Placental characteristics and risks of maternal mortality 50 years after delivery.

INTRODUCTION: Adverse pregnancy outcomes such as preterm delivery and preeclampsia are associated with a higher maternal risk for subsequent cardiovascular disease (CVD) and all-cause mortality. While such pregnancy conditions are related to abnormal placentation, little research has investigated whether pathologic placental measures could serve as a risk factor for future CVD mortality in mothers. METHODS: Longitudinal study of 33,336 women from the Collaborative Perinatal Project (CPP; 1959-1966) linked to mortality information through December 2016. Pathologists took extensive morphological and histopathological measures. Apart from assessing associations with morphological features, we derived an overall composite score and specific inflammation-related, hemorrhage-related, and hypoxia-related pathologic placenta index scores. Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for mortality adjusting for covariates. RESULTS: Thirty-nine percent of women died with mean (standard deviation, SD) time to death of 39 (12) years. Mean (SD) placental weight and birthweight were 436 g (98) and 3156 g (566), respectively. Placenta-to-birthweight ratio was associated with all-cause mortality (adjusted HR 1.03: 1.01, 1.05 per SD in ratio). In cause-specific analyses, it was significantly associated with respiratory (HR 1.06), dementia (HR: 1.10) and liver (HR 1.04) related deaths. CVD, cancer, diabetes and kidney related deaths also tended to increase, whereas infection related deaths did not (HR 0.94; 0.83, 1.06). Placental measures of thickness, diameters, and histopathological measures grouped by inflammatory, hemorrhagic, or hypoxic etiology were not associated with mortality. DISCUSSION: Placental weight in relation to birthweight was associated with long-term maternal mortality but other histopathologic or morphologic features were not.

Delayed conception in women with low-urinary iodine concentrations: a population-based prospective cohort study.

STUDY QUESTION: Is iodine deficiency associated with decreased fecundability? SUMMARY ANSWER: Moderate to severe iodine deficiency is associated with a 46% decrease in fecundability. WHAT IS KNOWN ALREADY: Iodine deficiency is common in women of childbearing age but its effect on fecundability has not been investigated. STUDY DESIGN, SIZE, DURATION: The LIFE Study, a population-based prospective cohort study, enrolled 501 women who had discontinued contraception within 2 months to become pregnant between 2005 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women reported on risk factors for infertility by interview then kept daily journals of relevant information. Women used fertility monitors to time intercourse relative to ovulation then used home digital pregnancy tests to identify pregnancies on the day of expected menstruation. Urine samples for iodine analysis were collected on enrollment. MAIN RESULTS AND THE ROLE OF CHANCE: Samples were in the deficiency range in 44.3% of participants. The group whose iodine-creatinine ratios were below 50 µg/g (moderate to severe deficiency) had a 46% reduction in fecundity (P = 0.028) compared with the group whose iodine-creatinine ratios were in the adequate range: adjusted fecundability odds ratio of becoming pregnant per cycle, 0.54 (95% confidence interval 0.31-0.94). LIMITATIONS, REASONS FOR CAUTION: Iodine concentrations vary within individuals over time, so the data must be interpreted by group as we have done; residual confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS: Significant delays in becoming pregnant occur at iodine concentrations that are common in women in the USA and parts of Europe. Replicating these findings will be important to determine whether improving iodine status could be beneficial in improving fecundability. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA. Contracts N01-HD-3-3355; N01-HD-3-3356; N01-HD-3-3358 and HHSN275201100001l/HHSN27500007. None of the authors has any conflict of interest to declare.

Genome-wide studies of von Willebrand factor propeptide identify loci contributing to variation in propeptide levels and von Willebrand factor clearance.

