Vitamin D and its associations with blood pressure in the Chronic Kidney Disease in Children (CKiD) cohort.

BACKGROUND: Vitamin D (25OHD) can modulate pathways and mechanisms that regulate blood pressure (BP). Observational studies in children and adults have shown an inverse association between 25OHD and BP. Studies evaluating associations between 25OHD and BP in pediatric chronic kidney disease are limited. METHODS: We evaluated the associations between 25OHD and BP using data from the Chronic Kidney Disease in Children (CKiD) study. Clinic or ambulatory BP index was defined as participant's BP divided by 95th age-sex-height-specific BP percentile, an index > 1 suggests hypertension. Primary outcomes of interest were changes in systolic and diastolic clinic and ambulatory BP indices over follow-up. Linear mixed-effects models were used to evaluate associations between BP indices and 25OHD. RESULTS: The study cohort consisted of 370 participants who contributed 970 person-visits. A subset of 194 participants with ambulatory BP data contributed 465 person-visits. There was an association between baseline 25OHD levels and clinic systolic BP index such that for every 10 ng/ml lower 25OHD, clinic systolic BP index was 1.0% higher (95%CI: 0.2-1.8, p = 0.016) between participants. The association between clinic diastolic BP index with baseline 25OHD was not significant. For within-person changes, longitudinal decreases in 25OHD were not significantly associated with concomitant increases in clinic systolic or diastolic BP index. There were no significant associations between 25OHD levels at baseline or longitudinally with 24-h ABPM indices. CONCLUSIONS: Low 25OHD levels were associated with higher clinic systolic BP in children with CKD. Vitamin D supplementation to maintain normal 25OHD levels might be a useful adjunctive treatment in optimizing BP control in these high-risk patients.

Evaluation of acquired antithrombin deficiency in paediatric patients supported on extracorporeal membrane oxygenation.

AIMS: There remains a paucity of literature regarding best practice for antithrombin (AT) monitoring, dosing and dose-response in paediatric extracorporeal membrane oxygenation (ECMO) patients. METHODS: We conducted a retrospective cohort study at a quaternary care paediatric intensive care unit in all patients <18 years of age supported on ECMO from 1 June 2011 to 30 April 2020. Adverse events and outcomes were characterized for all ECMO runs. AT activity and replacement were characterized and compared between two clinical protocols. AT activities measured post- vs. pre-AT replacement were compared in order to characterize a dose-response relationship. RESULTS: The final cohort included 191 patients with 201 ECMO runs and 2028 AT activity measurements. The median AT activity was 65% (interquartile range [IQR], 51-82) and 879 (43.3%) measurements met the criteria of deficient. The overall median AT dose and increase in AT activity were 50.6 units/kg/dose (IQR, 39.5-67.2) and 23.5% (IQR, 9.8-36.0), respectively. In the protocol that restricted AT activity measurements to clinical scenarios concerning for heparin resistance, there was significantly higher dosing in conjunction with significantly fewer overall administrations. Approximately one third of AT activity remained deficient after repletion. There was no difference in mechanical complications, reasons for discontinuation of ECMO support, time on ECMO or survival between protocols. CONCLUSIONS: There was a high prevalence of AT deficiency in paediatric ECMO patients. An AT replacement protocol based on evaluating heparin resistance is associated with fewer AT administrations, with similar circuit and patient outcomes. Further data are needed to identify optimal dosing strategies.

Longitudinal changes in uric acid concentration and their relationship with chronic kidney disease progression in children and adolescents.

