Jorge Carvajal

Preterm labor: placental pathology and clinical correlation.

OBJECTIVE To determine the relevance of ischemia in the incidence of preterm labor. A second objective was to document perinatal outcomes for patients with preterm labor classified according to its clinical, functional, and pathologic characteristics (infectious, ischemic, mixed, or idiopathic). METHODS Perinatal outcomes were evaluated for 145 consecutive patients with preterm labor, subdivided into etiologic categories according to clinical, functional (Doppler), and morphologic (placental pathology) characteristics. A group of 44 normal pregnancies delivered at term served as controls. RESULTS Of the preterm labor group, 28.3% were classified as ischemic, compared with 4.5% of the control group (odds ratio and 95% confidence interval = 8.28 [1.8, 51.8]; P < .05). Compared with the control group, the preterm labor patients who delivered preterm had higher rates of ischemia (31.4% compared with 4.5%; P < .05) and infection (16.1% compared with 2.3%; P < .05). Among the preterm labor group, patients classified in the infectious or ischemic subgroups had a higher rate of preterm delivery (95.0% and 90.2% compared with 73.2%; P < .05), admission to the neonatal intensive care unit (75.0% and 61.0% compared with 40.0%; P < .05), and newborn weight under 1500 g (35.0% and 19.5% compared with 3.7%; P < .05) than the idiopathic subgroup. CONCLUSION Preterm labor resulting from infection or ischemia is associated with a higher perinatal complication rate than idiopathic preterm labor.

Bile acids increase response and expression of human myometrial oxytocin receptor.

OBJECTIVE We tested the hypothesis that during intrahepatic cholestasis of pregnancy bile acids activate the myometrial oxytocin receptor pathway. STUDY DESIGN Myometrial sensitivity to oxytocin and oxytocin-receptor messenger RNA and protein level was investigated. The ability of cholic acid to mediate such changes was evaluated. RESULTS Cholestasis patients required lesser oxytocin to elicit four uterine contractions in 10 minutes (1.3+/-0.6 vs 3.6+/-0.8 U, P<.05, n=7) and had lower in vitro ED(50) (1.6 x 10(-10) mol/L vs 1.0 x 10(-8) mol/L, P<.05, n=7) than controls. The 24-hour incubation of control myometrial strips (n=7) with cholic acid (20 micromol/L) increased oxytocin sensitivity. Incubation of cultured myometrial cells (n=5) with cholic acid increased oxytocin-receptor expression (messenger RNA and protein). CONCLUSION We demonstrate that during intrahepatic cholestasis of pregnancy, an activation of the oxytocin receptor pathway occurs. This event seems to be the result of a cholic acid-mediated increase in oxytocin-receptor expression.

Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase

Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose‐ and time‐dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase‐8 and ‐9; BID cleavage, cytochrome C release and PARP cleavage. Statin‐sensitive cancers expressed high levels of HMG‐CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG‐CoA reductase since mevalonate pre‐incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG‐CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

Intrahepatic cholestasis of pregnancy: an intriguing pregnancy-specific disorder.

Objective: To review animal and human data available regarding the etiology, maternal and fetal impact, and treatment of intrahepatic cholestasis of pregnancy (ICP). Methods: Pertinent studies on human and animal models of ICP were selected through a MEDLINE database search, focusing on etiology and clinical impact of the disease. Analytic and descriptive studies were included, and the data were analyzed looking for crude numbers. Results: Intrahepatic cholestasis of pregnancy is a pregnancy-specific disorder. Its prevalence is higher in Chile and Sweden compared with any other population. Its etiology is largely unknown, although endocrine, genetic, and environmental factors have been postulated as responsible for the appearance of the disease. Maternal effects of ICP are mild; however, there is a clear association between ICP and poor perinatal outcome, including a higher frequency of fetal distress, preterm labor and delivery, and unexplained fetal death. The treatment is mainly symptomatic. Recent data suggest that oral use of ursodeoxycholic acid improves maternal condition and might prevent the fetal complications of ICP. Conclusions: Intrahepatic cholestasis of pregnancy should be considered a high-risk condition, and careful fetal assessment and appropriate medical intervention might improve perinatal outcome.

2-methoxyestradiol mediates apoptosis through caspase-dependent and independent mechanisms in ovarian cancer cells but not in normal counterparts.

Objective: The estrogen metabolite 2-methoxyestradiol has shown antitumorigenic action in some epithelial tumors. In the present work we investigate its effects in ovarian cancer used alone or in combination with other apoptotic-inducing reagents such as tumor necrosis factor-related apoptosis-inducing ligand. Methods: To assess the effect of 2-methoxyestradiol, dose response and time courses in ovarian cancer and normal cells were conducted. Apoptosis was confirmed through DNA laddering, by flow cytometry, and Western blotting of proteins involved in the apoptotic cascade. Results: 2-Methoxyestradiol induced apoptosis in ovarian cancer cells but not in normal counterparts. 2-Methoxyestradiol activates both the intrinsic and extrinsic apoptotic pathways. 2-Methoxyestradiol—mediated apoptosis involves reactive oxygen species generation and caspase-dependent and caspase-independent mechanisms. We also demonstrate that 2-methoxyestradiol selectively induces an additive/synergistic apoptotic response in ovarian cancer cells when used in combination with tumor necrosis factor-related apoptosis-inducing ligand. Conclusions: 2-Methoxyestradiol, alone or in combination with tumor necrosis factor-related apoptosis-inducing ligand, should be considered as a potential treatment for ovarian cancer.

