Deep learning prediction of renal anomalies for prenatal ultrasound diagnosis.

Deep learning algorithms have demonstrated remarkable potential in clinical diagnostics, particularly in the field of medical imaging. In this study, we investigated the application of deep learning models in early detection of fetal kidney anomalies. To provide an enhanced interpretation of those models' predictions, we proposed an adapted two-class representation and developed a multi-class model interpretation approach for problems with more than two labels and variable hierarchical grouping of labels. Additionally, we employed the explainable AI (XAI) visualization tools Grad-CAM and HiResCAM, to gain insights into model predictions and identify reasons for misclassifications. The study dataset consisted of 969 ultrasound images from unique patients; 646 control images and 323 cases of kidney anomalies, including 259 cases of unilateral urinary tract dilation and 64 cases of unilateral multicystic dysplastic kidney. The best performing model achieved a cross-validated area under the ROC curve of 91.28% ± 0.52%, with an overall accuracy of 84.03% ± 0.76%, sensitivity of 77.39% ± 1.99%, and specificity of 87.35% ± 1.28%. Our findings emphasize the potential of deep learning models in predicting kidney anomalies from limited prenatal ultrasound imagery. The proposed adaptations in model representation and interpretation represent a novel solution to multi-class prediction problems.

Persisting risk factors for preeclampsia among high-risk pregnancies already using prophylactic aspirin: a multi-country retrospective investigation.

BACKGROUND: Low-dose aspirin is recommended for pregnant individuals at high-risk of developing preeclampsia, but less is known about those that develop preeclampsia even while using prophylactic aspirin for preeclampsia prevention as the best course of treatment. OBJECTIVES: The objective of this study is to investigate the risk factors with the highest risk of developing preeclampsia among pregnant individuals already using aspirin from high-risk obstetrical centers across five countries. DESIGN: This is a secondary analysis of pregnant individuals from the Folic Acid Clinical Trial (FACT) who were using prophylactic aspirin before 16 weeks gestation. The FACT randomized control trial took place in 70 high risk obstetrical centers in Canada, United Kingdom, Australia, Jamaica, and Argentina between 2011-2015. Participants were included if they had any of the risk factors for preeclampsia: diabetes, chronic hypertension, twin pregnancy, history of preeclampsia, and/or obesity (Body Mass Index ≥35). The outcomes of interest were preeclampsia and preterm preeclampsia (<37 weeks). Log binomial regressions assessed factors significantly associated with any preeclampsia or preterm-preeclampsia (<37 weeks) using adjusted risk ratios (ARR) and 95% confidence intervals (CI). RESULTS: There were 2296 pregnant individuals with complete information on aspirin included in this study. At baseline, all patients were at high risk of preeclampsia and were eligible for aspirin prophylaxis, however, only 660 (28.7%) were taking aspirin. Among the 660 pregnant individuals taking aspirin, 132 (20%) developed preeclampsia and 60 (9.09%) preterm preeclampsia. Among pregnant individuals using aspirin, the risks of preeclampsia were highest for twins (ARR:2.62, 95% CI: 1.68-4.11), history of preeclampsia (ARR: 2.42, 95% CI: 1.74-3.38), and hypertension (ARR:1.92, 95% CI: 1.37-2.69). Similar trends were found for preterm-preeclampsia for twins (ARR:4.10, 95% CI:2.15-7.82), history of preeclampsia (ARR:2.75, 95% CI:1.62-4.67), and hypertension (ARR:2.18, 95% CI:1.28-3.72). No significant differences were found for obesity or diabetes. CONCLUSION: These findings suggest that individuals with twin pregnancies, a history of preeclampsia, or hypertension may not benefit from aspirin to the same extent as those with other complications such as obesity or diabetes. Careful clinical monitoring for these risks factors is recommended and future research into the effectiveness in these populations would increase our understanding of the current best practice of prophylactic aspirin use to prevent preeclampsia. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Gestational Folate and Folic Acid Intake among Women in Canada at Higher Risk of Pre-Eclampsia.

