Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation‐induced oxidative stress in a mouse model

Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro‐inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro‐inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.     

Placental transfer of lactate,glucose and 2-deoxyglucose in control and diabetic Wistar rats

Placental transfer of lactate, glucose and 2-deoxyglucose was examined employing the in situ perfused placenta. Control and streptozotocin induced diabetic Wistar rats were infused with [U-14C]-glucose and [3H]-2-deoxyglucose (2DG). The fetal side of the placenta was perfused with a cell free medium and glucose uptake was calculated in the adjacent fetuses. Despite the 5-fold higher maternal plasma glucose concentration in the diabetic dams the calculated fetal glucose metabolic index was not significantly different between the 2 groups. Placental blood flow was reduced in the diabetic animals compared with controls but reduction of transfer of [U-14C]-glucose and [3H]-2-deoxyglucose and endogenously derived [14C]-Lactate to the fetal compartment, could not be accounted for by reduced placental blood flow alone. There was no significant net production or uptake of lactate into the perfusion medium that had perfused the fetal side of the placenta in either group. The plasma lactate levels in the fetuses adjacent to the perfused placenta were found to be higher than in the maternal plasma and significantly higher in the fetuses of the diabetic group compared with control group. In this model the in-situ perfused placenta does not secrete significant quantities of lactate into the fetal compartment in either the control or diabetic group.     

Stillbirth after COVID-19 in Unvaccinated Mothers Can Result from SARS-CoV-2 Placentitis,Placental Insufficiency,and Hypoxic Ischemic Fetal Demise,Not Direct Fetal Infection: Potential Role of Maternal Vaccination in Pregnancy

Stillbirth is a recently recognized complication of COVID-19 in pregnant women. Other congenitally transmitted infections from viruses, bacteria and parasites can cause stillbirth by infecting fetal organs following transplacental transmission of the agent from the maternal bloodstream. However, recent research on pregnant women with COVID-19 having stillbirths indicates that there is another mechanism of stillbirth that can occur in placentas infected with SARS-CoV-2. In these cases, viral infection of the placenta results in SARS-CoV-2 placentitis, a combination of concurrent destructive findings that include increased fibrin deposition which typically reaches the level of massive perivillous fibrin deposition, chronic histiocytic intervillositis and trophoblast necrosis. These three pathological lesions, in some cases together with placental hemorrhage, thrombohematomas and villitis, result in severe and diffuse placental parenchymal destruction. This pathology can involve greater than one-half of the placental volume, averaging 77% in the largest study of 68 cases, effectively rendering the placenta incapable of performing its function of oxygenating the fetus. This destructive placental process can lead to stillbirth and neonatal death via malperfusion and placental insufficiency which is independent of fetal infection. Fetal autopsies show no evidence that direct infection of fetal organs is contributory. Because all mothers examined have been unvaccinated, maternal vaccination may prevent viremia and consequent placental infection.     

Bidirectional placental transfer (‘leak’) ofl-glucose in control and diabetic rats

The placental transfer ofd- andl-glucose was investigated in anaesthetised non-diabetic and streptozotocin-induced diabetic rats. Maternal to fetal transfer was determined by perfusing the fetal side of one placenta in situ whilst infusing a mixture ofd-[3-³H]glucose andl-[1-¹⁴C]glucose into the maternal circulation. Backtransfer from the fetal to maternal circulation was assessed by determining the uptake of the radiolabelled glucoses from the perfusion fluid during a single passage through the placenta on the fetal side. Maternal diabetes resulted in a reduced utero-placental blood flow but an increased bidirectional transfer ofd-glucose. Non-specific maternal to fetal placental transfer ofl-glucose was greater in diabetic rats than in controls, and the loss ofl-glucose during placental perfusion of the fetal side was, again, greater in diabetic than in control rats. This increased bidirectional leak of glucose possibly reflects a functionally compromised placenta, caused by its formation in a diabetic milieu, and may explain the greater fetal-maternal glucose ratios found in diabetic rats relative to controls.     

