Development of Preliminary Remission Criteria for Gout Using Delphi and 1000Minds(R) Consensus Exercises
OBJECTIVES: The aim of this study was to establish consensus for potential remission criteria for use in clinical trials of gout.
METHODS: Experts (n=88) in gout from multiple countries were invited to participate in a web-based questionnaire study. Three rounds of Delphi consensus exercises were conducted using SurveyMonkey(R) followed by a discrete choice experiment using 1000Minds(R). The exercises focused on identifying domains, definitions for each domain and the timeframe over which remission should be defined.
RESULTS: There were 49 respondents (56% response) to the initial survey with subsequent response rates ranging from 57% to 90%. Consensus was reached for the inclusion of serum urate (98% agreement), flares (96%), tophi (92%), pain (83%) and patient global assessment (93%) of disease activity as measurement domains in remission criteria. Consensus was also reached for domain definitions including serum urate ( < 0.36mM), pain ( < 2 on a 10-point scale) and patient global assessment ( < 2 on a 10-point scale), all of which should be measured at least twice over a set time interval. Consensus was not achieved in the Delphi exercise for the timeframe for remission with equal responses for six months (51%) and one year (49%). In the discrete choice experiment, there was a preference towards 12 months as a timeframe for remission.
CONCLUSION: These consensus exercises have identified domains and provisional definitions for gout remission criteria. Based on the results of these exercises, preliminary remission criteria are proposed with domains of serum urate, acute flares, tophus, pain and patient global assessment. These preliminary criteria now require testing in clinical datasets.
What started as a peaceful uprising in Syria in March 2011 escalated quickly to an armed conflict. By 2012 conflict had become the leading cause of death of Syrians. Health systems have been reshaped, now being separated into areas controlled by the government, the opposition, or self proclaimed Islamic State factions—we group the last two as non-state armed groups (NSAG; fig 1). These areas differ vastly in terms of service delivery capacity, number of trained staff, and accessto essential medicines.
Indirect conflict related deaths have arisen from poor sanitation and severe disruption to Syria’s healthcare system. In December 2014, 20% of Syria’s public hospitals were completely non-functional, and another 35% provided only partial services. Direct conflict related deaths are those that are caused by weapons and other violent methods used in warfare.
In this article we assess the direct conflict related deaths (hereafter termed violent deaths) of women and children among civilians killed in the Syrian conflict, because they are identified as vulnerable populations in public health and under specific laws of war such as the Geneva Conventions.
Knowledge, Attitudes and Provider Advice by Pre-Pregnancy Weight Status: A Qualitative Study of Pregnant Latinas With Excessive Gestational Weight Gain
Latina women are at high risk of excessive gestational weight gain (GWG) during pregnancy; yet little is known about whether factors related to GWG differ by pre-pregnancy body mass index (BMI) within this population. We conducted in-depth interviews with 62 pregnant Latina women with pre-pregnancy BMIs in the healthy, overweight, and obese ranges, gestational age > /=22 weeks, and GWG for gestational age above Institute of Medicine (IOM) guidelines. Compared to healthy weight and obese women, overweight women least often reported viewing weight as important, making efforts to control their GWG, being aware of the role of diet on GWG, and receiving GWG advice from health-care providers. Among those who received GWG advice, overweight women more often recalled a target GWG above IOM guidelines. Obese women more often reported low acceptance of their GWG, concern about GWG, having received GWG advice from providers, difficulty following providers' dietary advice, and emotional eating as a challenge for controlling GWG. Participants welcomed practical advice to manage GWG. Future interventions to prevent excessive GWG among Latina women should consider differences among women of varying pre-pregnancy BMIs and include multi-level strategies to address psychosocial as well as provider factors.
BACKGROUND: Thyroid diseases affect quality of life (QoL). The Thyroid-Related Patient-Reported Outcome (ThyPRO) is an international comprehensive well-validated patient-reported outcome, measuring thyroid-related QoL. The current version is rather long--85 items. The purpose of the present study was to develop an abbreviated version of the ThyPRO, with conserved good measurement properties.