BACKGROUND: Periconceptional folic acid (FA) supplementation is recommended to prevent neural tube defects; however, the extent to which recommendations are met through dietary sources and supplements is not clear. OBJECTIVES: Our objective was to evaluate the dietary and supplemental intakes of FA in a Canadian pregnancy cohort and to determine the proportions of pregnant women exceeding the Estimated Average Requirement (EAR) and Tolerable Upper Intake Level (UL). METHODS: FACT (the Folic Acid Clinical Trial) was an international multicenter, randomized, double-blinded, placebo-controlled, phase III trial investigating FA for the prevention of pre-eclampsia in high-risk pregnancies. Participants were enrolled from Canadian sites at 8-16 weeks of gestation. Dietary and supplemental FA intake data were collected through participant interviews and FFQs at the time of FACT enrollment. Categorical data were summarized as n (%) and continuous data as median (IQR). RESULTS: This study included 1198 participants. Participants consumed 485 µg dietary folate equivalents (DFE)/d (IQR: 370-630 µg DFE/d) from dietary sources of folate and FA. Through diet alone, 43.4% of participants consumed ≥520 µg DFE/d, the EAR for pregnant individuals. Of the 91.9% of participants who consumed daily FA supplements, 0.4% consumed <400 µg FA/d and 96.0% consumed ≥1000 µg/d, the UL for FA. Median (IQR) total folate intake was 2167 µg DFE/d (2032-2325 µg DFE/d); 95.3% of participants met or exceeded the EAR from all sources, but 1069 (89.2%) participants exceeded the UL. CONCLUSIONS: The majority of participants in this Canadian pregnancy cohort did not consume the recommended amount of folate from dietary sources. However, most prenatal supplements contained 1000 µg FA, resulting in the majority of women exceeding the UL. With no additional benefit associated with FA intakes beyond the UL for most women, modification of prenatal supplement formulations may be warranted to ensure women meet but do not exceed recommended FA intakes.FACT was registered at clinicaltrials.gov as NCT01355159 and at isrctn.com as ISRCTN23781770.

Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT).

BACKGROUND: Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA. OBJECTIVES: This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia. METHODS: For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests. RESULTS: Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ. CONCLUSIONS: High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism.

Client Experience with the Ontario Birth Center Demonstration Project.

INTRODUCTION: In 2014, 2 new freestanding midwifery-led birth centers opened in Ontario, Canada. As one part of a larger mixed-methods evaluation of the first year of operations of the centers, our primary objective was to compare the experiences of women receiving midwifery care who intended to give birth at the new birth centers with those intending to give birth at home or in hospital. METHODS: We conducted a cross-sectional survey of women cared for by midwives with admitting privileges at one of the 2 birth centers. Consenting women received the survey 3 to 6 weeks after their due date. We stratified the analysis by intended place of birth at the beginning of labor, regardless of where the actual birth occurred. One composite indicator was created (Composite Satisfaction Score, out of 20), and statistical significance (P < .05) was assessed using one-way analysis of variance. Responses to the open-ended questions were reviewed and grouped into broader categories. RESULTS: In total, 382 women completed the survey (response rate 54.6%). Half intended to give birth at a birth center (n = 191). There was a significant difference on the Composite Satisfaction Scores between the birth center (19.4), home (19.5), and hospital (18.9) groups (P < .001). Among women who intended to give birth in a birth center, scores were higher in the women admitted to the birth center compared with those who were not (P = .037). Overall, women giving birth at a birth center were satisfied with the learners present at their birth, the accessibility of the centers, and the physical amenities, and they had suggestions for minor improvements. DISCUSSION: We found positive experiences and high satisfaction among women receiving midwifery care, regardless of intended place of birth. Women admitted to the birth centers had positive experiences with these new centers; however, future research should be planned to reassess and further understand women's experiences.

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort.

OBJECTIVE: Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. DESIGN: Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. SETTING: Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. PARTICIPANTS: Women were recruited when presenting for prenatal care in the early second trimester. RESULTS: In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. CONCLUSIONS: We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.

OBJECTIVE: To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. DESIGN: Randomised, phase III, double blinded international, multicentre clinical trial. SETTING: 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). PARTICIPANTS: 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. INTERVENTION: Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. MAIN OUTCOME MEASURE: The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). RESULTS: Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. CONCLUSION: Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Comparison of risk factors and outcomes of gestational hypertension and pre-eclampsia.