不同血糖水平控制状况对妊娠糖尿病患者胎盘钙化、脐动脉血流动力学及分娩结局的影响

目的 探讨不同血糖水平控制状况对妊娠糖尿病患者胎盘钙化、脐动脉血流动力学及分娩结局的影响.方法 回顾性分析2017年1月至2019年8月在我院接受治疗的148例妊娠糖尿病患者的临床资料,根据患者的血糖控制状况,将患者分为血糖控制良好组(85例)和血糖控制不良组(63例),比较两组患者的胎盘钙化情况、脐动脉血流动力学检测...     

Ultrasound in the study of fetoplacental circulation

Exploration of fetal vessels is performed with a duplex system which combines a real-time linear imaging system 3.5 MHz and a pulsed Doppler (2.5 MHz). The transducers of the imaging and Doppler systems are associated in the same probe. Umbilical and aortic circulation have been investigated on 100 pregnancies. The umbilical artery Doppler spectrum shows an important diastolic flow which increases all along the pregnancy. A decrease of this flow occurs when the placental circulatory resistances increase. In case of severe hypertension one can note a decrease or the disappearance of the diastolic flow related to the existence of vascular placental defects (infarctus). This was observed in pathological pregnancies with hypotrophy or fetal death. The placental resistances can be quantified with the Pourcelot index R = A - D divided by A, where A is the maximum systolic amplitude and D the maximum end diastolic amplitude, both measured on the umbilical artery spectrum. Fetal blood flow measurements were performed with the same device. The mean value of the blood flow is about 170 ml/min/kg in the aorta and 120 ml/min/kg in the umbilical arteries at the end of the pregnancy. The possibility to record simultaneously fetal aorta and inferior vena cava enable us to detect abnormal heart rate such as the atrioventricular block.     

Transvaginal Doppler Ultrasonography in Early Pregnancy: Blood Flow Development in the Umbilical Cord

The umbilical arterial and venous blood flow of 60 pregnancies between the sixth and fifteenth week of gestation was investigated using Doppler ultrasound technology. Although fetal heart activity was detected from the fifth week, umbilical arterial blood flow was not identified until the sixth week, and venous flow was not seen until the seventh week. The characteristics of the Doppler velocity waveform changed significantly as gestation progressed. Initially, the waveform showed a short flat systolic component without diastolic flow. Systole gradually increased in duration and peaked. The diastolic component increased and became continuous at 14 weeks. After the fourteenth week, the velocity waveform did not differ greatly from those of later gestation. Arterial blood flow changes evidenced by a serial decline in the pulsatility index presumably reflects decreasing resistance of the embryonic and fetal placental vessels associated with maturation of the fetoplacental unit.     

Complexity analysis of placental blood flow in normal and high-risk pregnancies

Various strategems of complexity analysis of microvascular blood flow were carried out in several fields of medicine in the past, as such as angiology, ophthalmology and neurology. The introduction of colour-angio-mode, a special form of colour coded Doppler sonography, now makes possible to perform complexity analysis of the placental blood displacement even in the absence of information about hydrodynamic details such as directionality, velocity profile and number of displaced blood cells. Algorithms were developed which allows to extract information concerning the time averaged power of phonon-erythrocytes collision events (from the square of the frequencies of back scattered ultrasound recorded during 166 ms) in 20,000 to 40,000 regions of interest. The obtained values are being displayed as false coloured pixels on a video-screen, we succeeded to obtain quantitative data about displacement rates.In cross-sectional and longitudinal studies we generated typical diagrams displaying the "occurrence rate" of various powers of displacement over time. By this mode of display contour plots can be generated, showing a large amount of low intensity pixels and a small amount of high intensity pixels representing the parenchymatous blood flow inside the placenta. As was to be expected, interdependencies between the placental blood flow and the maternal and fetal heart rates as well as the maternal breathing can be found. While there was only limited influence of maternal and fetal heart rate on the placental blood flow, maternal breathing showed striking influence. Surprisingly, during expiration the power of placental blood movement was decreased, and there was a marked increase during inspiration. In cases of severe intrauterine growth retardation, colour pixel intensities were seen to transiently vanish during end-expiration. The power of placental blood displacement was marked increased subsequent to reducing maternal hematocrit during hemodilution therapy by infusion of artificial colloids. These interdependencies could be confirmed by ex vivo examinations perfusing and percolating the placenta after birth in a hemodynamic model. Additionally, we found interdependencies between fetal and maternal blood displacement inside the placenta. By modelling the decrease of fetal inotropic power in the ex vivo examinations, increase in the power of maternal blood displacement in the intervillous space. The two types of placental blood flow are known to be determined by many factors. While it is currently impossible to measure all these parameters determining an parenchymatous blood flow, it is possible to obtain useful informations about the physiologic and pathophysiologic changes of placental blood flow using colour-angio-mode as a tool of complexity analysis based on the distribution of local blood displacement. This new knowledge can help to understand clinically relevant changes in the individual patient as well their underlying causes.     