Brain Natriuretic Peptide (BNP) Produced by the Human Chorioamnion May Mediate Pregnancy Myometrial Quiescence

We aim to demonstrate that Brain Natriuretic Peptide (BNP) is synthesized and released from the fetal membranes and mediates pregnancy myometrial quiescence. Myometrium and fetal membranes (FM) were obtained from term and preterm pregnancies at the time of cesarean section, either in labor or not in labor. BNP was measured in term and preterm FM, in culture cells, and conditioned media. We found BNP (but not ANP or CNP) inhibited contractions of preterm, but not term, human myometrium. BNP (both protein and mRNA) was detected in all tissues, conditioned media and cultured cells. BNP was higher in samples from preterm women not in labor compared to those at term not in labor. BNP concentrations were significantly reduced in women in spontaneous preterm labor. We conclude that locally produced BNP may be involved in generating myometrial quiescence during pregnancy. Further, a premature decrease of BNP production may cause preterm labor.

Mechanisms of Paracrine Regulation by Fetal Membranes of Human Uterine Quiescence

Objective: To test the hypothesis that fetal membranes (chorion or amnion) release one or more factors responsible for myometrial quiescence. Methods: Myometrial samples were excised from women at elective term cesarean delivery prior to the onset of labor. Fetal membranes were obtained after cesarean delivery either before or during labor, and either term (greater than 37 weeks) or preterm (less than or equal to 36 weeks). Myometrial strips were placed in organ baths and contractions stimulated by oxytocin (10-8 M). Contractility was measured under isometric conditions before and after exposure to fetal memranes or conditioned medium. The impact of either memrane or conditioned media on contractility was determined before and after myometrial K+ channel blockade. Results: Both chorion and amnion and their respective conbditioned mediums decrease oxytocin-stimulated myometrial contraction. The inhibitory effect was greatest with membranes from preterm pregnancies (mean gestation 32 weeks, P <.05). The inhibitory effect was detectable in the presence of term labor, but was absent when the fetal membranes were obtained after prterm labor. Iberiotoxin, an inhibitor of large conductance Ca2+-activated K+ channels (BKCa) reduced the effect of fetal membranes by 50% (P <.05). Conclusion: We conclude that human fetal membranes release one or more factors that inhibit oxytocin-induced myometrial contractility. We suggest this factor (or factors) acts mainly by opening myometrial BKCa. The findinigs further support our hypothesis that the fetal membranes release a factor (or factors) that is central to myometrial quiescence and its premature loss leads to preterm delivery.

La edad de la mujer como factor de riesgo de mortalidad materna, fetal, neonatal e infantil

Background: Adolescent pregnancy and advanced maternal age are associated with increased risk for maternal, perinatal and infant death. However, the maternal age with the lowest reproductive risk has not been established. Aim: To determine the range of maternal age with the lowest reproductive risk. Material and methods: A population-based study (2005-2010) was performed analyzing raw data from vital statistics yearbooks of the National Institute of Statistics of Chile. The association of maternal, fetal, neonatal and infant mortality with maternal age was analyzed. The latter was stratified in quinquenniums, between ages 10 and 54 years. Maternal, fetal, neonatal and infant mortality rates were calculated for each quinquennium. The lowest rate was selected as a control group for risk analysis, which was estimated according to Odds Ratio with 95% confidence intervals. Results: Women of 20-29, 25-34 and under 30 years, had the lowest rate of fetal, neonatal/infant and maternal death, respectively. Women aged 45-49 years had the higher rate of maternal, fetal, neonatal and infant mortality. The risk of fetal, neonatal and infant mortality doubled from 40-44 years onwards, and maternal mortality from the age of 30-34 years. Conclusions: Our results suggest that the maternal age range with the lesser general reproductive risk is between 20-29 years. This finding should be considered in future studies of reproductive risk and for an appropriate counseling about conception.

Maternal, perinatal and infant outcome of spontaneous pregnancy in the sixth decade of life

UNLABELLED Pregnancy in the older woman is a well-known risk factor for perinatal morbidity and mortality. OBJECTIVE To evaluate perinatal and infant morbidity and mortality in women 50 or more years old. METHODS A retrospective population based study (1990-2004) evaluating spontaneously pregnant Chilean women more than 50 years old (217 live or stillbirths) compared to women 20-34 years old (2,817,742 neonates, control group). The comparison was performed using Chi Square with Yatess correction or exact Fisher test as appropriate. The risk analysis was performed by odds ratio (OR) and confidence interval of 95% (CI 95%). RESULTS Women over 50 had a significantly greater risk of fetal (OR: 3.7; CI 95%: 1.2-10.5), neonatal (OR: 10.4; CI 95%: 5.7-18.7), post-neonatal (OR: 9.5; CI 95%: 4.6-19.1) and infant death (OR: 10.5; CI 95%: 6.6-16.7). There were no differences between groups in the incidences of low and very low birth weight. CONCLUSION Pregnancy over 50 years of age entails a very high risk of fetal, neonatal and early childhood death. Unprotected sexual life for these women should be considered only after evaluation of their potential fertility.

MECHANISMS UNDERLYING MYOMETRIAL QUIESCENCE DURING PREGNANCY

The length of mammalian pregnancy is tightly regulated to assure the delivery of a newborn mature enough to survive the extra-uterine environment. A successful pregnancy requires near complete relaxation of the uterus for more than ninety-five percent of gestation, overcoming the inherent tendency of the myometrium to contract with stretch. This active and highly regulated process is called myometrial quiescence. It requires not only the near absence of myometrial contractions, but also its refractoriness to contractile agents.