BACKGROUND: It remains an enigma whether gestational hypertension (GH) and pre-eclampsia (PE) are distinct entities or different spectrum of the same disease. We aimed to compare the risk factors and outcomes between GH and PE. METHOD: A total of 7,633 pregnant women recruited between 12 and 20 weeks of gestation in the Ottawa and Kingston Birth Cohort from 2002 to 2009 were included in the analysis. Cox proportional hazards model was used to identify and compare the risk factors for GH and PE by treating gestational age at delivery as the survival time. Logistic regression model was used to compare outcome. Subgroup analysis was performed for early- and late-onset PE. RESULTS: GH and PE shared most risk factors including overweight and obesity, nulliparity, PE history, type 1 and 2 diabetes, and twin birth. Effect size of PE history (RR = 14.1 for GH vs. RR = 6.4 for PE) and twin birth (RR = 4.8 for GH vs. RR = 10.3 for PE) showed substantial difference. Risk factors modified gestational age at delivery in patients with GH and PE in similar pattern. Subgroup analysis showed that early- and late-onset PE shared some risk factors with different effect sizes, whereas folic acid supplementation showed protective effect for early-onset PE only. PE was strongly associated with several adverse outcomes including cesarean section, placental abruption, small for gestational age, preterm birth, and 5 min Apgar score < 7, whereas GH was associated with increased risk of preterm birth only. CONCLUSIONS: GH and PE shared common risk factors. Differences in effect sizes of risk factors and outcomes indicate that the conditions may have different pathophysiology and mechanism.

Serum Folate Shows an Inverse Association with Blood Pressure in a Cohort of Chinese Women of Childbearing Age: A Cross-Sectional Study.

BACKGROUND: It has been reported that higher folate intake from food and supplementation is associated with decreased blood pressure (BP). The association between serum folate concentration and BP has been examined in few studies. We aim to examine the association between serum folate and BP levels in a cohort of young Chinese women. METHODS: We used the baseline data from a pre-conception cohort of women of childbearing age in Liuyang, China, for this study. Demographic data were collected by structured interview. Serum folate concentration was measured by immunoassay, and homocysteine, blood glucose, triglyceride and total cholesterol were measured through standardized clinical procedures. Multiple linear regression and principal component regression model were applied in the analysis. RESULTS: A total of 1,532 healthy normotensive non-pregnant women were included in the final analysis. The mean concentration of serum folate was 7.5 ± 5.4 nmol/L and 55% of the women presented with folate deficiency (< 6.8 nmol/L). Multiple linear regression and principal component regression showed that serum folate levels were inversely associated with systolic and diastolic BP, after adjusting for demographic, anthropometric, and biochemical factors. CONCLUSIONS: Serum folate is inversely associated with BP in non-pregnant women of childbearing age with high prevalence of folate deficiency.

Serum and red-blood-cell folate demonstrate differential associations with BMI in pregnant women.

OBJECTIVE: To examine the association between BMI and folate concentrations in serum and red blood cells (RBC) in pregnant women. DESIGN: A cross-sectional comparison of folate concentrations in serum and RBC sampled simultaneously from the same individual. SETTING: The Ottawa Hospital and Kingston General Hospital, Ontario, Canada. SUBJECTS: Pregnant women recruited between 12 and 20 weeks of gestation. RESULTS: A total of 869 pregnant women recruited from April 2008 to April 2009 were included in the final analysis. Serum folate was inversely associated and RBC folate positively associated with BMI, after adjusting for folic acid supplementation, age, gestational age at blood sample collection, race, maternal education, annual income, smoking and MTHFR 677C→T genotype. In stratified analyses, this differential association was significant in women with the MTHFR CC variant. In women with the CT and TT variants, the differential associations were in the same direction but not significant. Folic acid supplementation during pregnancy did not alter the differential association of BMI with serum and RBC folate concentration. This indicates that the current RBC folate cut-off approach for assessing risk of neural tube defects in obese women may be limited. CONCLUSIONS: BMI is inversely associated with serum folate and positively associated with RBC folate in pregnant women, especially for those with the MTHFR CC variant.

Folic Acid Supplementation in Pregnancy and the Risk of Pre-Eclampsia-A Cohort Study.