Trophoblast expression of fms-like tyrosine kinase 1 is not required for the establishment of the maternal-fetal interface in the mouse placenta

Fms-like tyrosine kinase 1 (Flt1)/vascular endothelial growth factor (VEGF) receptor 1, a receptor for VEGF-A and placental growth factor, is expressed in the spongiotrophoblast layer that segregates the maternal and fetal vasculature in the mouse placenta. A soluble form of Flt1 (sFlt1) produced in the mouse and human placenta can also be detected in the maternal blood. Levels of maternal sFlt1 are elevated in preeclampsia, suggesting that placental sFlt1 plays roles in regulating the maternal vasculature during pregnancy. However, it remains to be determined whether placental Flt1/sFlt1 serves as a regulator of VEGF-A activity in the placenta per se. Here, we investigated the placental development in Flt1-deficient mice. Flt1 is expressed in a subpopulation of ectoplacental cone cells and later marks the spongiotrophoblast cells, peri/endovascular trophoblast cells, and trophoblast glycogen cells. The labyrinth of Flt1lacZ/lacZ placentae lacked the fetal capillary network because of a defect in allantoic mesoderm invasion. To address whether the absence of Flt1 in the trophoblast alone affects placental development, we investigated chimeric placentae comprised of Flt1lacZ/lacZ trophoblast and Flt1+/+ mesoderm, generated by tetraploid aggregation. Fetal growth was supported normally, and no defect in the formation of placental circulation into the maternal spiral artery or invasion of peri/endovascular trophoblast was detected. These findings indicate that trophoblast-derived Flt1/sFlt1 is dispensable for the initial establishment of the maternal-fetal interface in the mouse placenta. Targeting maternal sFlt1 levels for treatment of preeclampsia may thus be possible without affecting the proper formation of the placenta.     

Postoperative evaluation of radial artery grafts for coronary artery bypass grafting by transit-time Doppler flow measurements.

Due to the histological configuration of the vessel wall, the radial artery is prone to spasm as a result of handling or harvesting. Therefore, certain degrees of arterial wall spasm are unpreventable, even with appropriate pharmacologic treatment, while using the radial artery as a bypass graft in CABG. Consequently, the radial artery is only reluctantly used compared to saphenous vein grafts in CABG. In our clinical experience, the radial artery, if harvested carefully, has proved to be an excellent bypass graft. This investigation was undertaken to study the differences in blood flow measured directly after extracorporeal circulation in radial artery grafts and venous grafts. Both grafts were compared to the left internal mammarian artery anastomosed to the LAD. METHODS: Between January 1998 and December 1999, 198 patients who were undergoing coronary artery revascularization with two grafts were retrospectively investigated. In all patients, the left internal mammarian artery (LIMA) was anastomosed to the left anterior descending branch (LAD). For the second graft, either the saphenous vein or the radial artery was used. Proximal anstomoses were performed as end-to-side into the ascending aorta. Patients were divided into four groups: Group 1: n = 79 IMA-LAD, vein to the circumflex artery; Group 2: n = 56 IMA-LAD, vein to the right coronary artery; Group 3: n = 34; IMA-LAD, radial artery to the circumflex artery; Group 4: n = 29 IMA-LAD, radial artery to the right coronary artery. Graft-flow measurements were performed using the transit-time method after extracorporeal circulation was terminated. The mean systolic, diastolic, and mean blood flow were measured, and the pulsatility index was calculated. Statistical analysis was performed using the of t-test analysis between the variables mean blood flow and pulsatility index. A p-value of < 0.05 was defined as statistically significant. RESULTS: There were no statistically significant differences in mean blood flow or pulsatility index between radial artery and saphenous vein grafts to the right coronary artery and the circumflex artery, respectively. Also, there were no differences regarding vein grafts to the right coronary artery and to the circumflex artery, or regarding radial artery grafts to the two coronaries, respectively. In group 4, significantly lower blood flow to the LAD was found compared to group 1, and a significantly higher pulsatility index compared to groups 2 and 3. CONCLUSIONS: Radial artery grafts compared to saphenous vein grafts do not show significant differences early after operation in mean blood flow or pulsatility index. Further studies are needed to evaluate long-term performance of radial arteries as coronary bypass grafts and to compare the radial artery to the right mammarian artery and the standard saphenous vein graft.     

