Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1.

During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of endocannabinoids (ECs) and hypoxia as modulators of trophoblast cell death. However, the relation between these factors is still unknown. In this report, we evaluated the participation of ECs in placental apoptosis induced by cobalt chloride (CoCl2), a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α). We found that HIF-1α stabilization decreased FAAH mRNA and protein levels, suggesting an increase in ECs tone. Additionally, CoCl2 incubation and Met-AEA treatment reduced cell viability and increased TUNEL-positive staining in syncytiotrophoblast layer. Immunohistochemical analysis demonstrated Bax and Bcl-2 protein expression in the cytoplasm of syncytiotrophoblast. Finally, HIF-1α stabilization produced an increase in Bax/Bcl-2 ratio, activation of caspase 3 and PARP cleavage. All these changes in apoptotic parameters were reversed with AM251, a CB1 antagonist. These results demonstrate that HIF-1α may induce apoptosis in human placenta via intrinsic pathway by a mechanism that involves activation of CB1 receptor suggesting a role of the ECs in this process.

Differential expression of endocannabinoid system in normal and preeclamptic placentas: effects on nitric oxide synthesis.

Anandamide (AEA) is a lipid mediator that participates in the regulation of several reproductive functions. This study investigated the endocannabinoid system in normal (NP) and preeclamptic (PE) placentas, and analyzed the potential functional role of AEA in the regulation of nitric oxide synthesis. The protein expression and localization of NAPE-PLD, FAAH and CB1 receptor were analyzed in normal and preeclamptic pregnancies using immunoblotting and immunohistochemistry. NAPE-PLD expression was shown to be significantly higher (p < 0.05) in PE tissues than in NP. In contrast, a decrease in FAAH protein (p < 0.001) was detected in placentas collected from women with preeclampsia. Both enzymes were mainly located in the syncytiotrophoblasts from normal and preeclamptic tissues. No differences were seen in CB1 receptor from both groups of placental villous. Exogenous and endogenous AEA significantly increased NOS activity. Although pre-incubation with AM251 (CB1 antagonist) had no effect, co-incubation with both AEA and AM251 diminished NOS activity from normal term placentas. We observed increased NOS activity in placental villous from women with preeclampsia compared with normotensive pregnant women. Furthermore, NOS activity from preeclamptic tissues was diminished by co-treatment with AM251, illustrating that the NO levels could be modulated by AEA. These data suggest that AEA may be one of the factors involved in the regulation of NOS activity in normal and preeclamptic placental villous. Interestingly, the differential expression of NAPE-PLD and FAAH suggests that AEA could play an important role in the pathophysiology of PE.

Implementing rules to improve the quality of concept post-coordination with SNOMED CT.

The use of SNOMED CT as a standard reference terminology enables interoperability between clinical systems. This reference tool provides a method for creating post-coordinated terms by users according to local needs. While the creation of these terms is free, there are a number of rules, as defined in the user manual of SNOMED CT that must be followed.The Hospital Italiano of Buenos Aires has a Terminology Server that encodes medical terms, using SNOMED CT as the reference vocabulary. An interoperability analysis performed with the Nebraska Medical Center in 2006 found a high error rate (26%) in post-coordinated terms. Therefore, we implemented an automatic system of rules within the Terminology Server as defined in the user manual. Following rules implementation, the error rate decreased from 26% to 2%.

Dual effect of anandamide on rat placenta nitric oxide synthesis.