METHODS: A cross-sectional (N = 907) and a longitudinal sample (N = 435) of thyroid patients were analyzed. A graded item response theory (IRT) model was fitted to the cross-sectional data. Short-form scales with three items were aimed for, by selecting items with best fit according to the IRT model, avoiding cross-culturally noninvariant items. Seven scales measuring mental and social well-being and function as well as one overall QoL impact item were analyzed in a bifactor model, to develop a supplementary composite score. Short-form scales were linked to original scales with IRT-based summed-score-linking. Agreement between the short and long form was estimated by agreement plots, intraclass correlations, and mean score levels. Responsiveness was compared by relative validity indices, clinical validity by ability to detect clinically relevant differences, and test-retest reliability by intra-class correlation.
RESULTS: One four-item scale was not abbreviated and one two-item scale was omitted from the short-form. For the 11 scales undergoing abbreviation, 10 with three and one with four items were developed. A bifactor model with good overall fit was fitted to the composite score, including the single QoL item. Responsiveness and clinical validity of the short-form scales were preserved, as were test-retest reliability (0.75-0.89). Short- versus long-form intraclass correlations were high (0.89-0.98), and the mean scale levels were similar.
CONCLUSIONS: A 39-item version of the ThyPRO, with good measurement properties, was developed and is recommended for clinical use.
Why Women Join the Military: Enlistment Decisions and Postdeployment Experiences of Service Members and Veterans
Over the past three decades women's enlistment has continued to increase. In an effort to help social workers better meet the needs of female veterans, this study sought to learn women's enlistment motivations and postdeployment experiences. This qualitative study was nested within the Women Veterans Cohort Study. Using a semistructured interview guide, authors interviewed 18 enlisted female service members and veterans. The themes that emerged, based on grounded theory, included not only opportunity and calling, but also outcomes. Unexpectedly, enlistment resulted in a professional military career, with over half of the participants making the military their life's work. Further study on the motivation, retention, and the reintegration needs of women postmilitary is necessary, particularly with military recruitment targets of 20 percent women by the year 2020 and the increased awareness of the military as a potentially hostile work environment for women.
Comment on: Postoperative Surveillance and Long-term Outcomes After Endovascular Aneurysm Repair Among Medicare Beneficiaries. [JAMA Surg. 2015]
Prevalence and Correlates of Indoor Tanning in Nonsalon Locations Among a National Sample of Young Women
Indoor tanning is a public health threat, and the Surgeon General has called for its reduction in adolescents and young adults. Research on indoor tanning has not distinguished between tanning-only salons vs other businesses and private residences that provide tanning (ie, nonsalon tanning). For example, gyms often offer free tanning, which may lead to riskier tanning habits. Better understanding of nonsalon tanning could have policy, prevention, and clinical implications. Our study addresses this literature gap by examining the prevalence and correlates of nonsalon tanning in a nationally representative sample of young women, who have the highest rates of indoor tanning use.
National variation in preoperative imaging, carotid duplex ultrasound criteria, and threshold for surgery for asymptomatic carotid artery stenosis
OBJECTIVE: Carotid endarterectomy (CEA) for asymptomatic carotid artery stenosis is among the most common procedures performed in the United States. However, consensus is lacking regarding optimal preoperative imaging, carotid duplex ultrasound criteria, and ultimately, the threshold for surgery. We sought to characterize national variation in preoperative imaging, carotid duplex ultrasound criteria, and threshold for surgery for asymptomatic CEA.
METHODS: The Society for Vascular Surgery Vascular Quality Initiative (VQI) database was used to identify all CEA procedures performed for asymptomatic carotid artery stenosis between 2003 and 2014. VQI currently captures 100% of CEA procedures performed at > 300 centers by > 2000 physicians nationwide. Three analyses were performed to quantify the variation in (1) preoperative imaging, (2) carotid duplex ultrasound criteria, and (3) threshold for surgery.