BACKGROUND: Elevated serum uric acid concentration is a risk factor for CKD progression. Its change over time and association with CKD etiology and concomitant changes in estimated glomerular filtration rate (eGFR) in children and adolescents are unknown. METHODS: Longitudinal study of 153 children/adolescents with glomerular (G) and 540 with non-glomerular (NG) etiology from the CKD in Children (CKiD) study. Baseline serum uric acid, change in uric acid and eGFR over time, CKD etiology, and comorbidities were monitored. Adjusted linear mixed-effects regression models quantified the relationship between within-person changes in uric acid and concurrent within-person changes in eGFR. RESULTS: Participants with stable uric acid over follow-up had CKD progression which became worse for increased baseline uric acid (average annual percentage changes in eGFR were - 1.4%, - 7.7%, and - 14.7% in those with G CKD with baseline uric acid < 5.5 mg/dL, 5.5 - 7.5 mg/dL, and > 7.5 mg/dL, respectively; these changes were - 1.4%, - 4.1%, and - 8.6% in NG CKD). Each 1 mg/dL increase in uric acid over follow-up was independently associated with significant concomitant eGFR decreases of - 5.7% (95%CI - 8.4 to - 3.0%) (G) and - 5.1% (95%CI - 6.3 to - 4.0%) (NG) for those with baseline uric acid < 5.5 mg/dL and - 4.3% (95%CI - 6.8 to - 1.6%) (G) and - 3.3% (95%CI - 4.1 to - 2.6%) (NG) with baseline uric acid between 5.5 and 7.5 mg/dL. CONCLUSIONS: Higher uric acid levels and increases in uric acid over time are risk factors for more severe progression of CKD in children and adolescents. A higher resolution version of the Graphical abstract is available as Supplementary information.

Associations of body mass index (BMI) and BMI change with progression of chronic kidney disease in children.

BACKGROUND: Obesity is prevalent among children with chronic kidney disease (CKD) and is associated with cardiovascular disease and reduced quality of life. Its relationship with pediatric CKD progression has not been described. METHODS: We evaluated relationships between both body mass index (BMI) category (normal, overweight, obese) and BMI z-score (BMIz) change on CKD progression among participants of the Chronic Kidney Disease in Children study. Kaplan-Meier survival curves and multivariable parametric failure time models depict the association of baseline BMI category on time to kidney replacement therapy (KRT). Additionally, the annualized percentage change in estimated glomerular filtration rate (eGFR) was modeled against concurrent change in BMIz using multivariable linear regression with generalized estimating equations which allowed for quantification of the effect of BMIz change on annualized eGFR change. RESULTS: Participants had median age of 10.9 years [IQR: 6.5, 14.6], median eGFR of 50 ml/1.73 m2 [IQR: 37, 64] and 63% were male. 160 (27%) of 600 children with non-glomerular and 77 (31%) of 247 children with glomerular CKD progressed to KRT over a median of 5 years [IQR: 2, 8]. Times to KRT were not significantly associated with baseline BMI category. Children with non-glomerular CKD who were obese experienced significant improvement in eGFR (+ 0.62%; 95% CI: + 0.17%, + 1.08%) for every 0.1 standard deviation concurrent decrease in BMI. In participants with glomerular CKD who were obese, BMIz change was not significantly associated with annualized eGFR change. CONCLUSION: Obesity may represent a target of intervention to improve kidney function in children with non-glomerular CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Associations between collagen X biomarker and linear growth velocity in a pediatric chronic kidney disease cohort.

BACKGROUND: Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measured growth velocity in children with impaired kidney function. METHODS: We used data from children aged 2 through 16 years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up. RESULTS: A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1 cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1 cm/year change in measured growth. CONCLUSIONS: CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Left Ventricular Diastolic Dysfunction Among Youth with Obesity and History of Elevated Blood Pressure.

OBJECTIVE: To assess prevalence of and factors associated with left ventricular diastolic dysfunction (LVDD) in youth with obesity and elevated blood pressure (BP). STUDY DESIGN: This was a cross-sectional analysis of baseline and follow-up visits of 83 youth, 5-21 years, evaluated for overweight/obesity and elevated BP in a multidisciplinary clinic. LVDD was defined according to established adult criteria (LVDDadult; E/A < 1, E/e' > 14, or e'/a' < 0.8) and pediatric criteria (LVDDpeds; E/A <10th percentile, E/e' >99th percentile, or e'/a' <1st percentile) based on data from 103 age-sex matched healthy controls. Baseline factors associated with LVDDpeds were examined using Wilcoxon rank sum and χ2 tests. Multiple logistic regression analyses using generalized estimating equations to account for repeated measures evaluated the associations of adiposity and BP with LVDDpeds. RESULTS: The prevalence of LVDD ranged from 1.2% to 2.7% when we used adult criteria and 19% to 28% when we used pediatric criteria. Those with LVDDpeds were older, predominantly male, and non-African American and had greater weight, BP, BP medication use, and non-high-density lipoprotein cholesterol than those without LVDDpeds. Diastolic BP z score was associated with LVDDpeds by E/A (OR 1.95, 95% CI 1.15-3.32, P = .014) after we adjusted for age, sex, race, BP medications, and body mass index z score. CONCLUSIONS: LVDD was present in a substantial proportion of youth with overweight/obesity and elevated BP using pediatric criteria. Those with LVDDpeds had significantly greater measures of adiposity and BP compared with those without LVDDpeds, and diastolic BP z score was an independent predictor of LVDDpeds by E/A. These data emphasize the importance of prevention and treatment of cardiovascular disease risk factors in childhood.