Anandamide (AEA) has been reported to have pleiotropic effects on reproduction, but the mechanism by which it exerts these effects is unclear. The aim of this study is to characterize rat placental endocannabinoid system and to analyze the possible functional role of AEA in the regulation of NO levels in rat placenta during pregnancy. We found that cannabinoids receptors (CB1 and CB2), FAAH and TRPV1 were expressed in chorio-allantoic placenta. NOS activity peaked at day 13 and decreased with progression of pregnancy. Both exogenous and endogenous AEA significantly decreased NOS activity. Although pre-incubation with AM251 (CB1 antagonist) or AM630 (CB2 antagonist) had no effect, co-incubation with both antagonists induced NOS activity. Furthermore, pre-incubation with exogenous AEA and both antagonists resulted in the induction of placental NOS activity and this effect was reverted with capsazepine (selective TRPV1 antagonist). Additionally, the enhanced NO synthesis caused by capsaicin was abrogated by co-treatment with capsazepine, illustrating that NOS activity could be modulated by TRPV1. Finally, the inhibition of TRPV1 receptor by capsazepine caused a significant fall in NOS activity. These data support the concept that AEA modulates NO levels by two independent pathways: (1) diminishing the NOS activity via CBs; and (2) stimulating NO synthesis via TRPV1. We hypothesized that AEA have an important implication in the normal function of placental tissues.

Intensive interventional maternity care reduces infant morbidity and hospital costs.

OBJECTIVE: The purpose of this study was to introduce an intensive interventional maternity care program, called the Temple Infant and Parent Support Services (TIPSS) program, and to determine whether comprehensive maternal and infant care would reduce the high rate of infant morbidity and mortality. METHODS: The TIPSS program was comprehensive, offering multidisciplinary services that were family focused and community based. Program services included community outreach, health education, as well as clinical care for the entire family. The effect of this program was evaluated among a very high-risk group of women who were recruited into care versus a control group of high-risk patients from the same neighborhood who voluntarily sought care at the Temple University School of Medicine. Outcome parameters evaluated included gestational age at delivery, birth weight, neonatal intensive care admission, infant death and cost of infant care. RESULTS: Among the TIPSS study group, 5.2% of infants were below 2500 g versus 11% in the control group (p < 0.05). Similarly, preterm deliveries occurred in 4.2% and 12% of the study and control groups, respectively (p < 0.005). Other significant differences observed included the number of prenatal visits (p < 0.001), maternal weight gain (p < 0.05) and admission to the neonatal intensive care unit (2% vs. 6.6%; p < 0.05). The reduced admission rate among neonates from the TIPSS program resulted in significant cost savings: $2849 for neonates in the study group versus $8499 for those in the control group. This corresponds to a $5560 savings per infant born to mothers cared for in the TIPSS study group. CONCLUSIONS: The Temple Infant and Parent Support Services program demonstrated that infant morbidity could be reduced when a comprehensive prenatal program was made available to indigent patients, even if there were multiple factors that placed the mother and her infant at high risk for complications.

Blood glucose monitoring in gestational diabetes mellitus: 1- versus 2-h blood glucose determinations.

Gestational diabetes mellitus is a common disorder of pregnancy affecting 3-5% of pregnant women. Although significant controversy exists regarding its diagnosis and treatment, macrosomia has been consistently associated with maternal hyperglycemia. Numerous studies have addressed different approaches to monitoring blood glucose levels, but data on the ideal timing for postprandial determinations are scarce. This article reviews current recommendations and recent findings on the implications of 1- versus 2-h blood glucose determinations in pregnant women with gestational diabetes mellitus. Preliminary studies have shown a statistically significant reduction in macrosomia and decreased need for emergency Cesarean section among women monitored 1 h after meals. Until larger studies confirm these benefits, compliance is of the utmost importance for successful treatment. Therefore, patient preferences should be considered in planning a monitoring strategy.

Enhancement of amniotic cyclooxygenase type 2 activity in women with preterm delivery associated with twins or polyhydramnios.

OBJECTIVE: We tested the hypothesis that preterm delivery in women with twins or polyhydramnios is associated with enhanced expression and activity of cyclooxygenase type 2 in the amnion. STUDY DESIGN: We obtained amniotic tissue samples from women undergoing preterm delivery complicated by either twins or polyhydramnios and also from women undergoing preterm cesarean delivery before or after labor. We measured amniotic prostaglandin E2 content and determined cyclooxygenase type 1 and type 2 expressions. We inhibited cyclooxygenase type 1 and type 2 activities with selective inhibitors. RESULTS: Preterm delivery attributed to twins or polyhydramnios was associated with higher prostaglandin E2 production and enhanced amniotic expression of cyclooxygenase type 2. In contrast, cyclooxygenase type 1 expression was unchanged. Incubation of amniotic samples in vitro with either indomethacin or the selective cyclooxygenase type 2 inhibitor SC-236, but not with the cyclooxygenase type 1 inhibitor SC-560, effectively reduced prostaglandin E2 production. CONCLUSION: Preterm delivery related to multiple gestation or polyhydramnios was associated with enhanced amniotic expression and activity of cyclooxygenase type 2.