This prospective cohort study designed to assess the effect of folic acid supplementation in pregnancy on the risk of preeclampsia (PE) took place in Ottawa, ON and Kingston, ON, Canada, from September 1, 2002 to August 31, 2008. Pregnant women, less than 20 weeks gestational age were recruited and delivered in the Ottawa region and the Kingston General Hospital. Demographic characteristics of the study participants and the patterns of supplementation of folic acid were described and occurrence of PE between women with folic acid supplementation during pregnancy and women without were compared. Multiple logistic regression was used in the estimation of the independent effect of supplementation of folic acid. Additional analyses assessing the effect of low RBC and serum folate and dose-response relationship were performed. Analyses were performed in all study participants, and then in high risk and low risk sub-groups, respectively. A total of 7,669 participants were included in the final analysis. Ninety five percent of the study participants were taking folic acid supplementation in early second trimester. The rate of PE was lower in the supplementation group than in the no supplementation group, and the difference was statistically significant in high risk women. Similar patterns of associations were observed in analysis by RBC and serum folate levels and in dose-response analysis. Folic acid supplementation in pregnancy may reduce PE risk in pregnant women, especially in those women with increased risk of developing PE.

Universal bilirubin screening and health care utilization.

OBJECTIVE: To evaluate the impact of the implementation of universal bilirubin screening on neonatal health care use in the context of a large jurisdiction with universal health insurance. METHODS: We conducted a population-based retrospective cohort study of all newborns discharged after birth between April 2003 and February 2011 from 42 hospitals that implemented universal bilirubin screening between July 2007 and June 2010 in Ontario, Canada. We surveyed hospitals to determine their screening implementation date. We used multiple linked administrative health data sets to measure phototherapy use, length of stay (LOS), jaundice-related emergency department visits, and jaundice-related readmissions. We modeled the relationship between universal bilirubin screening and outcomes using generalized estimating equations to account for clustering by hospital, underlying temporal trends, and important covariates. RESULTS: Screening was associated with an increase in phototherapy during hospitalization at birth (relative risk, 1.32; 95% confidence interval, 1.09-1.59) and a decrease in jaundice-related emergency department visits (relative risk, 0.79; 95% confidence interval, 0.64-0.96) but no statistically significant difference in phototherapy after discharge, LOS, or jaundice-related readmissions after accounting for preexisting temporal trends in health care service use and other patient sociodemographic and hospital characteristics. CONCLUSIONS: Universal bilirubin screening may not be associated with increased neonatal LOS or increased subsequent hospital use. Our findings are relevant for determining the resource implications of universal bilirubin screening in Ontario. They highlight the limitations in generalizability of previous research on health care utilization associated with similar programs and underline the importance of context-specific local evaluation of guideline implementation.

Effect of folic acid supplementation in pregnancy on preeclampsia: the folic acid clinical trial study.

Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 8(0/7) and 16(6/7) weeks of gestation are randomized in a 1 : 1 ratio to folic acid 4.0 mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159.

The Ottawa and Kingston (OaK) Birth Cohort: development and achievements.

OBJECTIVE: The Ottawa and Kingston (OaK) Birth Cohort collected data on maternal and infant genetic and epidemiologic variables in order to (1) explore the association between folate supplementation or thrombophilias and adverse, placenta-mediated pregnancy outcomes; (2) create a biobank of maternal and infant biological and genetic samples; and (3) stimulate future research using this cohort data. METHODS: A prospective cohort design was used to collect mother and infant data. Women were recruited at 12 to 20 weeks' gestation, during prenatal care visits at The Ottawa Hospital and Kingston General Hospital from October 2002 to April 2009. Data on maternal and infant demographics, maternal health, obstetrical history, and pregnancy outcomes were collected. Testing was done for biological/serological markers associated with adverse pregnancy outcomes. Maternal and cord blood samples were biobanked. RESULTS: A total of 8085 mothers were recruited to the OaK Birth Cohort. Analysis of the cohort data showed that taking multivitamin supplements containing folic acid was associated with a reduced risk of preeclampsia (aOR 0.37; 95% CI 0.18 to 0.75). The majority of participants agreed to have their genetic/biological samples biobanked (samples collected for n = 7241 mothers, n = 2175 infants) and to be re-contacted regarding future research opportunities. CONCLUSION: Birth cohorts are a useful tool in determining associations between risk factors and adverse maternal and fetal outcomes, and can serve as a repository of data for future research. Creating strong research partnerships helped enhance financial resources and increase participant recruitment potential. Epidemiological and biobanked data and samples from the OaK Birth Cohort are available for use by other investigators.

Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain.

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.

Folic acid supplementation in early second trimester and the risk of preeclampsia.

