Hypoxia blocks 11beta-hydroxysteroid dehydrogenase type 2 induction in human trophoblast cells during differentiation by a time-dependent mechanism that involves both translation and transcription.

The present study was undertaken to determine (1) if hypoxia-induced down-regulation of placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2; encoded by HSD11B2 gene) activity and protein in human trophoblast cells during in vitro differentiation was mediated at the level of HSD11B2 gene transcription; and (2) whether the reduced placental 11beta-HSD2 in pregnancies complicated with fetal growth restriction (FGR) was a consequence of intrinsic abnormalities in trophoblast cells. Trophoblast cells were isolated from uncomplicated pregnancies and those complicated with FGR at term, and cultured for up to 72 h under normoxic (20% oxygen) or hypoxic (1% oxygen) conditions. Under normoxia, 11beta-HSD2 activity and protein increased progressively over the 72 h culture period, which was accompanied by a corresponding rise in 11beta-HSD2 mRNA. As demonstrated previously, hypoxia blocked the increase in levels of both 11beta-HSD2 activity and protein within the first 24h. In contrast, although hypoxia also prevented the rise in 11beta-HSD2 mRNA, it did not do so until 48 h. This time-dependent effect of hypoxia on placental 11beta-HSD2 activity/protein and mRNA suggests a dual mechanism of action whereby hypoxia may induce a rapid down-regulation of 11beta-HSD2 protein synthesis, which occurs initially at the level of translation, and later extends to the level of transcription. Indeed, transient transfection studies demonstrated that hypoxia diminished HSD11B2 promoter activity. When trophoblast cells isolated from FGR placentas were cultured and allowed to differentiate under the same conditions, they not only exhibited a similar pattern of 11beta-HSD2 activity and mRNA expression but also responded to hypoxia similarly to those from normal placentas. This suggests that the reduced placental 11beta-HSD2 in FGR is not due to intrinsic abnormalities in trophoblast cells, but likely a result of extrinsic factors associated with FGR.

Reducing agent and tunicamycin-responsive protein (RTP) mRNA expression in the placentae of normal and pre-eclamptic women.

Recently, the gene encoding a new stress-induced protein termed reducing agent and tunicamycin-responsive protein (RTP) was identified. The function of RTP is unknown, however, the strong upregulation of RTP during cellular differentiation, and exposure to stress conditions including hypoxia suggests a specific role for RTP in these processes. In pre-eclampsia, impaired spiral artery remodelling and reduced perfusion may reduce oxygen tension in the placenta and thereby alter trophoblast differentiation and function. We therefore hypothesized that the expression of RTP mRNA is altered in the placentae of women with pre-eclampsia. The aims of this study were to determine the regional distribution and cellular localization of RTP mRNA expression and compare mRNA abundance in different regions of normotensive control and pre-eclamptic placentae. In normal and pre-eclamptic placentae, RTP mRNA was expressed in the syncytiotrophoblasts and in the intermediate trophoblasts of the basal plate. In early onset pre-eclampsia, RTP mRNA was more abundant in the chorionic villi regions. A further increase was localized to the syncytial knots and to the trophoblasts in the peri-infarct regions. The increased RTP expression may reflect lower oxygen tension and/or other stress stimuli in the placenta in pre-eclampsia.

Adrenomedullin messenger ribonucleic acid expression in the placentae of normal and preeclamptic pregnancies.

In pathological pregnancies, alterations in circulating maternal and fetal adrenomedullin (ADM) concentrations may mediate compensatory vascular responses in the fetal or placental circulation. To address whether ADM is a potential paracrine vasoactive factor within the placenta, the regional distribution and cellular localization of ADM mRNA expression were determined by Northern blot and in situ hybridization of different regions of the placenta and fetal membranes from pregnancies complicated by severe preeclampsia [<28 wk (n = 7) and >28 wk (n = 13)] and from normotensive pregnancies [<28 wk (n = 6) and >28 wk (n = 15)]. Northern blotting revealed that ADM mRNA (1.3 kb) was expressed in chorionic villi and basal plate regions, but was most abundantly expressed in the choriodecidua. By in situ hybridization, ADM mRNA was localized to the syncytiotrophoblasts and the extravillous cytotrophoblasts in the basal plate and choriodecidua regions. ADM mRNA expression was increased in the choriodecidua, syncytial knots, and cytotrophoblasts in peri-infarct regions in preeclampsia. In chorionic villous explant studies maintained at reduced oxygen tension, ADM mRNA abundance was increased at 12, 24, and 48 h. ADM mRNA expressed in syncytiotrophoblasts and cytotrophoblasts in the basal plate decidua and choriodecidua may contribute to the maternal and fetal plasma levels. In preeclampsia, regional increases in ADM mRNA may be induced by hypoxia and mediate local fetal/placental adaptive responses to reduced placental perfusion.