African-American women have higher initial HbA1c levels in diabetic pregnancy.

OBJECTIVE: African-American women with diabetes are at greater risk for poor glycemic control outside of pregnancy. We evaluated the effect of race on glycemic control in a racially mixed population of women with diabetes entering prenatal care. RESEARCH DESIGN AND METHODS: HbA1c levels along with demographic data were collected at the first prenatal visit from a group of 234 women with preexisting diabetes. We applied logistic multivariate analysis to identify factors associated with HbA1c levels above the median for the group. RESULTS: The median HbA1c level for the group was 8%. HbA1c levels were 8.7 +/- 2.0% in African-Americans and 7.7 +/- 1.5% in Caucasians (P < 0.001). African-American racial designation was significantly and independently associated with high HbA1c when controlled for maternal age, parity, White classification, diabetes type, education, marital status, obesity, insurance type, and first trimester entry into care. The effect of race was confined to the nonobese patients, for whom the adjusted odds ratio for African-American race as a predictor of high HbA1c was 8.15 with a 95% CI of 2.41-27.58 (P = 0.001). CONCLUSIONS: We found a clear racial disparity in glycemic control among women entering prenatal care with preexisting diabetes. This study demonstrates that there generally is need for better glycemic control among reproductive-age women with diabetes, but especially among those who are African-American.

Effect of medical therapy on progressive nephropathy: influence of pregnancy, diabetes and hypertension.

Nephropathy is a complication of diabetes mellitus that can affect women in their reproductive years. This article reviews the effects on treatment on the main factors associated with short- and long-term complications in pregnant women with diabetic nephropathy. Tight glycemic control, adequate treatment of elevated blood pressure, and renal function in early pregnancy are the most significant predictors of maternal and perinatal outcomes. Contemporary methods of perinatal care and adequate treatment of blood pressure allow fetal survival rates of 95%. Furthermore, pregnancy per se does not appear to worsen the natural progression to end-stage renal disease for most women with renal insufficiency. However, patients with moderate to severe renal impairment may experience acceleration of renal disease.

Knowledge of likely time of ovulation and contraceptive use in unintended pregnancies.

This investigation analyzed social and demographic characteristics of women having an unwanted or mistimed pregnancy (unintended pregnancies at the current time) in South America. A sample of 5135 women having had a normal non-malformed live-born infant were interviewed immediately postpartum at 18 hospitals participating in the Latin American Collaborative Study of Congenital Malformations (Spanish acronym: ECLAMC). Half (2568/5135 = 50%) reported that their pregnancies had been unintended, and, of those, 59.3% (1522/2568 = 59.3%) declared that they were trying to avoid conception. The latter group (n = 1522) was the main sample for this study. Patients were asked about their knowledge of when during the menstrual cycle conception is most likely to occur, their biomedical and social characteristics, the type of contraceptive methods used, their opinion of reasons for contraceptive failure, and their reasons for not using contraceptive methods. Among women with unintended pregnancies who attempted to avoid conception, only 61.6% were using contraceptive methods. Reasons given for not using contraceptives included health problems, lack of knowledge and lack of access to contraception. Women with unintended pregnancies who had not attempted to avoid conception were younger, often primigravid, less educated, and less knowledgeable concerning when during the cycle pregnancy is most likely to occur. Thus, reproductive health policies should be aimed at this target group.

