Maternal Vascular Disease Research Articles

Gestational Age-Dependent Extravillous Cytotrophoblast Osteopontin(OPN) Immunolocalization in the Basal Plate and Uteroplacental Vasculature Differentiates between Normal and Growth-Restricted Fetuses † 261

Human placentation requires modulation of proliferative cytotrophoblasts to an invasive phenotype to create the intervillous space. Preeclampsia is characterized by failed trophoblast invasion and remodeling of the maternal spiral arteries. OPN is a secreted extracellular matrix protein found in many tissues including human trophoblast, and has been implicated in cell adhesion, invasion, spreading, and migration. To investigate gestational age-specific expression of OPN, immunohistochemical staining of post-partum placental tissue from 13 healthy women was performed using a monoclonal antibody against OPN (MPIIIB10-1). OPN protein was localized to the cytoplasm of invasive extravillous trophoblast from 24-28 wks (N=7). After 28 wks (N=6), OPN was undetectable in the extravillous trophoblast, and was not identified in non-invasive intravillous cytotrophoblast and syncytiotrophoblast at any gestational age (N=13). To investigate the role of OPN in uteroplacental vascular pathology, immunohistochemical staining of post-partum placentas from pregnancies complicated by preeclampsia (N=6) or intrauterine growth retardation (N=2) was performed using MPIIIB10-1 and compared to staining of placentas from gestational age-matched controls without pregnancy-induced maternal vascular disease (N=13). In the preecclampsia group, there was prominent proliferation of cytotrophoblast in the basal plate with intense OPN staining, in association with morphologic evidence of compromised uteroplacental perfusion. This staining pattern was identified in all preeclamptic placentas at 24-40 wks. In contrast, the normal and IUGR placentas did not display prominent cytotrophoblast proliferation or evidence of decreased uteroplacental perfusion: OPN staining was limited to the invasive extravillous cytotrophoblast and detected only until 28 wks. The data suggests a role for OPN in trophoblast invasion of the maternal vasculature and extracellular matrix during normal placentation, where OPN may serve as a marker for uteroplacental vascular remodeling in the human fetus. In the preeclamptic pregnancy, extravillous cytotrophoblast continues to express OPN even at advanced gestational ages, which supports the speculation that intervillous fibrin/fibrinoid may be actively involved in the remodeling of the intervillous space. OPN may be critical in this process, the successful maintenance of which may necessary for fetal compensation.

Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia.

A common missense mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, a C to T substitution at nucleotide 677, is responsible for reduced MTHFR activity and associated with modestly increased plasma...

FETAL SURVEILLANCE AND TIMING OF DELIVERY IN PREGNANCY COMPLICATED BY DIABETES MELLITUS

Protocols for antepartum fetal assessment in pregnancies complicated by diabetes mellitus are an important part of a care program that allows most of these pregnancies to reach term, ensuring fetal maturation. Maternal assessment of fetal activity serves as an efficient screening test in most surveillance programs. These programs have used primarily biophysical testing consisting of the nonstress test, cardiac stress test, or biophysical profile. Doppler studies have been investigated as an adjunct for identifying fetal compromise. These studies may prove most valuable in cases of maternal vascular disease. The success of these protocols continues to be predicated on careful regulation of maternal glycemia through aggressive therapy with insulin and diet. Reassuring tests of fetal condition are present in most diabetic women and, therefore, permit fetal maturation to occur prior to delivery.

Doppler velocimetry of the umbilical artery in pregnancies complicated by insulin-dependent diabetes mellitus

The purpose of this study was to investigate vascular resistance by Doppler ultrasound in the umbilical artery of insulin-dependent diabetics longitudinally over the course of pregnancy. Special interest was put on the effects of glycemic control and maternal vascular disease on the flow velocity waveform (FVW) and the predictive value of Doppler flow measurements with regard to perinatal morbidity. Using a duplex-pulsed wave scanner, the resistance-index (PR index) in the umbilical artery was calculated. The mean value of a 24-h blood glucose profile and the concentration of glycosylated hemoglobin (HBA 1C) were used as parameters of metabolic control. 53 pregnant diabetic women were examined longitudinally during the course of pregnancy on average on three occasions (range: 1–7) between 17 weeks of gestation and delivery at 37.7 ± 1.3 (mean ± SD) weeks. To test the predictive value of Doppler flow velocimetry with regard to perinatal morbidity the results were compared to the FVWs measured in the umbilical arteries of 30 non-diabetic women with normal fetal outcome. Vascular resistance in the umbilical artery of the diabetics declined significantly during the course of pregnancy, with a mean PR index of 0.729 (SD 0.051) at 17 weeks and 0.603 (SD 0.083) at the end of pregnancy ( P < 0.002). The majority of PR indices were within the range reported for normal pregnancy and measured in the non-diabetic women. Regression analysis showed no significant correlation between vascular resistance and mean blood glucose level ( r = 0.1325) or concentration of HBA 1C ( r = −0.0519). Maternal vascular disease had no effect on umbilical FVWs. Umbilical vascular resistance was slightly higher in small fetuses and fetuses with perinatal distress but could not predict macrosomia or other specific diabetic morbidity.