The regional expression of insulin-like growth factor II (IGF-II) and insulin-like growth factor binding protein-1 (IGFBP-1) in the placentae of women with pre-eclampsia.

Insulin-like growth factors and their binding proteins regulate cellular proliferation, differentiation and function, and play an important role in placental development. IGF-II and IGFBP-1 are abundantly expressed by cells at the maternal-fetal interface and mediate cell-to-cell communication between trophoblasts and decidua. Placentae of pre-eclamptic pregnancies show villous cytotrophoblast proliferation, increased syncytial sprout formation and impaired trophoblast invasion. We hypothesized that the expression of IGF-II and IGFBP-1 by cells at the maternal-fetal interface is altered in pre-eclampsia. We determined the regional abundance and cellular localization of IGF-II mRNA and IGFBP-1 mRNA and protein in placentae from normotensive control and pre-eclamptic pregnancies. IGF-II mRNA was expressed in both the chorionic villi and basal plate decidua regions. Increased IGF-II mRNA abundance was observed in the intermediate trophoblasts of peri-infarct regions. IGFBP-1 expression was present only in the decidua of the basal plate and membranes, and this expression was decreased significantly in pre-eclamptic placentae. The increased IGF-II expression in the intermediate trophoblast surrounding placental infarcts suggests a role for IGF-II in placental repair or remodelling. Decreased IGFBP-1 mRNA expression in the basal plate decidua suggests that the increased concentrations of IGFBP-1 the circulation of pre-eclamptic women is not of decidual origin. The altered IGF-II and IGFBP-1 expression at the fetomaternal interface may be important in the pathophysiology of pre-eclampsia.

Obstetrical intervention rates and maternal and neonatal outcomes of women with gestational hypertension.

OBJECTIVE: The purpose of this study was to determine the obstetrical intervention rates and maternal and neonatal outcomes of women with gestational hypertension. STUDY DESIGN: Induction and operative delivery rates and indices of maternal and neonatal morbidity were determined in women (37-41 completed weeks) with gestational hypertension (n = 979), preeclampsia (n = 165), chronic hypertension (n = 187), and control subjects (n = 11,434) in a retrospective review of St. Joseph's Health Care Perinatal Database from November 1, 1995, to October 31, 1999. Data were analyzed by chi-square test, analysis of variance, Dunnett's t -test, and pairwise chi-square tests with Bonferroni correction. RESULTS: The induction and cesarean delivery rates in gestational hypertension were similar to preeclampsia and chronic hypertension groups and almost double of control subjects. The length of labor and postpartum stays and the incidence of operative vaginal delivery, postpartum hemorrhage, and neonatal intensive care involvement were greater in the gestational hypertension group than in the control subjects. CONCLUSION: Women with gestational hypertension had obstetrical intervention rates much higher than control subjects and similar to those with preeclampsia and chronic hypertension.

Conditioned medium from hypoxic cytotrophoblasts alters arterial function.

OBJECTIVE: Our goal was to test the hypothesis that cytotrophoblasts, under low oxygen tension, release substances that affect vascular behavior. STUDY DESIGN: We studied the vascular response to the vasoconstrictors phenylephrine (receptor dependent) and potassium (receptor independent), the relaxation response to methacholine, and the vasomotor behavior of isolated resistance (mesenteric) arteries from early pregnant rats after incubation in conditioned medium from first-trimester cytotrophoblasts, maintained in standard or hypoxic (2%; 14 mm Hg) culture conditions. RESULTS: After incubation in medium from hypoxic cytotrophoblasts, arterial segments were more responsive to phenylephrine and to potassium-induced constriction but were less responsive to methacholine, and the vasomotor activity was increased compared with that found in vessels incubated in control medium. CONCLUSIONS: These changes in vascular behavior are similar to those reported in isolated arteries from women with preeclampsia. These studies provide evidence which suggests that the link between abnormal placentation and maternal vascular abnormality in preeclampsia is the elaboration of vasoactive factors by cytotrophoblasts in response to hypoxia.