UNLABELLED: Essentials Variants at ABO, von Willebrand Factor (VWF) and 2q12 contribute to the variation in plasma in VWF. We performed a genome-wide association study of plasma VWF propeptide in 3,238 individuals. ABO, VWF and 2q12 loci had weak or no association or linkage with plasma VWFpp levels. VWF associated variants at ABO, VWF and 2q12 loci primarily affect VWF clearance rates. SUMMARY: Background Previous studies identified common variants at the ABO and VWF loci and unknown variants in a chromosome 2q12 linkage interval that contributed to the variation in plasma von Willebrand factor (VWF) levels. Whereas the association with ABO haplotypes can be explained by differential VWF clearance, little is known about the mechanisms underlying the association with VWF single-nucleotide polymorphisms (SNPs) or with variants in the chromosome 2 linkage interval. VWF propeptide (VWFpp) and mature VWF are encoded by the VWF gene and secreted at the same rate, but have different plasma half-lives. Therefore, comparison of VWFpp and VWF association signals can be used to assess whether the variants are primarily affecting synthesis/secretion or clearance. Methods We measured plasma VWFpp levels and performed genome-wide linkage and association studies in 3238 young and healthy individuals for whom VWF levels had been analyzed previously. Results and conclusions Common variants in an intergenic region on chromosome 7q11 were associated with VWFpp levels. We found that ABO serotype-specific SNPs were associated with VWFpp levels in the same direction as for VWF, but with a much lower effect size. Neither the association at VWF nor the linkage on chromosome 2 previously reported for VWF was observed for VWFpp. Taken together, these results suggest that the major genetic factors affecting plasma VWF levels, i.e. variants at ABO, VWF and a locus on chromosome 2, operate primarily through their effects on VWF clearance.

Performance of prognostic markers in the prediction of wound healing or amputation among patients with foot ulcers in diabetes: a systematic review.

Prediction of wound healing and major amputation in patients with diabetic foot ulceration is clinically important to stratify risk and target interventions for limb salvage. No consensus exists as to which measure of peripheral artery disease (PAD) can best predict outcomes. To evaluate the prognostic utility of index PAD measures for the prediction of healing and/or major amputation among patients with active diabetic foot ulceration, two reviewers independently screened potential studies for inclusion. Two further reviewers independently extracted study data and performed an assessment of methodological quality using the Quality in Prognostic Studies instrument. Of 9476 citations reviewed, 11 studies reporting on 9 markers of PAD met the inclusion criteria. Annualized healing rates varied from 18% to 61%; corresponding major amputation rates varied from 3% to 19%. Among 10 studies, skin perfusion pressure ≥ 40 mmHg, toe pressure ≥ 30 mmHg (and ≥ 45 mmHg) and transcutaneous pressure of oxygen (TcPO2 ) ≥ 25 mmHg were associated with at least a 25% higher chance of healing. Four studies evaluated PAD measures for predicting major amputation. Ankle pressure < 70 mmHg and fluorescein toe slope < 18 units each increased the likelihood of major amputation by around 25%. The combined test of ankle pressure < 50 mmHg or an ankle brachial index (ABI) < 0.5 increased the likelihood of major amputation by approximately 40%. Among patients with diabetic foot ulceration, the measurement of skin perfusion pressures, toe pressures and TcPO2 appear to be more useful in predicting ulcer healing than ankle pressures or the ABI. Conversely, an ankle pressure of < 50 mmHg or an ABI < 0.5 is associated with a significant increase in the incidence of major amputation.

Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review.

