Placental villus morphology in relation to maternal hypoxia at high altitude.

Pregnancy at high altitude is associated with maternal hypoxaemic hypoxia with resultant intervillus blood hypoxia. Maternal haemoglobin concentration and blood gases were measured in pregnant women in two cities in Peru; Lima at sea level (n=18) and Cerro de Pasco at 4300 metres above sea level (n=12). Following delivery, placental sections from both groups were examined histomorphometrically using an image analysis system. Villus diameter, villus cross-sectional area, capillary diameter, capillary cross-sectional area and the percentage of villus cross-sectional area occupied by villus capillaries were calculated and parameters were compared between the two altitude groups. Maternal haemoglobin concentration and maternal blood pH were significantly higher, and maternal pO(2), pCO(2)and O(2)saturation were significantly lower in the high altitude group compared to those at sea level. The villus vessel area as a percentage of villus cross-sectional area and capillary diameter were significantly greater in the cases from the high altitude group and villus vessel area as a percentage of the villus cross-sectional area was significantly related to maternal pO(2)(r=-0.7, P=0.01), and maternal pCO(2)(r=0.7, P=0.02), but multiple regression analysis demonstrated that only pO(2)remained significantly independently associated with these villus histological findings (P=0.03). Placental terminal villi from term pregnancies at high altitude show different morphological features from pregnancies at sea level, and these changes are primarily related to maternal pO(2). The predominant morphological alteration is an increase in villus capillary diameter and therefore of the proportion of villus cross-sectional area occupied by capillary lumens.     

Placental anatomy and diffusing capacity in guinea pigs following long-term maternal hypoxia

To determine the relation of placental structure to placental diffusing capacity (DPCO), we exposed Hartley guinea pigs to 12 or 14 per cent O2 from day 15 of gestation to near term (64 days). At that time we measured DPCO and fetal body and placental weights. In addition, we used stereological techniques to measure placental parameters important to diffusing capacity. We also used a mathematical model with results from the stereological measurements to predict the diffusing capacity. In the first hypoxic group (E1), measured DPCO decreased 10.1 +/- 3.7 per cent, while that predicted was 2.4 per cent less than control. Total vascular volume decreased 6.6 +/- 3.6 per cent, while tissue volume and mean diffusion distance increased 10.2 +/- 5.6 per cent and 12.9 +/- 7.0 per cent, respectively. In the pair-fed animals, measured DPCO decreased 22.6 +/- 4.6 per cent, while that predicted was 20.0 per cent less than control. There were no significant stereological differences in this group. In the second (E2) hypoxic group, measured DPCO increased 27.2 +/- 7.4 per cent, while that predicted increased 38.2 per cent. For this same group, total vascular volume increased 11.7 +/- 3.0 per cent, and tissue volume and mean diffusion distance decreased 18.2 +/- 4.6 per cent and 17.8 +/- 3.8 per cent, respectively. These results demonstrate the dependence of placental diffusing capacity upon placental structure.     

Role of prostaglandins in the metabolic responses of the fetus to hypoxia.

OBJECTIVE: The effect of inhibiting prostaglandin synthesis on the fetal metabolic response to hypoxemia was examined by infusing indomethacin during periods of reduced maternal uterine blood flow. STUDY DESIGN: In seven fetal sheep we administered a 6-hour infusion of either indomethacin (n = 5), indomethacin plus prostaglandin E2, or a vehicle solution (n = 5). The last 4 hours of each infusion period coincided with a period of fetal hypoxemia induced by reduced maternal uterine blood flow. RESULTS: During reduced maternal uterine blood flow indomethacin infusions caused a significantly greater reduction in pHA (reduced from 7.36 +/- 0.01 to 7.10 +/- 0.02) than both the vehicle (from 7.36 +/- 0.01 to 7.20 +/- 0.03) and indomethacin plus prostaglandin E2 infusions (from 7.36 +/- 0.01 to 7.18 +/- 0.02). Before reduced maternal uterine blood flow was induced, indomethacin significantly elevated fetal plasma glucose and lactate concentrations from 0.6 +/- 0.04 and 2.2 +/- 0.1 to 1.3 +/- 0.2 and 6.7 +/- 0.7 mmol/L, respectively. During reduced maternal uterine blood flow indomethacin caused a significantly greater increase in plasma glucose and lactate concentrations than the vehicle; plasma glucose and lactate concentrations increased to a maximum of 1.8 +/- 0.2 and 22.7 +/- 0.8 mmol/L, respectively, during indomethacin infusions compared with 1.1 +/- 0.1 and 15.7 +/- 1.7 mmol/L, respectively, during vehicle infusions. The addition of prostaglandin E2 to the indomethacin infusion prevented the enhanced increase in glucose and lactate concentrations during reduced maternal uterine blood flow and caused a significant increase in fetal plasma insulin concentrations from 12.6 +/- 0.7 to 60.9 +/- 28.1 microU/ml. CONCLUSION: The inhibition of prostaglandin synthesis during fetal hypoxemia alters the metabolic response of the fetus, leading to a severe metabolic acidosis.     