Social Determinants of Cardiovascular Health in African American Children With CKD: An Analysis of the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: To identify differences in socioeconomic factors (SES) and subclinical cardiovascular disease (CVD) markers by race among Chronic Kidney Disease in Children (CKiD) participants and determine whether differences in CVD markers persist after adjusting for SES. STUDY DESIGN: Analysis of 3,103 visits with repeated measures from 628 children (497 White participants; 131 African American participants) enrolled in the CKiD study. SETTING & PARTICIPANTS: Children with mild-moderate CKD with at least 1 cardiovascular (CV) parameter (ambulatory blood pressure, left ventricular mass index [LVMI], or lipid profile) measured. EXPOSURE: African American race. OUTCOMES: Ambulatory hypertension, LVMI, triglycerides, high-density lipoprotein cholesterol. ANALYTICAL APPROACH: Due to increased CV risks of glomerular disease, the analysis was stratified by CKD cause. Inverse probability weighting was used to adjust for SES (health insurance, household income, maternal education, food insecurity, abnormal birth history). Linear and logistic regression were used to evaluate association of race with CV markers. RESULTS: African American children were disproportionately affected by adverse SES. African Americans with nonglomerular CKD had more instances of ambulatory hypertension and higher LVMI but more favorable lipid profiles. After adjustment for SES, age, and sex, the magnitude of differences in these CV markers was attenuated but remained statistically significant. Only LVMI differed by race in the glomerular CKD group, despite adjustment for SES. LIMITATIONS: Study design limits causal inference. CONCLUSION: African American children with CKD are disproportionately affected by socioeconomic disadvantages compared with White children. The degree to which CV markers differ by race is influenced by disease etiology. African Americans with nonglomerular CKD have increased LVMI, more ambulatory hypertension, and favorable lipid profile, but attenuation in magnitude after adjustment for SES was observed. African Americans with glomerular CKD had increased LVMI, which persisted after SES adjustment. As many social determinants of health were not captured, future research should examine effects of systemic racism on CV health in this population.

Longitudinal outcomes of body mass index in overweight and obese children with chronic kidney disease.

BACKGROUND: Longitudinal changes in body mass index (BMI) among overweight and obese children with chronic kidney disease (CKD) are not well characterized. We studied longitudinal trajectories and correlates of these trajectories, as results may identify opportunities to optimize health outcomes. METHODS: Longitudinal changes in age-sex-specific BMI z-scores over 1851 person-years of follow-up were assessed in 524 participants of the Chronic Kidney Disease in Children Study. A total of 353 participants were categorized as normal (BMI > 5th to < 85th percentile), 56 overweight (BMI ≥ 85th to 95th percentile) and 115 obese (BMI ≥ 95th percentile) based on the average of three BMI measurements during the first year of follow-up. Studied covariates included age, sex, race, CKD etiology, corticosteroid usage, household income, and maternal education. RESULTS: In unadjusted analysis, BMI z-scores decreased over time in elevated BMI groups (overweight: mean = - 0.06 standard deviations (SD) per year, 95% CI: - 0.11, - 0.01; obese: mean = - 0.04 SD per year, 95% CI: - 0.07, - 0.01). Among obese children, only age was associated with change in BMI z-score; children < 6 years had a mean decrease of 0.19 SD during follow-up (95% CI: - 0.30, - 0.09). Socioeconomic factors were not associated with change in BMI. CONCLUSION: Overweight and obese children with CKD demonstrated a significant annual decline in BMI, though the absolute change was modest. Among obese children, only age < 6 years was associated with significant decline in BMI. Persistence of elevated BMI in older children and adolescents with CKD underscores the need for early prevention and effective intervention.