Non-invasive tests for the detection of peripheral artery disease (PAD) among individuals with diabetes mellitus are important to estimate the risk of amputation, ulceration, wound healing and the presence of cardiovascular disease, yet there are no consensus recommendations to support a particular diagnostic modality over another and to evaluate the performance of index non-invasive diagnostic tests against reference standard imaging techniques (magnetic resonance angiography, computed tomography angiography, digital subtraction angiography and colour duplex ultrasound) for the detection of PAD among patients with diabetes. Two reviewers independently screened potential studies for inclusion and extracted study data. Eligible studies evaluated an index test for PAD against a reference test. An assessment of methodological quality was performed using the quality assessment for diagnostic accuracy studies instrument. Of the 6629 studies identified, ten met the criteria for inclusion. In these studies, the patients had a median age of 60-74 years and a median duration of diabetes of 9-24 years. Two studies reported exclusively on patients with symptomatic (ulcerated/infected) feet, two on patients with asymptomatic (intact) feet only, and the remaining six on patients both with and without foot ulceration. Ankle brachial index (ABI) was the most widely assessed index test. Overall, the positive likelihood ratio and negative likelihood ratio (NLR) of an ABI threshold <0.9 ranged from 2 to 25 (median 8) and <0.1 to 0.7 (median 0.3), respectively. In patients with neuropathy, the NLR of the ABI was generally higher (two out of three studies), indicating poorer performance, and ranged between 0.3 and 0.5. A toe brachial index <0.75 was associated with a median positive likelihood ratio and NLRs of 3 and ≤ 0.1, respectively, and was less affected by neuropathy in one study. Also, in two separate studies, pulse oximetry used to measure the oxygen saturation of peripheral blood and Doppler wave form analyses had NLRs of 0.2 and <0.1. The reported performance of ABI for the diagnosis of PAD in patients with diabetes mellitus is variable and is adversely affected by the presence of neuropathy. Limited evidence suggests that toe brachial index, pulse oximetry and wave form analysis may be superior to ABI for diagnosing PAD in patients with neuropathy with and without foot ulcers. There were insufficient data to support the adoption of one particular diagnostic modality over another and no comparisons existed with clinical examination. The quality of studies evaluating diagnostic techniques for the detection of PAD in individuals with diabetes is poor. Improved compliance with guidelines for methodological quality is needed in future studies.

Effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review.

Symptoms or signs of peripheral artery disease (PAD) can be observed in up to 50% of the patients with a diabetic foot ulcer and is a risk factor for poor healing and amputation. In 2012, a multidisciplinary working group of the International Working Group on the Diabetic Foot published a systematic review on the effectiveness of revascularization of the ulcerated foot in patients with diabetes and PAD. This publication is an update of this review and now includes the results of a systematic search for therapies to revascularize the ulcerated foot in patients with diabetes and PAD from 1980 to June 2014. Only clinically relevant outcomes were assessed. The research conformed to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, and Scottish Intercollegiate Guidelines Network methodological scores were assigned. A total of 56 articles were eligible for full-text review. There were no randomized controlled trials, but there were four nonrandomized studies with a control group. The major outcomes following endovascular or open bypass surgery were broadly similar among the studies. Following open surgery, the 1-year limb salvage rates were a median of 85% (interquartile range of 80-90%), and following endovascular revascularization, these rates were 78% (70-89%). At 1-year follow-up, 60% or more of ulcers had healed following revascularization with either open bypass surgery or endovascular techniques. Studies appeared to demonstrate improved rates of limb salvage associated with revascularization compared with the results of conservatively treated patients in the literature. There were insufficient data to recommend one method of revascularization over another. There is a real need for standardized reporting of baseline demographic data, severity of disease and outcome reporting in this group of patients.

Management of inferior vena cava aneurysm.