Hyperthermia prevents metabolic and cerebral flow responses to hypoxia in the fetal sheep

OBJECTIVE: Fetal brain temperature has been found to decrease during hypoxia, strongly suggesting a reduction in cerebral O2 consumption and increases in cerebral blood flow. These responses may protect the brain in part against hypoxic injury. This study was undertaken to examine whether these compensatory mechanisms are lost during fetal hyperthermia. METHODS: Intermittent fetal hypoxemia was induced by administering low-O2 gas mixtures to nine near-term ewes. Fetal brain and body core temperature responses were measured with and without fetal hyperthermia induced by circulating warm water through a plastic coil looped about the fetus in utero. RESULTS: In normothermic fetuses, fetal brain temperature relative to core decreased during a 30-minute period of hypoxia and then returned to normal during recovery. This response may be explained by a combination of cerebral hypometabolism and increased cerebral blood flow. However, in hyperthermic fetuses (intrauterine warming for 1 hour, raising body core and brain temperatures 0.66 +/- 0.06 and 0.61 +/- 0.10 C, respectively) a subsequent period of hypoxia no longer induced a reduction in brain temperature relative to body core. CONCLUSION: When temperature of the fetal sheep is elevated, as may occur with maternal fever, prolonged exercise, and elevated environmental temperatures, the fetal brain is less well protected against hypoxic injury.     

Relationship of maternal placental blood flow to the placental clearance of maternal plasma dehydroisoandrosterone sulfate through placental estradiol formation

We have suggested that the placental clearance of maternal plasma dehydroisoandrosterone sulfate (DS) through estradiol (E2) formation (PC-DSE2) is reflective of uteroplacental blood flow (F). Clewell and Meschia13 suggested that PC-DSE2 is related to F as follows: Cobs = F(1-e-C/F), where Cobs = PC-DSE2 and C = total placental clearance of maternal plasma DS. This equation contains two unknown quantities, F and C. To solve the equation, Clewell and Meschia assumed that C was constant. Using 19.7 ml/min for C, they allowed PC-DSE2 to vary widely and computed F. Upon finding that F was unrealistically low for some values of PC-DSE2, they concluded that reductions in PC-DSE2 do not reflect alterations in uteroplacental blood flow. In the analysis of the relationship of F to PC-DSE2, it is important to know the value of C. Since the direct measurement of C is not possible at this time, we have evaluated C by measuring the difference between the metabolic clearance rate of DS (MCR-DS) prior to and immediately following delivery. Any change in MCR-DS before and after delivery should be a reflection of the amount of maternal plasma DS cleared by the placenta through all metabolic routes including PC-DSE2, providing nonplacental clearances of maternal plasma DS before and immediately after delivery are the same. We measured MCR-DS and PC-DSE2 in 15 pregnant women within 5 days before delivery and repeated the MCR-DS measurement in these women beginning 90 minutes after delivery. Among these 15 women, C ranged from a low of 4.7 ml/min in a woman with severe pre-eclampsia to a high of 28.5 ml/min in a woman with twins. In addition to the finding that C varied widely, it was also ascertained that PC-DSE2 was positively correlated with C (r = 0.908; p less than 0.001). The finding that low or high values for PC-DSE2, observed in complicated pregnancies, were associated with similar changes in C is suggestive that a change in PC-DSE2 is reflective of a change in uteroplacental blood flow.     

The effects of maternal nutrition and body condition on placental and foetal growth in the ewe

This study investigated the effects of maternal body condition and nutrition on placental and foetal growth in mid-gestation. Welsh Mountain ewes (n=24) of body condition 3.5 (high, H) and 2.0 (low, L) at mating, were fed either 100 per cent or 70 per cent of their daily maintenance requirements from day 22 of gestation, yielding four groups: H100 (n=5), H70 (n=6), L100 (n=7) and L70 (n=6). On day 65, placental and foetal parameters were measured. Whilst the placentome number tended to be lower in L than H ewes, the mean placentome weight was significantly greater in L100 than H100 animals. Nutritionally related changes in IGFBP expression within the placentome and intercotyledonary endometrium may explain these findings, with IGFBP-3 expression in the luminal epithelium and caruncular stroma of the placentome villi being inversely correlated to placentome number and the total placentome weight respectively. The foetal CRL was shorter and the ponderal index greater in L than H ewes. The foetal CRL was positively correlated to maternal IGF-I concentrations and the placentome number, although the foetal weight remained unaltered by treatment. This study therefore demonstrates that body condition and ration can alter foetal and placental growth, perhaps by modifying systemic parameters and uterine IGF expression.     