脑梗死患者血流动力学的季节性变化

目的 应用经颅多普勒(TCD)探讨季节变化对脑梗死患者颅内血流动力学的影响.方法 对脑梗死组和对照组进行TCD检测,冬季检测一次,夏季复检一次,观察双侧大脑中动脉(MCA)的收缩期峰值血流速度(Vs)、舒张末期血流速度(Vd)、平均血流速度(Vm)、搏动指数(PI)的变化特征,对两组在不同季节的TCD血流指标改变进行统计学分析.结果 ①脑梗死组与对照组的PI值冬夏季差异均有统计学意义(P<0.001),脑梗死组PI值均高于对照组;②两组冬夏季血流指标自身比较差异均无统计学意义(P>0.05);③脑梗死组中进展组的Vs在不同季节差异有统计学意义,冬季Vs明显比夏季慢;④脑梗死组各危险因素分组中,MCA狭窄组的Vs、Vm在不同季节差异有统计学意义,冬季Vs、Vm均高于夏季;高血压组、血脂异常组、NIHSS评分分组在冬夏季差异无统计学意义.结论 季节变化与脑梗死患者颅内血流动力学改变有相关性,有MCA狭窄的脑梗死患者脑血流动力学改变更易受寒冷刺激影响.     

糖尿病肾血流变化的彩色多普勒超声观察

用彩色多普勒血流显象（ＣＤＥＩ）和脉冲多普勒超声心动图（ＰＤＥ）检测２６例肾功能正常的非胰岛素依赖型糖尿病病人及２０例正常人的双侧肾动脉血流，以探讨糖尿病肾病血流动力学改变。糖尿病病人与正常人对照，肾动脉内径增宽（Ｐ〈０．０１），血流量增加（Ｐ〈０．０１），搏动指数及阻力指数降低（Ｐ〈０．０５）。结果表明，糖尿病临床肾病前期呈高灌注、低阻力改变。提示ＣＤＦＩ和ＰＤＥ可为临床异期发现糖尿糖尿病肾病提     

Fetal diabetes in rats and its effect on placental glycogen

Summary The role of fetal insulin in placental glycogen accumulation, which occurs despite insulin deficiency in maternal diabetes, was studied in rats. Streptozotocin was injected into fetuses of non-diabetic and streptozotocin-diabetic mothers on days 19.5 and 20.5 of gestation, causing fetal hypoinsulinaemia and pancreatic insulin depletion. Placental glycogen content of either 1.6 mg/g in non-diabetic rats or 6.5 mg/g in diabetic rats was not affected by fetal streptozotocin treatment. Glycogen distribution was also measured in the placenta to assess the effect of fetal hypoinsulinaemia on glycogen content in its fetal segment. The glycogen concentration ratio between the fetal and maternal segments in diabetic rats was 0.3 and increased to 0.5 in diabetic rats, without being affected by fetal hypoinsulinaemia. There was no significant effect of fetal hypoinsulinaemia on the activities of placental glycogen synthase or glycogen phosphorylase, both in nondiabetic and diabetic rats. Fetal hypoinsulinaemia was associated, however, with a marked decrease in fetal liver glycogen together with a decrease in fetal liver weight, which was more pronounced than the decrease in fetal body weight. Administration of insulin to the streptozotocin-treated fetuses restored the impaired glycogen synthesis (measured by incorporation of U-[¹⁴C]-glucose and ³H₂O in the fetal liver) without affecting glycogen synthesis in the placenta. These results demonstrate: (1) placental glycogen metabolism in contrast to fetal liver glycogen metabolism, is not regulated by fetal insulin; (2) the reduced fetal liver weight and its glycogen content, rather than hyperglycaemia, are the salient features of fetal insulin deficiency; and (3) placental glycogen accumulation in diabetes is related to the hyperglycaemia of maternal origin and not to the changes in maternal or fetal insulin availability.     