RESULTS: Of 35,695 CEA procedures in 33,488 patients, the study cohort was limited to 19,610 CEA procedures (55%) performed for asymptomatic disease. The preoperative imaging modality used before CEA varied widely, with 57% of patients receiving a single preoperative imaging study (duplex ultrasound imaging, 46%; computed tomography angiography, 7.5%; magnetic resonance angiography, 2.0%; cerebral angiography, 1.3%) and 43% of patients receiving multiple preoperative imaging studies. Of the 16,452 asymptomatic patients (89%) who underwent preoperative duplex ultrasound imaging, there was significant variability between centers in the degree of stenosis (50%-69%, 70%-79%, 80%-99%) designated for a given peak systolic velocity, end diastolic velocity, and internal carotid artery-to-common carotid artery ratio. Although 68% of CEA procedures in asymptomatic patients were performed for an 80% to 99% stenosis, 26% were performed for a 70% to 79% stenosis, and 4.1% were performed for a 50% to 69% stenosis. At the surgeon level, the range in the percentage of CEA procedures performed for a < 80% asymptomatic carotid artery stenosis is from 0% to 100%. Similarly, at the center level, institutions range in the percentage of CEA procedures performed for a < 80% asymptomatic carotid artery stenosis from 0% to 100%.
CONCLUSIONS: Despite CEA being an extremely common procedure, there is widespread variation in the three primary determinants-preoperative imaging, carotid duplex ultrasound criteria, and threshold for surgery-of whether CEA is performed for asymptomatic carotid stenosis. Standardizing the approach to care for asymptomatic carotid artery stenosis will mitigate the significant downstream effects of this variation on health care costs.
Risk Factors for Relapse and Higher Costs Among Medicaid Members with Opioid Dependence or Abuse: Opioid Agonists, Comorbidities, and Treatment History
Clinical trials show that opioid agonist therapy (OAT) with methadone or buprenorphine is more effective than behavioral treatments, but state policymakers remain ambivalent about covering OAT for long periods. We used Medicaid claims for 52,278 Massachusetts Medicaid beneficiaries with a diagnosis of opioid abuse or dependence between 2004 and 2010 to study associations between use of methadone, buprenorphine or other behavioral health treatment without OAT, and time to relapse and total healthcare expenditures. Cox Proportional Hazards ratios for patients treated with either methadone or buprenorphine showed approximately 50% lower risk of relapse than behavioral treatment without OAT. Expenditures per month were from $153 to $233 lower for OAT episodes compared to other behavioral treatment. Co-occurring alcohol abuse/dependence quadrupled the risk of relapse, other non-opioid abuse/dependence doubled the relapse risk and severe mental illness added 80% greater risk compared to those without each of those disorders. Longer current treatment episodes were associated with lower risk of relapse. Relapse risk increased as prior treatment exposure increased but prior treatment was associated with slightly lower total healthcare expenditures. These findings suggest that the effectiveness of OAT that has been demonstrated in clinical trials persists at the population level in a less controlled setting and that OAT is associated with lower total healthcare expenditures compared to other forms of behavioral treatment for patients with opioid addiction. Co-occurring other substance use and mental illness exert strong influences on cost and risk of relapse, suggesting that individuals with these conditions need more comprehensive treatment.
BACKGROUND: Delirium is common, morbid, and costly, yet is greatly under-recognized among hospitalized older adults.
OBJECTIVE: To identify the best single and pair of mental status test items that predict the presence of delirium.
DESIGN, SETTING: Diagnostic test evaluation study that enrolled medicine inpatients aged 75 years or older at an academic medical center.
METHODS: Patients underwent a clinical reference standard assessment involving a patient interview, medical record review, and interviews with family members and nurses to determine the presence or absence of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition defined delirium. Participants also underwent the three-dimensional Confusion Assessment Method (3D-CAM), a brief, validated assessment for delirium. Individual items and pairs of items from the 3D-CAM were evaluated to determine sensitivity and specificity relative to the reference standard delirium diagnosis.
RESULTS: Of the 201 participants (mean age 84 years, 62% female), 42 (21%) had delirium based on the clinical reference standard. The single item with the best test characteristics was "months of the year backwards" with a sensitivity of 83% (95% confidence interval [CI]: 69%-93%) and specificity of 69% (95% CI: 61%-76%). The best 2-item screen was the combination of "months of the year backwards" and "what is the day of the week?" with a sensitivity of 93% (95% CI: 81%-99%) and specificity of 64% (95% CI: 56%-70%).
CONCLUSIONS: We identified a single item with > 80% and pair of items with > 90% sensitivity for delirium. If validated prospectively, these items will serve as an initial innovative screening step for delirium identification in hospitalized older adults.