The response of the foetal lamb to maternal lymphocytes

Foetal lambs were inoculated with either maternal or third-party lymphocytes. Of foetuses transfused in the first half of pregnancy (from 49 to 73 days), one quarter survived until the fifth month. Examination of the immunological reactivity of these survivors revealed that all rejected skin grafts from the lymphocyte donors and manifested normal mixed lymphocyte reactivity. In two instances, responsiveness of the transfused lambs to normal lymphocyte transfer was reduced. Foetal lambs transfused with large numbers of maternal lymphocytes in the last third of pregnancy could survive provided the donor ewe had not been sensitized against foetal or paternal determinants. Following intravenous challenge with maternal lymphocytes, cells collected over a prolonged period from the thoracic duct of the foetal recipient exhibited depression of anti-maternal reactivity in mixed lymphocyte culture.     

Review: Nutrient sulfate supply from mother to fetus: Placental adaptive responses during human and animal gestation

Nutrient sulfate has numerous roles in mammalian physiology and is essential for healthy fetal growth and development. The fetus has limited capacity to generate sulfate and relies on sulfate supplied from the maternal circulation via placental sulfate transporters. The placenta also has a high sulfate requirement for numerous molecular and cellular functions, including sulfate conjugation (sulfonation) to estrogen and thyroid hormone which leads to their inactivation. Accordingly, the ratio of sulfonated (inactive) to unconjugated (active) hormones modulates endocrine function in fetal, placental and maternal tissues. During pregnancy, there is a marked increase in the expression of genes involved in transport and generation of sulfate in the mouse placenta, in line with increasing fetal and placental demands for sulfate. The maternal circulation also provides a vital reservoir of sulfate for the placenta and fetus, with maternal circulating sulfate levels increasing by 2-fold from mid-gestation. However, despite evidence from animal studies showing the requirement of maternal sulfate supply for placental and fetal physiology, there are no routine clinical measurements of sulfate or consideration of dietary sulfate intake in pregnant women. This is also relevant to certain xenobiotics or pharmacological drugs which when taken by the mother use significant quantities of circulating sulfate for detoxification and clearance, and thereby have the potential to decrease sulfonation capacity in the placenta and fetus. This article will review the physiological adaptations of the placenta for maintaining sulfate homeostasis in the fetus and placenta, with a focus on pathophysiological outcomes in animal models of disturbed sulfate homeostasis.     

A comparative study of placental transmission of foetal erythrocyte in maternal circulation between spontaneous abortion and pregnancy termination cases

100 cases of abortion, 45 cases of incomplete abortion, 15 cases of complete abortion, and 40 cases of pregnancy termination under 12 weeks, were studied in a comparison of placental transmission of fetal erythrocytes in maternal circulation under these conditions. Positive control smears (fresh cord blood of newborn babies) and negative control smears (adult males). The results of this study show that the incidence of transplacental hemorrhage is higher in abortion cases, whether spontaneous or induced, as compared with normal pregnancy and labor. 20% of cases where duration of pregnancy was more than 8 weeks needed 2nd curettage within 15 days of termination. Of these transplacental hemorrhage was found to be 100%. This is highly significant for Rh negative females.     

Fetal adaptive responses to asphyxia

The fetal environment is thus well suited for normal growth and development with oxygen availability exceeding oxidative needs. With impairments in blood gas exchange this excess oxygen acts as a "margin of safety," providing for the maintenance of oxidative metabolism through increases in fractional O2 extraction, although with resultant fetal hypoxemia. Increases in blood O2 capacity and redistribution of cardiac output in response to this hypoxemia further protect fetal oxygenation. Additional adaptive mechanisms involve a decrease in energy-consuming processes, including growth restriction, decreasing fetal movements, and behavioral state alterations. Although protective in so far as essential metabolic functions are maintained, pathologic change may occur as the "oxygen margin of safety" becomes limited or energy-conserving measures give rise to abnormal growth and development.     