AIM: Inferior vena cava (IVC) aneurysm is an infrequent but potentially lethal abnormality. We have seen one such case in our group practice. We have added this case to a review of 53 previously reported cases in order to develop a management algorithm for this entity. METHODS: We conducted a MedLine search of all English-language articles from the first reported case in 1950 through August 2013. Patient demographics, clinical data, management and outcomes were extracted. IVC aneurysms were categorized in 4 types as per Gradman and Steinberg classification. RESULTS: The mean patient age was 27.1 years (range 5-89) and 57.4% were male. A total of 11 (20.3%) had associated vascular anomalies and iliocaval thrombosis was found in 10 (18.5%). There were 23 type I aneurysms, 8 type IIs, 21 type IIIs and 2 type IVs. All but 1 type I was successfully managed conservatively without complications. For type IIs, only 3 patients were managed conservatively with 1 death related to stroke from paradoxical embolus. For type IIIs, resection was the most common management option (14 patients). One patient was treated endovascularly with aneurysm embolization. A total of 6 asymptomatic patients were treated conservatively with 1 death due to thromboembolism. For type IVs, all cases underwent expectant management with 1 death due to aneurysm rupture. CONCLUSION: IVC aneurysms are rare with only 54 cases reported in the literature. Associated vascular anomalies and iliocaval thrombosis should be expected in approximately 20% of cases. Type I aneurysms can be managed expectantly with close surveillance unless symptomatic. For type II-IV, surgical consideration should be given based on high rates of thromboembolic complications and non-negligible risk of rupture.

The pros and cons of endovascular and open surgical treatments for patients with acute limb ischemia.

The present review addresses the pros and cons of the current, wide variety of therapeutic options available for the treatment of acute limb ischemia (ALI). Despite five prospective randomized controlled trials comparing catheter directed thrombolysis and open surgical revascularization, no single treatment strategy can yet be considered optimal for patients with ALI. This report includes 20 years of published data to evaluate the efficacy and safety profile of thrombolytic agents and adjunctive endovascular techniques when compared to open surgical revascularization.

A systematic review of the effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral arterial disease.

In several large recent observational studies, peripheral arterial disease (PAD) was present in up to 50% of the patients with a diabetic foot ulcer and was an independent risk factor for amputation. The International Working Group on the Diabetic Foot therefore established a multidisciplinary working group to evaluate the effectiveness of revascularization of the ulcerated foot in patients with diabetes and PAD. A systematic search was performed for therapies to revascularize the ulcerated foot in patients with diabetes and PAD from 1980-June 2010. Only clinically relevant outcomes were assessed. The research conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the Scottish Intercollegiate Guidelines Network methodological scores were assigned. A total of 49 papers were eligible for full text review. There were no randomized controlled trials, but there were three nonrandomized studies with a control group. The major outcomes following endovascular or open bypass surgery were broadly similar among the studies. Following open surgery, the 1-year limb salvage rates were a median of 85% (interquartile range of 80-90%), and following endovascular revascularization, these rates were 78% (70.5-85.5%). At 1-year follow-up, 60% or more of ulcers had healed following revascularization with either open bypass surgery or endovascular revascularization. Studies appeared to demonstrate improved rates of limb salvage associated with revascularization compared with the results of medically treated patients in the literature. There were insufficient data to recommend one method of revascularization over another. There is a real need for standardized reporting of baseline demographic data, severity of disease and outcome reporting in this group of patients.

Diagnosis and treatment of peripheral arterial disease in diabetic patients with a foot ulcer. A progress report of the International Working Group on the Diabetic Foot.

The International Working Group on the Diabetic Foot (IWDGF) has produced in 2011 a guideline on the diagnosis and treatment of peripheral arterial disease in patients with diabetes and a foot ulcer. This document, together with a systematic review that provided the background information on management, was produced by a multidisciplinary working group of experts in the field and was endorsed by the IWDGF. This progress report is based on these two documents and earlier consensus texts of the IWDGF on the diagnosis and management of diabetic foot ulcers. Its aim is to give the clinician clear guidance on when and how to diagnose peripheral arterial disease in patients with diabetes and a foot ulcer and when and which treatment modalities should be considered, taking both risks and benefits into account.

Polymeric endoaortic paving: Mechanical, thermoforming, and degradation properties of polycaprolactone/polyurethane blends for cardiovascular applications.