Effects of Vivax Malaria Acquired Before 20 Weeks of Pregnancy on Subsequent Changes in Fetal Growth

The resistance index (RI), pulsatility index (PI), fetal biometry, fetal heart rate (FHR), placental thickness, and hemoglobin levels were compared in 30 Plasmodium vivax-infected women between 14 and 20 weeks of pregnancy and a control group. Evaluations were performed at the moment of the malaria diagnosis and 26 weeks of pregnancy. The malaria group had lower levels of hemoglobin and greater placental thickness in both assessments, higher FHR in the first evaluation, and lower values on fetal biometry in the second assessment. There were no differences when comparing RI and PI on umbilical arteries between the two groups. Birth weight and height were lower in newborns in the malaria group than the control group. The results suggest that P. vivax infections at an earlier gestational age do not affect umbilical arteries blood flow but do affect fetal biometry in the second trimester of pregnancy and at birth.     

Fetal risk with the use of coumarin anticoagulant agents in pregnant patients with intracardiac ball valve prosthesis

This is a report of the outcome of the pregnancy in 6 patients with intracardiac ball valve prostheses. Only 1 was not receiving anticoagulant agents, and she had a normal delivery with a live baby. The remaining 5 patients were receiving a coumarin anticoagulant agent throughout their pregnancies.

Two patients had premature deliveries with live babies that died a few hours later. Three patients had stillbirths; in only 1 patient was an excessive anticoagulant effect observed during a week which coincided with the calculated date of fetal death. This was the only case in which the placenta was studied, disclosing scattered areas of infarction and hemorrhage. Autopsy of the fetus or infant was performed in 2 cases and multiple hemorrhages were found.

The literature is reviewed and the probable relation between the use of coumarin anticoagulant agents and fetal and infant death is discussed. Recommendations are made for adequate control and management of pregnancy in women with an intracardiac prosthesis.     

Postprandial middle cerebral arterial vasoconstriction in cirrhotic patients. A placebo, controlled evaluation

BACKGROUND/AIMS: The objective of this study was to determine whether cerebral arterial vasoconstriction occurs in relation to postprandial splanchnic blood pooling in cirrhotic patients. METHODS: The pulsatility and the resistive indexes and blood flow in the middle cerebral artery were measured by magnetic resonance imaging in 21 cirrhotics and 14 controls. These measurements were repeated 30 min after ingestion of a 400 kcal liquid meal or placebo. Seven controls and 14 patients received the meal, and seven controls and seven patients received placebo. RESULTS: In the fasting conditions, cirrhotics had a greater pulsatility index (0.81 +/- 0.10 vs. 0.67 +/- 0.05, P < 0.001) and a greater resistive index (0.61 +/- 0.04 vs. 0.53 +/- 0.04, P < 0.001) and a lower blood flow (127 +/- 42 ml/min vs. 167 +/- 37 ml/min, P < 0.03) in the middle cerebral artery compared with controls. Meal ingestion significantly increased the pulsatility index (P < 0.03) and the resistive index (P < 0.01) and decreased blood flow (P < 0.03) in the middle cerebral artery in cirrhotics but not in controls. In contrast, placebo ingestion had no effect on the hemodynamic parameters in the middle cerebral artery in the two groups. CONCLUSIONS: Results support the hypothesis that middle cerebral arterial vasoconstriction seen in cirrhotic patients is one of the cerebral artery's homeostatic responses to underfilling of the splanchnic arterial circulation.     