Maternal ovine placental vascular responses to adenosine

We have examined the effect of adenosine given via retrograde uterine artery catheter at 25 mg/min to nine chronically catheterized near-term sheep pretreated with angiotensin II, 5 micrograms/min, via the jugular vein. Blood flows were measured by the microsphere technique. Flows were measured at rest, after 10 minutes of angiotensin II infusion, and after 1.5 minute of adenosine infusion. Blood pressure increased with angiotensin II infusion from 101 +/- 2.63 to 130 +/- 4.33 mm Hg (p less than 0.05) and then remained unchanged with local adenosine infusion at 129 +/- 4.33 mm Hg (NS). Organ resistances were: Tissue Control Angiotensin II Adenosine Uterine resistance/gm 299 +/- 0.04 767 +/- 83 (p less than 0.05) 355 +/- 37.7 (p less than 0.05) Cotyledonary resistance/gm 37.9 +/- 4.83 48.1 +/- 4.93 (p less than 0.05) 50.10 +/- 5.27 (p less than 0.05) The experimental uterine tissue resistance increased with angiotensin II and showed vasodilation in response to adenosine. The cotyledonary resistance increased with angiotensin II infusion but showed no change in response to adenosine. The maternal-placental response was anomalous. Angiotensin II-induced maternal-placental vasoconstriction cannot be opposed by the exogenous administration of adenosine.     

Placental vascular responses to nicardipine in the hypertensive ewe

Calcium channel blockers are arterial vasodilators effective in the treatment of hypertension. Therefore nicardipine, a dihydropyridine calcium channel blocker, should modulate angiotensin II-induced vasoconstriction. Regional blood flows were measured with radioactive microspheres in five chronically catheterized near-term ewes both before and 15 minutes after maternal infusion of angiotensin II at 5 micrograms/min. Nicardipine was then administered intravenously at 20 micrograms/kg/min over 2 minutes while the angiotensin II infusion was maintained. Blood flows were measured after 5 minutes. Maternal blood pressure levels were increased by angiotensin II from 83 +/- 4 mm Hg to 114 +/- 5 mm Hg, and were decreased to 70 +/- 4 mm Hg by nicardipine (p less than 0.05). Nicardipine also reversed angiotensin II-induced vasoconstriction in the renal and endomyometrial vascular beds (p less than 0.05). Unexpectedly, however, nicardipine worsened placental vasoconstriction caused by angiotensin II, as placental blood flow fell from 242 +/- 32 ml.min-1.kg-1 fetal weight to 128 +/- 7 ml.min-1.kg-1 fetal weight (p less than 0.05), and placental resistance increased from 0.48 +/- 0.04 mm Hg.ml-1.min.kg-1 fetal weight to 0.55 +/- 0.05 mm Hg.ml-1.min.kg-1 fetal weight (p less than 0.05). Nicardipine reverses angiotensin II-induced vasoconstriction systemically and in the kidney and uterus of the pregnant ewe, but does not reverse placental vasoconstriction and may significantly alter fetal cardiorespiratory status.     

The effects of gestational age and maternal hypoxia on the placental renin angiotensin system in the mouse

IntroductionThe renin angiotensin system (RAS) is an important mediator of placental development. However, a comprehensive expression profile for 8 key components of the placental RAS throughout murine gestation has not been performed. Furthermore, maternal hypoxia induces dysregulation of RAS expression in fetal tissues but the effects on the murine placental RAS are less well known.MethodsPlacentas were collected from male and female CD1 mouse fetuses at seven gestational ages for qPCR analysis of Agt, Ren1, Atp6ap2, Ace, Ace2, Agtr1a, Agtr2 and Mas1. mRNA localisation of Agtr1 and Mas1 and protein localisation of ACE and ACE2 was determined at E18.5. To determine the effects of maternal hypoxia on the placental RAS, mice were housed in 12% oxygen from E14.5–E18.5 and placentas examined at E18.5.ResultsAll RAS genes were expressed in the placenta throughout pregnancy and expression varied with fetal sex and age. Agtr1 was expressed within the labyrinth while Mas1 was expressed within the intraplacental yolk sac. ACE and ACE2 were localised to both labyrinth and junctional zones. In response to maternal hypoxia the expression of Agt, Ace and Ace2 was decreased but expression of Agtr1a was increased. Ace and Agtr1a mRNA levels were affected to a greater extent in females compared to males.DiscussionCollectively, the location within the placenta as well as the expression profiles identified, support a role for the placental RAS in labyrinth development. The placental RAS is disturbed by maternal hypoxia in a sexually dimorphic manner and may contribute to impairment of placental vascular development.