Antecedents of the child behavior checklist-dysregulation profile in children born extremely preterm
OBJECTIVE: Extremely preterm newborns are at heightened risk for emotional and behavioral dysregulation later in childhood. Our goal was to systematically evaluate the antenatal and early postnatal antecedents that might mediate the association between extreme preterm birth and emotional and behavioral dysregulation at age 2 years (corrected age).
METHOD: In a multi-site prospective study, the parents of 826 infants born before 28 weeks gestation completed a Child Behavior Checklist (CBCL) when the child was 2 years corrected age. We compared the maternal, pregnancy, placenta, delivery, and newborn characteristics, as well as early postnatal characteristics and exposures of those who satisfied criteria for the CBCL-Dysregulation Profile (CBCL-DP) to those of their peers. We then used time-oriented logistic regression models, starting first with antenatal variables that distinguished children with the CBCL-DP profile from their peers, and then added the distinguishing postnatal variables.
RESULTS: Approximately 9% of the children had a CBCL-DP. In the time-oriented logistic regression model with antenatal variables only, low maternal education achievement, passive smoking, and recovery of Mycoplasma from the placenta were associated with increased risk, whereas histologic chorioamnionitis was associated with reduced risk. None of the postnatal variables added statistically significant discriminating information.
CONCLUSION: Very preterm newborns who later manifest the CBCL-DP at age 2 years differ in multiple ways from their preterm peers who do not develop the CBCL-DP, raising the possibility that potentially modifiable antenatal and early postnatal phenomena contribute to the risk of developing emotional and behavioral dysregulation.
The remote brief intervention and referral to treatment model: Development, functionality, acceptability, and feasibility
BACKGROUND: Screening, brief intervention, and referral to treatment (SBIRT) is effective for reducing risky alcohol use across a variety of medical settings. However, most programs have been unsustainable because of cost and time demands. Telehealth may alleviate on-site clinician burden. This exploratory study examines the feasibility of a new Remote Brief Intervention and Referral to Treatment (R-BIRT) model.
METHODS: Eligible emergency department (ED) patients were enrolled into one of five models. (1) Warm Handoff: clinician-facilitated phone call during ED visit. (2) Patient Direct: patient-initiated call during visit. (3) Electronic Referral: patient contacted by R-BIRT personnel post visit. (4) Patient Choice: choice of models 1-3. (5) Modified Patient Choice: choice of models 1-2, Electronic Referral offered if 1-2 were declined. Once connected, a health coach offered assessment, counseling, and referral to treatment. Follow up assessments were conducted at 1 and 3 months. Primary outcomes measured were acceptance, satisfaction, and completion rates.
RESULTS: Of 125 eligible patients, 50 were enrolled, for an acceptance rate of 40%. Feedback and satisfaction ratings were generally positive. Completion rates were 58% overall, with patients enrolled into a model wherein the consultation occurred during the ED visit, as opposed to after the visit, much more likely to complete a consultation, 90% vs. 10%, chi(2) (4, N=50)=34.8, p < 0.001.
CONCLUSIONS: The R-BIRT offers a feasible alternative to in-person alcohol SBIRT and should be studied further. The public health impact of having accessible, sustainable, evidence-based SBIRT for substance use across a range of medical settings could be considerable.
A Comparison of Training Experience, Training Satisfaction, and Job Search Experiences between Integrated Vascular Surgery Residency and Traditional Vascular Surgery Fellowship Graduates
BACKGROUND: The first 2 integrated vascular residents in the United States graduated in 2012, and in 2013, 11 more entered the job market. The purpose of this study was to compare the job search experiences of the first cohort of integrated 0 + 5 graduates to their counterparts completing traditional 5 + 2 fellowship programs.
METHODS: An anonymous, Web-based, 15-question survey was sent to all 11 graduating integrated residents in 2013 and to the 25 corresponding 5 + 2 graduating fellows within the same institution. Questions focused on the following domains: training experience, job search timelines and outcomes, and overall satisfaction with each training paradigm.
RESULTS: Survey response was nearly 81% for the 0 + 5 graduates and 64% for the 5 + 2 graduates. Overall, there was no significant difference between residents and fellows in the operative experience obtained as measured by the number of open and endovascular cases logged. Dedicated research time during the entire training period was similar between residents and fellows. Nearly all graduates were extremely satisfied with their training and had positive experiences during their job searches with respect to starting salaries, numbers of offers, and desired practice type. More 0 + 5 residents chose academic and mixed practices over private practices compared with 5 + 2 fellowship graduates.