Fetal surveillance in pregnancies complicated by insulin-dependent diabetes mellitus

Our objective was to determine whether maternal vascular disease and/or glycemic control can be related to tests of fetal condition in diabetic pregnancies. A total of 114 women with insulin-dependent diabetes who used a memory-based glucose reflectance meter were prospectively evaluated. Nonstress testing was begun weekly at 28 to 30 weeks and twice weekly at 32 weeks. A nonreactive nonstress test was followed by a biophysical profile in all cases. A total of 1676 nonstress tests was performed (14.7 +/- 3.2 tests per patient). Eight percent (n = 134) were nonreactive, necessitating a biophysical profile. A comparison of ambulatory glucose profile data, including mean blood glucose level, variation, and excursions from the median, revealed no significant differences in patients with reactive versus nonreactive nonstress tests. Ten patients, including eight with vascular disease, were delivered because of abnormal test results of fetal condition. Nephropathy or hypertension was associated with intervention for fetal well-being in 8 of 20 women (40%) with these risk factors. Only 2 of 94 patients (2%) without nephropathy or hypertension required delivery because of abnormal results of fetal testing (p less than 0.001). One fetal death occurred. No significant differences in the various glycemic parameters were found in women delivered for suspected fetal jeopardy versus the nonintervention group. Pregnancies complicated by vascular disease are at greatest risk for abnormal results of fetal testing that necessitate early delivery. Women without vascular complications and with maintenance of good glycemic control rarely have fetal compromise.

Maternal factors in developmental toxicity.

The maternal organism provides the developing embryo with its physical environment, nutrients, and a mechanism for eliminating metabolic wastes. Since the physiological state of the pregnant female affects her ability to provide those requirements for the developing embryo, it is not surprising that there are maternal factors that can affect the wellbeing of the embryo. Extremes of maternal age in both humans and animals have been implicated in growth retardation, as well as autosomal trisomies. The influence of maternal size on fetal size is more pronounced among larger species with longer gestation periods such as humans and domestic animals. A clear relationship between the parity of the mother and potential developmental toxicity in humans has not been established due to the confounding influences of maternal age. Among laboratory rodents, however, it appears that offspring of multiparous animals are at increased risk of developmental toxicity. A variety of infectious agents, particularly viruses, have either been demonstrated or implicated as causes of developmental toxicity. In addition, hyperthermia is a possible confounding factor inherent with maternal infection. Although under experimental conditions hyperthermia is teratogenic in laboratory animals, a causative role for transient hyperthermia, which occurs during febrile states concomitant with infections, cannot be clearly established. Chronic maternal vascular disease states including essential hypertension, heart disease, or diabetes mellitus are likely to contribute to uteroplacental insufficiency and developmental toxicity. Poor maternal nutrition among humans contributes to growth retardation, but not to malformations. The production of "abnormal" maternal antibodies, such as are present in Rh incompatibility, can cause fetal wastage. An important maternal factor in humans is uteroplacental insufficiency, which can occur in normal states like twinning, as well as in abnormal conditions including reduced placental size, chronic maternal hypoxia, or uterine ischemia. Although all these maternal factors can contribute to developmental toxicity, they do not necessarily occur as isolated events. Some developmental toxicants exert deleterious effects within both the embryo and the maternal system.

Placentas in pregnancies complicated by maternal diabetes.

PDMs tend to be large and the size is generally in proportion to fetal size. Infarcts are both more numerous and more common in PDMs than in normal placentas. These reflect the in utero hypoxia found in IDMs. Placental infarcts are increased not only in cases of severe DM (classes D, F-R) but also mild and early DM (class A). We infer from this that maternal vascular disease may be present functionally long before pathologic changes can be detected by direct examination of vessels. More subtle evidence of hypoxia in PDMs, such as an increased number of syncytial knots, has been suggested by qualitative data but has not been confirmed by morphometric analysis. Other qualitative observations in PDMs include thickened basement membranes, flattened microvilli on trophoblasts, ectasia of capillaries and villous stromal edema; changes in intracellular organelles and structures include enlarged mitochondria, increased pinocytotic vesicles, and dilated profiles of endoplasmic reticulum. Quantitative morphometric analysis shows no differences between normal placentas and PDMs with regard to these changes. The transport and secretory functions of the placenta, especially important in pregnancy complicated by DM, are not addressed here. As our understanding of placental physiology enlarges, it will be useful to relate each function with its structural counterpart. Perhaps this review will in part provide rational data from which to proceed with the task.

Amniotic fluid lecithin/sphingomyelin ratio in complicated pregnancies

Amniotic fluid (AF) lecithin/sphingomyelin (L/S) ratios were obtained in 223 pregnancies. Gestations complicated by maternal diabetes (71), vascular disease (50), and fetal growth retardation (47) were included. Elevated L/S ratios at 34 to 36 weeks' gestation were observed to accompany maternal vascular disease; higher ratios were also related to fetal sex (female) and race (black). Declining L/S ratios were observed in 14 of 35 diabetic patients studied serially (40 per cent) and were accompanied by increased perinatal morbidity and deaths. These data suggest an urgent need for further studies concerning the clinical usefulness of a serial decline in the L/S ratio as a predictor of fetal compromise.

Amniotic fluid creatinine in pregnancies complicated by diabetes

Amniotic fluid (AF) creatinine concentrations, determined in 353 samples from 167 pregnancies complicated by maternal diabetes, are similar to those found at comparable gestation in uncomplicated pregnancy. Added maternal vascular disease significantly raises AF creatinine to such a degree that overestimation of fetal (renal) maturity is a clinical hazard if based solely on this parameter. Relative concentrations of creatinine in AF and maternal plasma (AF/MP ratio) are related to gestational age. Failure of AF creatinine to rise consistently on successive serial samples accompanies an increased risk of perinatal death in the pregnancy complicated by diabetes, four of five deaths in the present series following declines in this measurement.