Plasma Soluble Urokinase Plasminogen Activator Receptor (suPAR) and CKD Progression in Children.

RATIONALE & OBJECTIVE: Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker associated with incident chronic kidney disease (CKD) and has been identified as an independent risk factor for CKD progression in children, although these findings remain preliminary, limited to a single point in time, and unreplicated in pediatric cohorts. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 565 participants aged 1 to 16 years enrolled in the Chronic Kidney Disease in Children (CKiD) Study. EXPOSURE: Plasma suPAR levels, categorized by quartiles, measured at study entry and a 6-month follow-up interval. OUTCOME: CKD progression, defined as the initiation of kidney replacement therapy (dialysis or transplantation) or >50% decline in estimated glomerular filtrate rate (eGFR). ANALYTIC APPROACH: Associations between plasma suPAR quartiles and risk for CKD progression were estimated using lognormal survival models, adjusting for potential confounders. RESULTS: Participants in the highest suPAR quartile experienced 54% faster progression compared with the lowest quartile after adjustment for demographic and traditional CKD risk factors (P < 0.001). Addition of eGFR to the model attenuated the risk, although those in the highest quartile experienced 33% faster progression compared with the lowest quartile (P = 0.008). Plasma suPAR levels showed little change over 6 months. LIMITATIONS: Potential for residual confounding, reliance on observational data, relatively fewer patients with higher eGFRs for subgroup analysis. CONCLUSIONS: Higher suPAR levels are associated with shorter time to kidney replacement therapy or halving of eGFR in children with CKD. This association is attenuated slightly with inclusion of eGFR in regression modeling but remains a significant association for participants with the highest suPAR levels.

Adiposity, Sex, and Cardiovascular Disease Risk in Children With CKD: A Longitudinal Study of Youth Enrolled in the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Traditional and nontraditional cardiovascular disease risk factors are highly prevalent in children with chronic kidney disease (CKD). We examined the longitudinal association of adiposity with cardiac damage among children with CKD and explored whether this association was modified by sex. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study at 49 pediatric nephrology centers across North America. EXPOSURE: Age- and sex-specific body mass index (BMI) z score. OUTCOME: Age- and sex-specific left ventricular mass index (LVMI) z score and left ventricular hypertrophy (LVH). ANALYTICAL APPROACH: Longitudinal analyses using mixed-effects models to estimate sex-specific associations of BMI z scores with LVMI z score and with LVH, accounting for repeated measurements over time. RESULTS: Among 725 children with 2,829 person-years of follow-up, median age was 11.0 years and median estimated glomerular filtration rate was 52.6mL/min/1.73m2. Nearly one-third of both boys and girls were overweight or obese, median LVMI z score was 0.18 (IQR: -0.67, 1.08), and 11% had LVH. Greater BMI z scores were independently associated with greater LVMI z scores and greater odds of LVH. For each 1-unit higher BMI z score, LVMI z score was 0.24 (95% CI, 0.17-0.31) higher in boys and 0.38 (95% CI, 0.29-0.47) higher in girls (Pinteraction = 0.01). For each 1-unit higher BMI z score, the odds of LVH was 1.5-fold (95% CI, 1.1-2.1) higher in boys and 3.1-fold (95% CI, 1.8-4.4) higher in girls (Pinteraction = 0.005). LIMITATIONS: Not all children had repeated measurements. LVH is a surrogate and not a hard cardiac outcome. The observational design limits causal inference. CONCLUSIONS: In children, adiposity is independently associated with the markers of cardiac damage, LVMI z score and LVH. This association is stronger among girls than boys. Pediatric overweight and obesity may therefore have a substantial impact on cardiovascular risk among children with CKD.

Correction to: Mode of initial renal replacement therapy and transplant outcomes in the chronic kidney disease in children (CKiD) study.

The original version of this article unfortunately contained a mistake.

Mode of initial renal replacement therapy and transplant outcomes in the chronic kidney disease in children (CKiD) study.