CONCLUSIONS: Although longer term data are needed to understand the impact of the addition of 0 + 5 graduating residents to the vascular surgery work force, preliminary survey results suggest that both training paradigms (0 + 5 and 5 + 2) provide positive training experiences that result in excellent job search experiences. Based on the current and future need for vascular surgeons in the work force, the continued growth and expansion of integrated 0 + 5 vascular surgery residency positions as an alternative to traditional fellowship training is thus far justified.
Evaluating Use of Higher Dose Oxybutynin in Combination with Desmopressin for Refractory Nocturnal Enuresis
Background: Nocturnal enuresis is a common pediatric condition with limited treatment options. In older children, pharmacologic therapy is often the preferred treatment. Pharmacologic therapies including Desmopressin (DDAVP) or Imipramine are effective in 40-50% of children. However Imipramine has serious safety concerns. DDAVP in combination with a fixed dose anticholinergic has been shown to be useful in individuals who fail DDAVP monotherapy, but still fails to achieve success rates greater than 60%.
Objective: Our goal is to explore the efficacy and safety of using combination therapy DDAVP plus Oxybutynin with increasing dose ofOxybutynin in patients refractory to standard combination therapy.
Study Design: A single institution, IRB approved, retrospective chart review of 61 patients (ages 7-18) including those with monosymptomatic primary nocturnal enuresis and non-monosymptomatic enuresis with Controlled Daytime Voiding Symptoms (CDVS) treated initially with DDAVP. All patients who failed initial therapy with DDAVP were started on combination therapy DDAVP (0.6 mg) plus standard dose (5 mg) Oxybutynin. In patients who failed standard combination therapy, the dose of Oxybutynin was titrated upwards until response or maximum dose 10 mg was achieved. Demographic and medical history data were evaluated to determine predictive factors associated with response/failure to different therapy groups.
Results: The use of escalating doses of Oxybutynin in combination with DDAVP achieved an overall response rate of 96.7% defined as a two-week period without any enuretic events following initiation oftreatment. Low Dose Combination Therapy (LDCT) (0.6mg DDAVP + 5 mg Oxybutynin) had a response rate of 68%. Advanced Dose Combination Therapy (ADCT) (0.6 mg DDAVP + 7.5-10 mg Oxybutynin) had a response rate of75.0%. A statistically significant relationship was found correlating both ADD/ADHD and CDVS with failure on monotherapy. No patients in the study reported any adverse events or side effects from the medications.
Discussion: The overall success rate of 96.7% with titrated doses of Oxybutynin in combination with DDAVP is considerably higher than the response rates on fixed dose combination therapy quoted in the literature and supports the need for further evaluation in larger studies. Additionally, we found a statistically significant association between monotherapy failure and children with either ADD/ADHD or controlled daytime voiding symptoms. Our study is limited by small numbers and larger studies are needed to confirm these results.
Conclusion: Our results suggest that ADCT is a safe and effective treatment option for primary nocturnal enuresis refractory to standard and low dose combination therapy.
Multiple Imputation based Clustering Validation (MIV) for Big Longitudinal Trial Data with Missing Values in eHealth
Web-delivered trials are an important component in eHealth services. These trials, mostly behavior-based, generate big heterogeneous data that are longitudinal, high dimensional with missing values. Unsupervised learning methods have been widely applied in this area, however, validating the optimal number of clusters has been challenging. Built upon our multiple imputation (MI) based fuzzy clustering, MIfuzzy, we proposed a new multiple imputation based validation (MIV) framework and corresponding MIV algorithms for clustering big longitudinal eHealth data with missing values, more generally for fuzzy-logic based clustering methods. Specifically, we detect the optimal number of clusters by auto-searching and -synthesizing a suite of MI-based validation methods and indices, including conventional (bootstrap or cross-validation based) and emerging (modularity-based) validation indices for general clustering methods as well as the specific one (Xie and Beni) for fuzzy clustering. The MIV performance was demonstrated on a big longitudinal dataset from a real web-delivered trial and using simulation. The results indicate MI-based Xie and Beni index for fuzzy-clustering are more appropriate for detecting the optimal number of clusters for such complex data. The MIV concept and algorithms could be easily adapted to different types of clustering that could process big incomplete longitudinal trial data in eHealth services.