OBJECTIVE: The objective of the study was to evaluate the association between folic acid supplementation in early second trimester and the risk of developing preeclampsia. STUDY DESIGN: We carried out a prospective cohort study between October 2002-December 2005. We recruited women who had their prenatal care visit (12-20 weeks' gestation) at the Ottawa Hospital and Kingston General Hospital. All charts for participants with a diagnosis of preeclampsia were audited and blindly adjudicated by 4 study investigators to validate the diagnosis. RESULTS: A total of 2951 pregnant women were included in the final analysis. Supplementation of multivitamins containing folic acid was associated with increased serum folate (on average 10.51 micromol/L), decreased plasma homocysteine (on average 0.39 micromol/L), and reduced risk of preeclampsia (adjusted odds ratio, 0.37; 95% confidence interval, 0.18-0.75). CONCLUSION: Supplementation of multivitamins containing folic acid in the second trimester is associated with reduced risk of preeclampsia.

A survey of preconceptional folic acid use in a group of Canadian women.

BACKGROUND: Randomized controlled trials have demonstrated that periconceptional folic acid supplementation has a dramatic effect in reducing neural tube defects, one of the most serious congenital anomalies. Unfortunately, supplementation tends to be suboptimal in disadvantaged populations. OBJECTIVE: The primary objective was to determine patient factors associated with a lack of use of periconceptional folic acid among Canadian women in a multi-ethnic, urban setting. Our secondary objective was to assess patient knowledge about folic acid tablet supplementation and its link to reduced birth defects. METHODS: We undertook a cross-sectional study to survey postpartum Toronto women on their use and knowledge of periconceptional folic acid. RESULTS: Of the 383 women surveyed, only 28% took folic acid or a multivitamin containing folic acid during the periconceptional period. Multivariate analysis revealed that the use of periconceptional folic acid was more common among women of Jewish descent (adjusted relative risk [RR] 0.3; 95% confidence interval [CI], 0.04-0.9) and those who had 1 or no children (adjusted RR 0.6; 95% CI, 0.4-0.8). Not taking folic acid was associated with unplanned pregnancy (adjusted RR 1.5; 95% CI, 1.4-1.6) and a lack of knowledge about when folic acid should be taken (adjusted RR 1.8; 95% CI, 1.6-1.8). CONCLUSION: Ethnic background is an independent predictor of periconceptional folic acid use.

Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity.

The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human COX-1 and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans.

Cardiogenic hypertrophic osteopathy in a dog with a right-to-left shunting patent ductus arteriosus.

A 5-year-old castrated male Shetland Sheepdog was examined because of progressive bilateral hind limb thickening. Cyanosis of the preputial mucous membranes was evident, whereas the oral mucous membranes had a normal color. A well-structured, palisade-like periosteal reaction with no underlying bone destruction was evident on radiographs of the hind limbs. The radiographic changes were consistent with hypertrophic osteopathy (HO). Severe right-sided cardiomegaly was seen on thoracic radiographs, and a diagnosis of patent ductus arteriosus with right-to-left shunting was made by means of echocardiography and contrast echoaortography. The cyanotic heart disease was believed to be the cause of the HO. Hypertrophic osteopathy has been associated with a number of diseases in animals and humans. In humans, congenital heart defects that cause cyanosis are among the most common causes of HO.

The prevention of congenital anomalies with periconceptional folic acid supplementation.

Large randomized trials have demonstrated the critical role of folic acid supplementation in the prevention of neural tube defects. Since 1992, a number of national and international professional societies have released guidelines recommending folic acid supplementation of at least 0.4 mg/day for all women of childbearing age or women planning pregnancies, and 4 mg/day for women with a previous infant with a neural tube defect. Furthermore, a reduction in the incidence of congenital cardiac and urologic anomalies has been demonstrated in some studies following periconceptional folic acid supplementation. There is growing evidence of a possible role of folic acid supplementation in the prevention of other congenital anomalies, including cardiac defects. Since 1998, mandatory fortification of certain foods with folate has been associated with at least a 54% reduction in the incidence of open neural tube defects, yet rates of periconceptional folic acid use remain suboptimal, especially in minority women. Innovative strategies in educating women, health-care providers, and pharmacists on the benefits of folic acid supplementation need to be explored. Mandatory folate fortification of foods needs to be defined and monitored.