Contribution of vasomotion to vascular resistance: a comparison of arteries from virgin and pregnant rats.

Intrinsic oscillatory activity, or vasomotion, within the microcirculation has many potential functions, including modulation of vascular resistance. Alterations in oscillatory activity during pregnancy may contribute to the marked reduction in vascular resistance. The purpose of this study was 1) to mathematically model the oscillatory changes in vessel diameter and determine the effect on vascular resistance and 2) to characterize the vasomotion in resistance arteries of pregnant and nonpregnant (virgin) rats. Mesenteric arteries were isolated from Sprague-Dawley rats and studied in a pressurized arteriograph. Mathematical modeling demonstrated that the resistance in a vessel with vasomotion was greater than that in a static vessel with the same mean radius. During constriction with the alpha1-adrenergic agonist phenylephrine, the amplitude of oscillation was less in the arteries from pregnant rats. We conclude that vasomotor activity may provide a mechanism to regulate vascular resistance and blood flow independent of static changes in arterial diameter. During pregnancy the decrease in vasomotor activity in resistance arteries may contribute to the reduction in peripheral vascular resistance.

Choroid plexus cysts and trisomy 18: risk modification based on maternal age and multiple-marker screening.

Choroid plexus cysts are more common in fetuses with chromosomal aneuploidies, particularly trisomy 18. Although it is accepted that the risk of karyotypic abnormality justifies amniocentesis when associated abnormalities are present, disagreement continues as to the risk of trisomy 18 in a fetus with an isolated choroid plexus cyst. We propose consideration of maternal age and multiple-marker screening for chromosomal aneuploidy in the assessment of risk. Bayesian statistical modeling was used to calculate the risk of trisomy 18 from age-related risk figures for trisomy 18 and the incidence of isolated choroid plexus cysts in fetuses with trisomy 18. The risk was further modified on the basis of the ability of multiple-marker screening to detect fetuses with trisomy 18. From risk estimates calculated across maternal ages 20 to 45 years, the risk of trisomy 18 does not approach that of amniocentesis until a maternal age of > or = 37 years. Therefore in the presence of an isolated choroid plexus cyst and normal multiple-marker screen results amniocentesis is justified only in the patient with advanced maternal age.

Translabial ultrasonography and placenta previa: does measurement of the os-placenta distance predict outcome?

The aim of this study was to assess the value of the measurement of os-placenta distance by translabial ultrasonography in the evaluation of placenta previa. This method was used in 40 women with suspected placenta previa to measure the distance between the placenta and internal cervical os. Sonographic diagnoses were compared to placental location determined at delivery. Translabial ultrasonography proved superior to the transabdominal route in both diagnosis and exclusion of placenta previa. Measurement of the os-placenta distance can be used as an adjunct to clinical assessment to predict the likelihood of safe vaginal delivery in cases of suspected placenta previa.

An aggressive philosophy in controlled ovarian stimulation cycles increases pregnancy rates.

To assess the effect of timing of human chorionic gonadotrophin (HCG) administration in ovarian stimulation cycles, the serum oestradiol concentration and follicle profile were compared with the clinical pregnancy rate in 582 ovarian stimulation-intra-uterine insemination (OS-IUI) cycles and 3917 in-vitro fertilization-embryo transfer (IVF-ET) cycles. The pregnancy rates increased exponentially with increasing oestradiol in both OS-IUI and IVF-ET cycles (R2 = 0.720, P < 0.001) but then decreased in OS-IUI cycles when the oestradiol concentration exceeded 5000 pmol/l (R2 = 0.936, P < 0.004) at HCG administration. In OS-IUI cycles the percentages of cycles with three or more mature follicles (> or = 18 mm diameter) increased up to an oestradiol concentration of 5000 pmol/l then declined, mirroring the pregnancy rate (R2 = 0.900, P = 0.01). The exponential increase in pregnancy rate with increasing oestradiol concentration in IVF-ET cycles suggests that high oestradiol concentration does not have a deleterious effect on endometrial receptivity. The decrease in pregnancy rate in OS-IUI cycles when oestradiol concentration exceeded 5000 pmol/l reflected fewer mature follicles, resulting from premature administration of HCG to avoid severe ovarian hyperstimulation syndrome (OHSS). We recommend that HCG administration be delayed until multiple follicles have reached maturity, and reducing the risk of severe OHSS by converting high risk OS-IUI cycles to IVF-ET, or if funds or facilities are unavailable, transvaginally draining all but four or five mature follicles.