Sammon mapping is a widely used visualization technique to display complex data from high-to low-dimensional space. However, its extensive computational cost may pose potential computational challenges to big data visualization. This paper proposes a computationally-enhanced Sammon mapping (ESammon) by leveraging the characteristics of spatial data density. Unlike the conventional Sammon, ESammon preserves critical pairwise distances between data points in the process of projection, instead of all distances. Specifically, we integrated the Directed-Acyclic-Graph (DAG) based data density characterization method to select the critical distances. The numerical results demonstrated that our ESammon can achieve comparable projection results as the conventional Sammon mapping while reducing the computational cost from O(N2) to O(N).
We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5(-/-) LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5(-/-) LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and beta-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML.
Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML.
Durable Results with In Situ Graft Repair of Ruptured Salmonella Aneurysm in a Patient with Autoimmune Deficiency Syndrome
We describe a case of a 42-year-old male patient with advanced autoimmune deficiency syndrome (AIDS) (CD4 count of 16 cells/mm) found to have a ruptured infected infrarenal aortic aneurysm. Emergent in situ repair was performed with a Hemashield Dacron graft (Boston Scientific, Natick, MA). Aortic tissue cultures grew group DSalmonella. Patient was placed initially on intravenous ciprofloxacin followed by lifelong oral levofloxacin and trimethoprim. Over 2 years following repair, he remains asymptomatic, with repair intact and no recurrent infection. This case is the first reported successful long-term repair of a ruptured salmonella infected abdominal aortic aneurysm in the setting of advanced AIDS.
Association between First Trimester Pregnancy Associated Plasma Protein–A (PAPP-A) and Gestational Diabetes Mellitus Development
Background: Gestational diabetes (GDM) is a common pregnancy complication with significant cardiometabolic consequences for mothers and offspring. Previous research from our group suggests that adipose tissue IGFBP-5 and its unique metalloprotease PAPP-A (Pregnancy Associated Plasma Protein-A) may play mechanistic roles in GDM development by regulating functional IGF-1 levels and lipid storage and metabolism.
Aim: To examine the relationship between circulating PAPP-A levels and GDM development. We hypothesized that high first trimester PAPP-A levels would be associated with decreased GDM risk.
Methods: A retrospective cohort of women delivering singleton gestations at UMass Memorial Healthcare (2009, 2010, 2014, 2015) was assembled by abstracting electronic medical records. PAPP-A was measured in first trimester (11-14 weeks), and reported as quartiles of multiples of the mean (MoM) based on gestational age and adjusted for maternal weight and race/ethnicity. GDM diagnosis based on standard 2-step protocol (~24-28 weeks; failed 50g 1hr glucola screen then ≥2 abnormal values per Carpenter-Coustan criteria on 100g 3hr glucose tolerance test). Crude and multivariable-adjusted logistic regression models estimated the association between PAPP-A MoM quartiles and GDM.
Results: Women (N=1,251) were 29.7 (SD:5.7) years old and 12.5 (SD:0.6) weeks gestation at PAPP-A measurement. 7.6% (n=95) developed GDM. Median PAPP-A MoM were 0.7 (inter-quartile range [IQR]=0.5-1.0) among women with GDM and 0.9 (IQR=0.6-1.3) among controls; 39% versus 23% were in the 1st quartile, respectively. After adjusting for pre-pregnancy body mass index, nuchal translucency, crown rump length, smoking status, and parity, women with PAPP-A MoM in 2nd, 3rd, and 4th quartiles had 52% (OR=0.48, 95%CI=0.26-0.88), 45% (OR=0.55, 95%CI=0.30-0.99) and 73% (OR=0.27, 95%CI=0.13-0.53) lower odds of GDM compared to women in the 1st quartile.
Conclusion: Higher PAPP-A MoM levels were associated with lower GDM risk. Future studies will assess whether higher PAPP-A levels are associated with enhanced IGF-1 signaling and improved pregnancy metabolic homeostasis.