BACKGROUND: Kidney transplant is the renal replacement therapy (RRT) of choice for children with end stage kidney disease (ESKD). Only 21.3% of children who initiate RRT receive a preemptive kidney transplant (PKT). We characterized the transition to RRT in children in the CKiD cohort including the prevalence of dialysis as first RRT vs. PKT and graft survival. METHODS: 258 children enrolled in CKiD have initiated RRT, and 202 had post-RRT initiation data collected through phone or in-person follow-up. Characteristics by first RRT modality were compared using Chi-square and Kruskal-Wallis tests. Parametric-accelerated failure time models were fit for transplantation. Graft failure was characterized using Kaplan-Meier methods and log rank tests. RESULTS: Sixty-one percent received dialysis as first RRT modality and 39% PKT. Those with PKT were less likely to have glomerular disease and to be African-American, and had higher household-income. African-American subjects were nearly twice as likely to undergo dialysis prior to transplant. Those with a living donor and a college-educated mother had 40%-decreased odds of being dialysis experienced. Children with PKT were more likely to receive a living donor transplant. Only 5% of PKT subjects had graft failure by 4 years compared to 16% of those initially treated with dialysis (p = 0.092); however, after adjustment the effect of dialysis exposure was attenuated (p = 0.206). CONCLUSION: CKiD subjects undergo PKT more often compared to nationally-reported rates, and are more likely to receive a kidney transplant within 1 year of starting dialysis. African-American race and lower household-income are associated with decreased access to PKT.

Longitudinal Changes in the Genital Hiatus Preceding the Development of Pelvic Organ Prolapse.

We aimed to explore relationships between changes in genital hiatus (GH) and development of pelvic organ prolapse using data from the Mothers' Outcomes After Delivery (MOAD) Study, a Baltimore, Maryland, cohort study of parous women who underwent annual assessments during 2008-2018. Prolapse was defined as any vaginal segment protrusion beyond the hymen or reported prolapse surgery. For each case, 5 controls (matched on birth type and interval from first delivery to study enrollment) were selected using incidence sampling methods. We used a mixed model whose fixed effects described the initial size and slope of the GH as a function of prolapse status (case vs. control) and with nested (women within matched sets) random effects. Among 1,198 women followed for 1.0-7.3 years, 153 (13%) developed prolapse; 754 controls were matched to those women, yielding 3,664 visits for analysis. GH was 20% larger among the cases at enrollment (3.16 cm in cases vs. 2.62 cm in controls; P < 0.001), and the mean rate of increase in the size of the GH was more than 3 times greater (0.56 cm per 5-year period vs. 0.15 cm per 5-year period in controls; P < 0.001). Thus, to identify women at highest risk for developing prolapse, health-care providers could evaluate not simply the size of the GH but also changes in the GH over time.

Pelvic organ prolapse as a function of levator ani avulsion, hiatus size, and strength.

BACKGROUND: Obstetrical levator ani muscle avulsion is detected after 10%-30% of vaginal deliveries and is associated with pelvic organ prolapse later in life. However, the mechanism by which levator avulsion may contribute to prolapse is unknown. OBJECTIVES: This study investigated the extent by which size of the levator hiatus and pelvic muscle weakness may explain the association between levator avulsion and pelvic organ prolapse. STUDY DESIGN: This was a supplementary study of a longitudinal cohort of parous women enrolled 5-10 years after first delivery and assessed annually for prolapse (defined as descent beyond the hymen) for up to 9 annual visits. For this substudy, vaginally parous participants were assessed for levator avulsion using 3-dimensional transperineal ultrasound. Ultrasound was performed at a median interval of 11 years from delivery. Ultrasound volumes also were used to measure levator hiatus area with Valsalva. Pelvic muscle strength was measured with perineometry. Women with and without pelvic organ prolapse were compared for levator avulsion, levator hiatus area, and pelvic muscle strength, using multivariable logistic regression yielding a measure of mediation. Bootstrap methods were used to calculate the confidence interval corresponding to the measure of mediation by hiatus area and pelvic muscle strength. RESULTS: Prolapse was identified in 109 of 429 (25%) and was significantly associated with levator avulsion (odds ratio, 4.17; 95% confidence interval, 2.28-7.31). Prolapse also was associated with levator hiatus area (odds ratio, 1.52 per 5 cm2; 95% confidence interval, 1.34-1.73) and inversely with muscle strength (odds ratio, 0.87 per 5 cm H2O; 95% confidence interval, 0.81-0.94). In a multivariable logistic model including levator avulsion, levator hiatus area, and strength, the association between levator avulsion and prolapse was substantially attenuated and indeed was no longer statistically significant (odds ratio, 1.75; 95% confidence interval, 0.91-3.39). Hiatus area and strength mediated 61% (95% confidence interval, 34%-106%) of the association between avulsion and prolapse. Furthermore, since the 95% confidence interval for this estimate contained 100%, it cannot be ruled out that the 2 markers fully mediate the effect of avulsion on prolapse. CONCLUSIONS: The strong association between pelvic organ prolapse and levator avulsion can be explained to a large extent by a larger levator hiatus and weaker pelvic muscles after levator avulsion.