PIP: This study analyzes the social and demographic characteristics of women having an unwanted or unintended pregnancy in South America between 1992 and 1994. The study was conducted among 5135 women who had a normal non-malformed live-born infant and were interviewed at 18 hospitals participating in the Latin American Collaborative Study of Congenital Malformations. Patients were asked about their knowledge of when conception is most likely to occur during the menstrual cycle, their biomedical and social characteristics, the type of contraceptive methods used, their opinion and reasons for contraceptive failure, and their reasons for failing to use contraceptive methods. Results indicate that 50% of the respondents had unintended pregnancies, and about 59% declared that they were trying to avoid conception. However, among women with unintended pregnancies who attempted to avoid conception, only 61.6% were using contraceptive methods. Reasons for failure to use contraceptives include health problems, lack of knowledge, and lack of access to contraception. Meanwhile, women with unintended pregnancies who had not attempted to avoid conception were younger, often primigravid, less educated, and less knowledgeable concerning the likelihood that pregnancy will occur during menstrual cycle. This study implies that reproductive health policies should be aimed at this target group.

Pregnancy performance and outcomes associated with diabetic nephropathy.

The purpose of the current study is to report the effect of diabetic nephropathy on pregnancy outcomes based on a review of the world's literature from 1981 to 1996. In addition, the effects of pregnancy on renal function in a select subpopulation of patients is also presented. The Medline Computer System was used to survey the English language literature on diabetic nephropathy complicating pregnancy between 1981 and 1996, which yielded a total patient population of 315. The database was analyzed according to patient population, clinical management, maternal complications and outcomes, and fetal complications and outcomes. The frequency of chronic hypertension was 42% with 60% of women manifesting hypertension by the third trimester. Pre-eclampsia developed in 41% of patients; proliferative retinopathy was observed in 63% of patients prior to pregnancy, and cesarean section delivery was performed in 74% of the patients. Among the fetal outcomes, intrauterine growth restriction (IUGR) was observed in 15%, preterm delivery in 22%, and major congenital malformations in 8% of the patients included in the database. The observed overall perinatal morality rate was 5%. Gestational age at delivery was significantly correlated with first-trimester Cr/Cl (p < 0.01), third-trimester Cr/Cl (p < 0.05), third trimester proteinuria (p < 0.01), and third-trimester blood pressure (p < 0.001). Birth weight was significantly correlated with first-trimester Cr/Cl (p < 0.01), third-trimester Cr/Cl (p < 0.001), third-trimester proteinuria (p < 0.01), and third-trimester blood pressure (p < 0.001). Of the 185 patients available for long-term follow-up (mean 35 months), 17% developed end-stage renal disease, and 5% died as a result of renal insufficiency. Among the renovascular parameters, proteinuria and mean arterial pressure significantly increased from the first to the third trimester (p < 0.05). When these parameters were evaluated at follow-up, blood pressure did not show a significant increase from first trimester values, however, proteinuria did show a weak, but significant, increase postpartum. These data suggest that with contemporary methods of perinatal care, fetal survival rates of 95% are achievable in diabetic women with nephropathy. Furthermore, although many women experienced a temporary decline in renal function during gestation, pregnancy per se, does not appear to worsen the natural progression to end-stage renal disease for most women with renal insufficiency.

Stringent controls in diabetic nephropathy associated with optimization of pregnancy outcomes.

To evaluate maternal-fetal outcomes in pregnancies complicated by diabetic nephropathy were evaluated. Nephropathy was defined as proteinuria of >300 mg/24, or albuminuria >300 mg/24 hr in the absence of infection. Twenty-seven pregnant women with variable degrees of diabetic nephropathy were included in the study. Prenatal care included stringent metabolic control and management of hypertension. Fetal and maternal outcomes were obtained by medical record review. There were no fetal deaths. One neonatal death occurred in a fetus delivered at 29 weeks gestation. IUGR and major congenital malformations were observed in 9% of the neonates; 26% of the infants were delivered preterm. Chronic hypertension (77%) and preeclampsia (53%) were common maternal complications; 63% of women required delivery by cesarean section. Successful pregnancy outcomes were achieved in >95% of the women in our population. Modern management of the pregnancy complicated by diabetes has substantially improved the outcome of class F/FR diabetic mothers and their infants.