were significantly higher than in the controls, p50.001. Vascular lesions related to maternal underperfusion were significantly more prevalent in the GDM + H than in the GDM H or the controls 17.1% versus 4% versus 2.1% respectively, p50.0001; Villous lesions related to maternal underperfusion were significantly less frequent in the controls than in either of the other two GDM groups (p50.0001). In relation to fetal vascular supply lesions, only distal villous immaturity was more common, in the GDM H than in either of the other two groups (p ¼ 0.022), but the difference between the controls and the GDM + H was not significant (p ¼ 0.17). Other placental lesions did not differ significantly between the three groups.
Discussion In the present study we analyzed pregnancy outcome and correlated results to placental pathological findings, in a cohort of women diagnosed with GDM, with and without hypertensive disorders. Those with GDM and hypertensive disorders were more obese and less nulliparous. Placentas from women with GDM and hypertension had more placental maternal vascular lesions and higher rate of placental fetal vascular lesions consistent with fetal thrombo-occlusive diseases, compared with women with GDM only. Such placental findings are well recognized, and known to be important contributors to adverse pregnancy outcome [16]. In contrast, placental villous immaturity was more common (though with borderline statistical significant) in GDM compared with those with hypertension. Different placental findings were observed in these two groups, yet, similar bad neonatal outcome was evident. More than a third of the neonates in both the groups were admitted to NICU and 22% of them had adverse composite outcome. Comparison between hypertensive GDM women versus hypertensive non-diabetic patients revealed similar high rate of composite neonatal outcome. Pregnancy outcome was associated with higher placental weight in the GDM group, but with similar high rate of maternal and fetal vascular placental lesions in both the groups. GDM during pregnancy is known to be associated with increased perinatal morbidity and mortality [17–19], and probably some of these pregnancy complications may arise from altered placental development and function. Placental lesions observed in GDM suggest that chronic insult occur in diabetic pregnancies. Specifically, the high rate of villous immaturity, as observed in the current study, and is in concordance with previous studies [3,5], may lead to chronic fetal hypoxemia due to increased diffusion distance between
DOI: 10.3109/14767058.2015.1051024
Placental pathology in diabetes with and without hypertensive disorders
5
Table 6. Comparison of placental findings of the three groups of patients: GDM + H, GDM H and normal healthy controls, matched by mode of labor.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Placental weight (g) Maternal vascular supply lesions Placental hemorrhage (%) Vascular lesions related to maternal under perfusion (%) Villous changes related to maternal under perfusion (%)
GDM + H n ¼ 41
GDM H n ¼ 151
Controls n ¼ 192
p value
575 ± 123
536 ± 132
492 ± 104
50.001
0 7 (17)
1 (0.6) 6 (4)
2 (1) 4 (2)
0.772 50.001
16 (39)
67 (44.4)
47 (24.5)
50.001
Fetal vascular supply lesions Vascular lesions consistent with FTOD (%) Villous lesions consistent with FTOD (%) Villous immaturity (%)
5 (12.2) 6 (14.6) 1 (2.4)
5 (3.3) 13 (8.6) 20 (13.2)
11 (5.7) 19 (10) 1 (0.5)
0.183 0.519 0.022
Inflammatory lesions MIR (%) FIR (%) Chronic villitis
5 (12.2) 1 (2.4) 1 (2.4)
26 (17.2) 11 (7.3) 4 (2.6)
38 (19.8) 10 (5.2) 12 (6.2)
NS NS NS
Continuous variables are presented as mean ± SD and categorical variables as n (%). GDM – gestational diabetes, FTOD – fetal thrombo-occlusive disease, FIR – fetal inflammatory response, MIR – maternal inflammatory response.
inter-villous space and fetal capillaries [20]. This placental abnormality has been independently associated with an increased risk of perinatal mortality [21]. Our findings suggest that different placental pathology in women with GDM, with or without hypertension result in a common pathway to worse pregnancy outcome. The high rate of placental vascular lesions associated with GDM and hypertensive disorders may suggest that different mechanisms like vascular dysfunction versus placental dysmaturity lead to similar neonatal outcome. The present study is unique in several aspects. First, to the best of our knowledge, we are the first to compare between term pregnancies of GDM patients with and without hypertensive disorders, matched by mode of delivery, thus controlling confounding factors, such as preterm labor and mode of delivery, which may affect placental histopathology. Second, by applying placental histopathology criteria that were validated and adopted by the Society of Pediatrics Pathology [10], we were able to analyze placentas in terms of maternal and fetal vascular supply and maternal and fetal inflammatory responses, thereby separating the maternal and fetal placental compartments. Third, we compared placental pathology between GDM women, with and without hypertensive disorder and healthy controls, demonstrating the dominance of maternal vascular lesions in the GDM placentas. Our study has several limitations; first, there is the lack of information regarding maternal diabetic control, as the level of maternal HB A1C during pregnancy or the level of blood cord c-peptide. We are aware that maternal diabetic control could influence the degree and the rate of several placental lesions as well as on the rate of neonatal complications. However, placental vascular lesions, as observed by us, may also persist despite tight metabolic control [22], correlating with increased risk of fetal and neonatal complications. Second, other factors, such as maternal obesity or maternal weight gain, might also influence placental pathology. It has been proposed that maternal obesity cause an accumulation of
pro-inflammatory mediators in the placenta that lead to high cytokine content and increased markers of oxidative stress, that eventually cause placental dysfunction and altered placental development [23]. Moreover, maternal prepregnancy obesity was found to be associated with higher risk of maternal origin vascular lesions and inflammatory lesions [24]. Third, different maternal hypertensive disorders were included in the study. Yet, it has been demonstrated that although the clinical presentation of gestational hypertension is less severe, as compared to other hypertensive disorders, the placental pathology lesions in these disorders are similar [25]. In conclusion, the present study demonstrates that worse pregnancy outcome is the end result of various placental lesions in women with diabetes. In those without hypertensive disorders villous immaturity is dominant, and in those with hypertensive disorders placental maternal and fetal origin vascular lesions are dominant. Difference in placental pathology may reflect differences in pathophysiology among diabetic patients with and without hypertensive disorders.