Polymeric endoaortic paving (PEAP) is a process by which a polymer is endovascularly delivered and thermoformed to coat or "pave" the lumen of the aorta. This method may offer an improvement to conventional endoaortic therapy in allowing conformal graft application with reduced risk of endoleak and customization to complex patient geometries. Polycaprolactone (PCL)/polyurethane (PU) blends of various blend ratios were assessed as a potential material for PEAP by characterizing their mechanical, thermoforming and degradation properties. Biaxial tension testing revealed that the blends' stiffness is similar to that of aortic tissue, is higher for blends with more PCL content, and may be affected by thermoforming and degradation. Tubes of blends were able to maintain a higher diameter increase after thermoforming at higher PCL content and higher heating temperatures; 50/50 blend tubes heated to 55 °C were able to maintain 90% of the diameter increase applied. Delamination forces of the blends ranged from 41 to 235 N m⁻². In a Pseudomonas lipase solution, the 50/50 blend had a 94% lower degradation rate than pure PCL, and the 10/90 blend exhibited no degradation. These results indicate that PEAP, consisting of a PCL/PU blend, may be useful in developing the next generation of endoaortic therapy.

Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects.

OBJECTIVE: Women who have low cobalamin (vitamin B(12)) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCblR) mediates uptake of cobalamin into cells. Inherited variants in the TCblR gene as NTD risk factors were evaluated. METHODS: Case-control and family-based tests of association were used to screen common variation in TCblR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings. RESULTS: 2 tightly linked variants associated with NTDs in a recessive model were found: TCblR rs2336573 (G220R; p(corr)=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (p(corr)=0.0279). These variants were also associated with NTDs in a family-based test before multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R; RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). A copy number variant distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms were described. CONCLUSIONS: TCblR rs2336573 (G220R) and TCblR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly 1000 controls, indicating that this NTD risk factor may be of low frequency and high penetrance. 9 other variants are in perfect linkage disequilibrium with the associated single nucleotide polymorphisms. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCblR plays a role in NTD risk and that these variants may modulate cobalamin metabolism.

Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development.

The effects of DNA repair and transcription gene abnormalities in human pre-natal life have never been studied. Trichothiodystrophy (TTD) is a rare (affected frequency of 10(-6)) recessive disorder caused by mutations in genes involved in nucleotide excision repair (NER) pathway and in transcription. Based on our novel clinical observations, we conducted a genetic epidemiologic study to investigate gestational outcomes associated with TTD. We compared pregnancies resulting in TTD-affected offspring (n = 24) with respect to abnormalities during their antenatal and neonatal periods to pregnancies resulting in their unaffected siblings (n = 18), accounting for correlation, and to population reference values. Significantly higher incidence of several severe gestational complications was noted in TTD-affected pregnancies. Small for gestational age (SGA) <10th percentile [Relative risk (RR ) = 9.3, 95% CI = 1.4-60.5, p = 0.02], SGA <3rd percentile (RR = 7.2, 95% CI = 1.1-48.1, p = 0.04), and neonatal intensive care unit (NICU) hospitalization (RR = 6.4, 95% CI = 1.4-29.5, p = 0.02) occurred more frequently among TTD-affected neonates compared with their unaffected siblings. Compared with reference values from general obstetrical population, pregnancies that resulted in TTD-affected infants were significantly more likely to be complicated by hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (RR = 35.7, 95% CI = 7.6-92.5, p = 0.0002), elevated mid-trimester maternal serum human chorionic gonadotropin (hCG) levels (RR = 14.3, 95% CI = 7.0-16.6, p < 0.0001), SGA <3rd percentile (RR = 13.9, 95% CI = 7.4-21.1, p < 0.0001), pre-term delivery (<32 weeks) (RR = 12.0, 95% CI = 4.9-21.6, p < 0.0001), pre-eclampsia (RR = 4.0, 95% CI = 1.6-7.4, p = 0.006), and decreased fetal movement (RR = 3.3, 95% CI = 1.6-5.2, p = 0.0018). Abnormal placental development is an underlying mechanism that may explain the constellation of observed complications in our study. Thus, we hypothesize that TTD DNA repair and transcription genes play an important role in normal human placental development.

