Joanne Hempstock

Onset of Maternal Arterial Blood Flow and Placental Oxidative Stress : A Possible Factor in Human Early Pregnancy Failure

The aim was to measure changes in the oxygen tension within the human placenta associated with onset of the maternal arterial circulation at the end of the first trimester of pregnancy, and the impact on placental tissues. Using a multiparameter probe we established that the oxygen tension rises steeply from <20 mmHg at 8 weeks of gestation to >50 mmHg at 12 weeks. This rise coincides with morphological changes in the uterine arteries that allow free flow of maternal blood into the placenta, and is associated with increases in the mRNA concentrations and activities of the antioxidant enzymes catalase, glutathione peroxidase, and manganese and copper/zinc superoxide dismutase within placental tissues. Between 8 to 9 weeks there is a sharp peak of expression of the inducible form of heat shock protein 70, formation of nitrotyrosine residues, and derangement of the mitochondrial cristae within the syncytiotrophoblast. We conclude that a burst of oxidative stress occurs in the normal placenta as the maternal circulation is established. We speculate that this may serve a physiological role in stimulating normal placental differentiation, but may also be a factor in the pathogenesis of pre-eclampsia and early pregnancy failure if antioxidant defenses are depleted.

Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies

Onset of the maternal-placental circulation was studied by Doppler ultrasonography in 65 pairs of age-matched normal and abnormal pregnancies. In normal pregnancies intervillous blood flow increased with gestational age, being detected in 9 of 25 cases at 8 to 9 weeks but in 18 of 20 at 12 to 13 weeks (P = 0.001). By contrast, in abnormal pregnancies flow was detected in nearly all cases (22 of 25) at 8 to 9 weeks (P < 0.001). In addition, regional differences were observed between the groups. Early flow was restricted to the peripheral regions of most normal placentas (P < 0.001), whereas in missed miscarriages it was most common in central regions or throughout the placenta (P < 0.05 and P < 0.001, respectively). Immunoreactivity for heat shock protein 70 and nitrotyrosine residues was greater in samples from peripheral than from central regions of normal placentas (P = 0.028 and P = 0.019, respectively), and from missed miscarriages compared to controls (P = 0.005 and P = 0.001, respectively). Our results indicate that oxidative damage to the trophoblast, induced by premature and widespread onset of the maternal placental circulation secondary to shallow trophoblast invasion, is a key factor in early pregnancy loss. High oxygen concentrations in the periphery of normal early placentas may similarly induce local regression of the villi, leading to formation of the chorion laeve.

Oxygen, early embryonic metabolism and free radical-mediated embryopathies

Free radicals, once the preserve of chemists, are now recognized as playing a central role in many biological systems. They are formed as an inevitable by-product of aerobic respiration and various cytoplasmic processes at a rate dependent upon the prevailing oxygen tension. At physiological concentrations, oxygen and nitrogen free radical species play key roles in intracellular signalling, regulating many homeostatic mechanisms and mediating stress responses. If concentrations exceed cellular defences, however, then indiscriminate damage may occur to lipids, proteins and DNA. Cell function may be perturbed, and in the most severe cases apoptosis may result. Although there are significant species differences, many aspects of early mammalian development, from fertilization through to differentiation of the principal organ systems, take place in vivo in a low oxygen environment. This may serve to protect the embryo from free radical damage, for exposure of early embryos to ambient oxygen concentrations or the products of maternal metabolic disorders is often associated with reduced viability and an increased rate of congenital malformations. Administration of free radical scavengers, including vitamins C and E, can mitigate many of these effects, indicating the importance of a balanced maternal diet to successful reproduction.

Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy: A morphological and immunohistochemical study

BackgroundThe maternal circulation to the human placenta is not fully established until 10–12 weeks of pregnancy. During the first trimester the intervillous space is filled by a clear fluid, in part derived from secretions from the endometrial glands via openings in the basal plate. The aim was to determine the activity of the glands throughout the first trimester, and to identify components of the secretions.MethodsSamples of human decidua basalis from 5–14 weeks gestational age were examined by transmission electron microscopy and immunohistochemically. An archival collection of placenta-in-situ samples was also reviewed.ResultsThe thickness of the endometrium beneath the implantation site reduced from approximately 5 mm at 6 weeks to 1 mm at 14 weeks of gestation. The glandular epithelium also transformed from tall columnar cells, packed with secretory organelles, to a low cuboidal layer over this period. The lumens of the glands were always filled with precipitated secretions, and communications with the intervillous space could be traced until at least 10 weeks. The glandular epithelium reacted strongly for leukaemia inhibitory factor, vascular endothelial growth factor, epidermal growth factor, transforming growth factor beta, alpha tocopherol transfer protein, MUC-1 and glycodelin, and weakly for lactoferrin. As gestation advanced uterine natural killer cells became closely approximated to the basal surface of the epithelium. These cells were also immunopositive for epidermal growth factor.ConclusionsMorphologically the endometrial glands are best developed and most active during early human pregnancy. The glands gradually regress over the first trimester, but still communicate with the intervillous space until at least 10 weeks. Hence, they could provide an important source of nutrients, growth factors and cytokines for the feto-placental unit. The endometrium may therefore play a greater role in regulating placental growth and differentiation post-implantation than previously appreciated.

Comparison of ultrasonographic and Doppler mapping of the intervillous circulation in normal and abnormal early pregnancies

OBJECTIVE To assess the value of ultrasonography and Doppler imaging in characterizing the intervillous circulation in normal and abnormal early pregnancy. DESIGN Cross-sectional study. SETTING Tertiary care academic hospital. PATIENT(S) Eighty-five normal pregnancies and 125 missed miscarriages at 7 to 13 weeks of gestation. INTERVENTION(S) Grey-scale ultrasonography was used to evaluate the placental anatomy and detect moving echoes inside the intervillous space, and color power Doppler imaging was used to detect continuous venous-like flow in the placental tissue. MAIN OUTCOME MEASURE(S) Degree of agreement between two investigators for use of grey-scale imaging, comparison of detection of moving echoes in normal and abnormal pregnancies, and comparison of detection of intervillous circulation with grey-scale and color Doppler imaging in abnormal pregnancies. RESULT(S) The overall degree of agreement between the two investigators was good. A significantly different distribution of blood flow was found between normal and abnormal pregnancies at 7 to 9 weeks and 10 to 11 weeks but not at 12 to 13 weeks. Intervillous moving echoes were detected by grey-scale imaging significantly more frequently than an intervillous blood flow was detected with color Doppler imaging. CONCLUSION(S) In early pregnancy failure, there is a premature and diffuse onset of intervillous blood flow that can be detected by grey-scale imaging. This abnormal blood flow pattern may increase the oxidative stress on the early placental tissue and subsequently impair placental development.

Relationship among maternal serum endocrinology, placental karyotype, and intervillous circulation in early pregnancy failure.

OBJECTIVE To evaluate the relationship among maternal serum endocrinology, placental karyotype, and intervillous blood flow in missed miscarriage. DESIGN Cross-sectional study of maternal serum, transvaginal ultrasound/Doppler, and placental cytogenetic and immunohistochemical investigations. SETTING Tertiary care academic hospital. PATIENT(S) One hundred fifty-two women with missed miscarriage between 7 and 13 weeks of gestation. INTERVENTION(S) Ultrasound features, placental intervillous circulation findings on color Doppler imaging, and maternal serum level of alpha-fetoprotein (AFP), beta-hCG, E(2), P, and inhibin A were compared retrospectively with placenta karyotype and hCG immunochemistry. MAIN OUTCOME MEASURES Data were analyzed according to karyotype results, presence or absence of an intervillous circulation, and delay between fetal demise and evacuation. RESULT(S) The presence of intervillous blood flow and serum concentrations of the different hormones were independent of placental karyotype. Serum beta-hCG and P were significantly higher in cases with intervillous blood flow. No difference in immunostaining for beta-hCG was found between placental tissues from normal pregnancies and missed miscarriages, but significantly higher villous beta-hCG content was found on Western blotting in miscarriage with a recent fetal demise. CONCLUSION(S) The excessive entry of maternal blood inside the placenta in the early stage of most miscarriages is unrelated to conceptus karyotype, and hCG features may reflect a temporary attempt of the trophoblast to stabilize after the initial oxidative insult.