Declaration of interest The authors report no conflict of interest.
References 1. Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med 2004;21:103–13. 2. Leach L. Placental vascular dysfunction in diabetic pregnancies: intimations of fetal cardiovascular disease? Microcirculation 2011; 18:263–9. 3. Daskalakis G, Marinopoulos S, Krielesi V, et al. Placental pathology in women with gestational diabetes. Acta Obstet Gynecol Scand 2008;87:403–7. 4. Huynh J, Dawson D, Roberts D, Bentley-Lewis R. A systematic review of placental pathology in maternal diabetes mellitus. Placenta 2015;36:101–14. 5. Madazli R, Tuten A, Calay Z, et al. The incidence of placental abnormalities, maternal and cord plasma malondialdehyde and
6
6. 7.
8.
9.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
10. 11. 12. 13. 14. 15.
M. Kovo et al. vascular endothelial growth factor levels in women with gestational diabetes mellitus and nondiabetic controls. Gynecol Obstet Invest 2008;65:227–32. al-Okail MS, al-Attas OS. Histological changes in placental syncytiotrophoblasts of poorly controlled gestational diabetic patients. Endocr J 1994;41:355–60. Bjork O, Persson B. Villous structure in different parts of the cotyledon in placentas of insulin-dependent diabetic women. A morphometric study. Acta Obstet Gynecol Scand 1984;63: 37–43. Kovo M, Schreiber L, Ben-Haroush A, et al. Placental vascular lesion differences in pregnancy-induced hypertension and normotensive fetal growth restriction. Am J Obstet Gynecol 2010;202:561 e561–5. Redline RW. Placental pathology: a systematic approach with clinical correlations. Placenta 2008;29:S86–91. Redline RW, Heller D, Keating S, Kingdom J. Placental diagnostic criteria and clinical correlation – a workshop report. Placenta 2005; 26:S114–17. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008;31:S55–60. Bulletins–Obstetrics ACoP. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99:159–67. Dollberg S, Haklai Z, Mimouni FB, et al. Birth weight standards in the live-born population in Israel. IMAJ 2005;7:311–14. Kovo M, Schreiber L, Ben-Haroush A, et al. Association of nonreassuring fetal heart rate and fetal acidosis with placental histopathology. Placenta 2011;32:450–3. Kovo M, Schreiber L, Ben-Haroush A, et al. The placental factor in spontaneous preterm labor with and without premature rupture of membranes. J Perinat Med 2011;39:423–9.
J Matern Fetal Neonatal Med, Early Online: 1–6
16. Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol 2005;192: 452–7. 17. Crowther CA, Hiller JE, Moss JR, et al., Australian Carbohydrate Intolerance Study in Pregnant Women Trial G. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–86. 18. Landon MB, Gabbe SG. Fetal surveillance in the pregnancy complicated by diabetes mellitus. Clin Perinatol 1993;20:549–60. 19. Kjos SL, Walther FJ, Montoro M, et al. Prevalence and etiology of respiratory distress in infants of diabetic mothers: predictive value of fetal lung maturation tests. Am J Obstet Gynecol 1990;163: 898–903. 20. Jauniaux E, Burton GJ. Villous histomorphometry and placental bed biopsy investigation in Type I diabetic pregnancies. Placenta 2006;27:468–74. 21. Higgins M, McAuliffe FM, Mooney EE. Clinical associations with a placental diagnosis of delayed villous maturation: a retrospective study. Pediatr Dev Pathol 2011;14:273–9. 22. Laurini RN, Visser GH, van Ballegooie E, Schoots CJ. Morphological findings in placentae of insulin-dependent diabetic patients treated with continuous subcutaneous insulin infusion (CSII). Placenta 1987;8:153–65. 23. Jeve YB, Konje JC, Doshani A. Placental dysfunction in obese women and antenatal surveillance strategies. Best Pract Res Clin Obstetr Gynaecol 2015;29:350–64. 24. Huang L, Liu J, Feng L, et al. Maternal prepregnancy obesity is associated with higher risk of placental pathological lesions. Placenta 2014;35:563–9. 25. Maloney KF, Heller D, Baergen RN. Types of maternal hypertensive disease and their association with pathologic lesions and clinical factors. Fetal Pediatr Pathol 2012;31:319–23.