Testing for genetic association with constrained models using triads.

It has been shown that it is preferable to use a robust model that incorporated constraints on the genotype relative risk rather than rely on a model that assumes the disease operates in a recessive or dominant fashion. Previous methods are applicable to case-control studies, but not to family based studies of case children along with their parents (triads). We show here how to implement analogous constraints while analyzing triad data. The likelihood, conditional on the parents genotype, is maximized over the appropriately constrained parameter space. The asymptotic distribution for the maximized likelihood ratio statistic is found and used to estimate the null distribution of the test statistics. The properties of several methods of testing for association are compared by simulation. The constrained method provides higher power across a wide range of genetic models with little cost when compared to methods that restrict to a dominant, recessive, or multiplicative model, or make no modeling restriction. The methods are applied to two SNPs on the methylenetetrahydrofolate reductase (MTHFR) gene with neural tube defect (NTD) triads.

Degenerative aneurysms of the superficial femoral artery.

PURPOSE: To review the pathogenesis, diagnosis, presentation, diagnosis, management and outcomes (morbidity and mortality) of superficial femoral artery aneurysms. METHODS: A comprehensive review of this entity was performed based on the available literature in all languages and a detailed discussion of our findings is also provided. RESULTS: Our review identified 61 cases of SFA aneurysms. They were most often seen in elderly men, predominately affected the right lower extremity, and were most often located in the middle-third of the artery. At the time of diagnosis, SFA aneurysms were frequently symptomatic because they reached a relative large diameter before the diagnosis was made. The most frequent presentation was localized pain in association with a pulsatile mass. In contrast to popliteal aneurysms, SFA aneurysms more frequently present with rupture than distal ischemia. Angiography was by far the most commonly utilized diagnostic tool. Treatment was primarily by means of an interposition graft, followed by exclusion and surgical bypass. Endovascular repair of SFA aneurysms has only been reported in three instances. SFA aneurysm repair was most often associated with favorable outcomes, with low reported rates of ischemia and limb loss.

Aortic paraprosthetic-colonic fistulae: a review of the literature.

BACKGROUND: Aortic graft-colonic fistulae are a rare complication of aortic reconstructive surgery. METHODS AND FINDINGS: A comprehensive review of this entity was performed based on the available literature from 1950 until 2006. Available reports were analyzed with respect to demographics, prior surgical intervention and its indication, prosthetic material used during the initial intervention, clinical presentation, the time interval in between the initial operation and symptoms, the method of treatment of the aortic graft-colonic fistula and its outcome.

Long term cognitive development in children with prolonged crying.

BACKGROUND: Long term studies of cognitive development and colic have not differentiated between typical colic and prolonged crying. OBJECTIVE: To evaluate whether colic and excessive crying that persists beyond 3 months is associated with adverse cognitive development. DESIGN: Prospective cohort study. A sample of 561 women was enrolled in the second trimester of pregnancy. Colic and prolonged crying were based on crying behaviour assessed at 6 and 13 weeks. Children's intelligence, motor abilities, and behaviour were measured at 5 years (n = 327). Known risk factors for cognitive impairment were ascertained prenatally, after birth, at 6 and 13 weeks, at 6, 9, and 13 months, and at 5 years of age. RESULTS: Children with prolonged crying (but not those with colic only) had an adjusted mean IQ that was 9 points lower than the control group. Their performance and verbal IQ scores were 9.2 and 6.7 points lower than the control group, respectively. The prolonged crying group also had significantly poorer fine motor abilities compared with the control group. Colic had no effect on cognitive development. CONCLUSIONS: Excessive, uncontrolled crying that persists beyond 3 months of age in infants without other signs of neurological damage may be a marker for cognitive deficits during childhood. Such infants need to be examined and followed up more intensively.