Breastfeeding and pelvic floor disorders one to two decades after vaginal delivery.

BACKGROUND: Postpartum recovery from pelvic floor trauma associated with vaginal delivery may be impaired by the transient hypoestrogenic state associated with breastfeeding. OBJECTIVE: The aim of our study was to examine the association between exclusive breastfeeding and pelvic floor disorders 1-2 decades after the first vaginal delivery. We hypothesize that compared with women who did not breastfeed following vaginal delivery, women who breastfeed would have a higher proportion of pelvic floor disorders s, and those women who practiced sustained exclusive/unsupplemented breastfeeding would have the highest proportion. STUDY DESIGN: This is a secondary analysis of the Mothers' Outcomes After Delivery study, a prospective cohort study of pelvic floor disorders after childbirth. Participants were recruited 5-10 years after their first delivery and followed up annually for up to 9 years. This analysis focused on participants who experienced at least 1 vaginal delivery. Each participant completed a self-administered questionnaire regarding breastfeeding. Based on questionnaire responses, breastfeeding status was classified into 3 ordinal categories: unexposed (did not breastfeed or breastfed <1 week); limited exclusive breastfeeding (breastfed without supplementation for ≥1 week but <12 weeks); and sustained exclusive breastfeeding (unsupplemented breastfeeding ≥12 weeks). Our primary outcomes of interest were the proportions of stress urinary incontinence, anal incontinence, and pelvic organ prolapse. The outcomes of interest were defined using the Epidemiology of Prolapse and Incontinence Questionnaire and the Pelvic Organ Prolapse Quantification Examination at enrollment and annually for up to 9 years thereafter. Additionally, a subanalysis examined the relationship between breastfeeding and anal incontinence in an obstetric anal sphincter injury-specific population. Generalized estimating equations were utilized to determine the relationship between breastfeeding and the outcomes of interest. RESULTS: Among 705 women, 189 (27%) were classified as unexposed, 145 (20%) were categorized as limited exclusive breastfeeding, and the remaining 371 women (53%) met our definition of sustained exclusive breastfeeding. Median follow-up was 5 years, contributing to a total of 3079 person years. The proportion of each pelvic floor disorder, based on 3079 person-years of follow-up was: stress urinary incontinence (27%), pelvic organ prolapse (20%), or anal incontinence (25%). Using generalized estimating equations adjusting for race, education, parity, and body mass index, sustained exclusive breastfeeding was not significantly associated with stress urinary incontinence (adjusted odds ratio, 0.82, 95% confidence interval, 0.55-1.23), pelvic organ prolapse (adjusted odds ratio, 0.78, 95% confidence interval, 0.49-1.26), and anal incontinence (adjusted odds ratio, 0.67, 95% confidence interval, 0.44-1.00). Regarding our obstetric anal sphincter injury subanalysis, 123 women within our cohort experienced obstetric anal sphincter injuries at delivery. Anal incontinence was reported in 32% of these women. However, there was no observed relationship between breastfeeding and the development of anal incontinence during study follow-up in this population. CONCLUSION: Breastfeeding after vaginal childbirth was not associated with the development of stress urinary incontinence, pelvic organ prolapse, or anal incontinence 1-2 decades after the first vaginal delivery.

Longitudinal study of quantitative changes in pelvic organ support among parous women.