经颅多普勒和P300检测评价老年糖尿病患者并发脑血管病变和认知功能的意义

目的　探讨老年糖尿病患者并发脑血管病变和认知功能的意义。方法　对 80例老年糖尿病患者及 6 0例年龄和性别相匹配的健康老年志愿者进行经颅多普勒 (TCD)和P30 0测试。结果　糖尿病患者颈内动脉颅外段血流速度明显高于对照组 (P <0 .0 1)。糖尿病并腔隙性脑梗死患者的动脉搏动指数明显高于无脑梗死组和对照组 (P<0 .0 1)。搏动指数与病程密切相关 (r =0 .4 9)。糖尿病并腔隙性脑梗死组与无脑梗死组和对照组比较 ,P30 0潜伏期显著延长 ,波幅降低 (P <0 .0 1)。糖尿病组P30 0潜伏期和波幅与糖尿病病程长短和有无高血压无明显相关性。结论　采用TCD、P30 0检测评价老年糖尿病患者的脑血管病变和大脑认知功能对临床有一定意义。     

Assessment of uterine placental circulation in thrombophilic women

Thrombophilia is associated with several complications of pregnancy including first and second trimester fetal loss, intrauterine fetal death, intrauterine growth restriction, preeclampsia, and placental abruption. Few studies have documented thrombotic lesions observed on the pathologic examination of the placenta in women with severe pregnancy complications. Moreover, a significantly higher rate of factor V Leiden and prothrombin G20210A gene mutations have been found in placentas with thrombotic events compared with normal placentas. In addition, clinical studies have been performed, using Doppler ultrasonography, to assess the uterine placental circulation in women with thrombophilia. Doppler studies of the umbilical artery in cases of intrauterine growth retardation have shown a high systolic to diastolic ratio (S/D) ratio, suggesting an increase in the resistance of the placental small vessels. When these placental vessels were examined after delivery, significant differences were found in comparison with placental vessels of normal pregnancies. Most of the Doppler studies of the umbilical and uterine arteries in pregnancies with thrombophilia were performed in women with antiphospholipid antibodies. The other pathologic conditions associated with thrombophilia and complications of pregnancy were published only recently. These few studies have demonstrated abnormal umbilical and uterine arteries blood flow in complicated pregnancies. Finally, few Doppler studies also suggest improved uterine placental circulation when women with thrombophilia received thromboprophylaxis.     

胎羊体外循环与胎盘功能保护研究进展

随着诊断技术的不断提高,许多胎儿先天性心脏病在宫内即能通过超声心动图早期诊断[1]。一些复杂畸形如瓣膜狭窄或闭锁由于产生严重的心脏继发性病变,出生后外科手术干预效果不佳。原发病如在宫内纠治则可使胎儿在出生前心脏得以正常发育。这就要求建立一种安全可靠的胎儿体外循环(CPB)技术,以便胎儿心脏外科手术的顺利进行。CPB必然对胎盘功能及胎儿产生一系列影响,如胎盘血管阻力(PVR)升高,胎盘血流量(PBF)减少,胎盘功能障碍引起胎儿气体交换障碍,导致胎儿严重代谢性酸中毒,甚至死亡[2-6]。因此对作为维持胎儿生命的重要脏器——胎盘…     

Lupus pregnancy. A prospective study of placental changes

Eleven patients with systemic lupus erythematosus (SLE) were monitored prospectively during pregnancy. Clinical and serologic features of disease activity were recorded, and after delivery, a careful search for pathologic changes in the placenta was carried out. Seven patients delivered live infants, and 4 patients had unsuccessful pregnancies, with fetal loss occurring between 12 and 27 weeks of gestation. One of these 4 patients had active SLE at delivery, and all had circulating lupus anticoagulant and thrombocytopenia. Other serologic abnormalities, including anticardiolipin and anti-Ro antibodies, were not associated with fetal loss. The overall placental size was reduced in SLE patients compared with that in healthy controls and in diabetic controls. A variety of pathologic changes were noted, including placental infarction, intraplacental hematoma, deposition of immunoglobulin and complement, and thickening of the trophoblast basement membrane. The reduction in placental size appeared to enhance the clinical significance of these pathologic changes.