BACKGROUND: Pelvic organ prolapse is more common among parous (vs nulliparous) women and also more common after vaginal (vs cesarean) birth. However, very little is known about how childbirth affects the course and progression of the genital hiatus across a woman's life span. OBJECTIVE: The objective of the sttudy was to investigate the longitudinal, quantitative changes in pelvic organ support after childbirth, focusing on the impact of vaginal vs cesarean delivery. STUDY DESIGN: This was a prospective longitudinal cohort study in which parous women were recruited 5-10 years from first delivery and followed up annually. Using data from annual pelvic organ prolapse quantification examinations, we considered changes in vaginal support at the anterior vaginal wall (point Ba), the vaginal apex (point C), and the posterior wall (point Bp). In univariate and multivariable models, we compared pelvic organ support between women who had delivered at least 1 child vaginally vs those delivered exclusively by cesarean. Other covariates considered included race, age at first delivery, and the size of the genital hiatus. For models of support at Ba and Bp, we also considered the independent association with apical support. For women who delivered vaginally, we also considered forceps birth. RESULTS: A total of 1224 women participated for a total of 7055 woman-visits. In multivariable models, vaginal birth was associated with significantly worse support 5 years from first delivery. Also, women with at least 1 vaginal birth had more rapid worsening of support at point C. The width of the genital hiatus was a significant independent predictor of worse support 5 years from delivery as well as the rate of change over time. In models that controlled for the genital hiatus, the strength of the impact of vaginal birth was attenuated. CONCLUSION: Vaginal birth was associated with worse support 5 years from first delivery and with more rapid deterioration in support at the apex. Above and beyond the impact of vaginal birth, the size of the genital hiatus may be an independent marker for those at greatest risk of prolapse progression.

Longitudinal changes in pelvic floor muscle strength among parous women.

BACKGROUND: There is limited knowledge of the effects of time on change in pelvic floor muscle strength after childbirth. OBJECTIVE: The objectives of this study were to estimate the change in pelvic floor muscle strength in parous women over time and to identify maternal and obstetric characteristics associated with the rate of change. STUDY DESIGN: This is an institutional review board-approved prospective cohort study of parous women. Participants were recruited 5-10 years after first delivery and followed annually. Pelvic floor muscle strength (peak pressure with voluntary contraction) was measured at 2 annual visits approximately 4 years apart with the use of a perineometer. We calculated the change in peak pressures, which were standardized per 5-year interval. Linear regression was used to identify maternal and obstetric characteristics that are associated with the rate of change in peak pressure. The obstetric variable of greatest interest was delivery group. Participants were classified into 3 delivery groups (considering all deliveries for each multiparous woman). Delivery categories included cesarean only, at least 1 vaginal birth but no forceps-assisted deliveries, and at least 1 forceps-assisted vaginal birth. Statistical analysis was completed with statistical software. RESULTS: Five hundred forty-three participants completed 2 perineometer measurements with a median 4 years between measures (interquartile range, 3.1-4.8). At initial measurement, women were, on average, 40 years old and 8 years from first delivery. Initial strength was higher in participants who delivered all their children by cesarean (38.5 cm H2O) as compared with women with any vaginal non-forceps delivery (26.0 cm H2O) or vaginal forceps delivery (13.5 cm H2O; P<.001). There was a strong correlation between the first and second perineometry measurement (r=0.84). Median change in pelvic floor muscle strength was small at 1.2 cm H2O per 5 years (interquartile range, -5.6, 9.9 cm H2O). In multivariable analysis, women who delivered by cesarean only demonstrated almost no change in strength over 5 years (0.2 increase cm H2O per 5 years); those who experienced at least 1 vaginal or vacuum delivery increased strength (4.8 cm H2O per 5 years) as did women with at least 1 forceps delivery (5.0 cm H2O per 5 years). Additionally, obese women had a significant reduction in strength (-3.1 cm H2O per 5 years) compared with normal weight participants (0.2 cm H2O per 5 years). CONCLUSION: Among parous women, pelvic muscle strength increased minimally over time with an average change of 1.2 cm H2O per 5 years; change in strength was associated with mode of delivery and obesity.

Waist-to-height ratio, body mass index, and cardiovascular risk profile in children with chronic kidney disease.

BACKGROUND: Cardiovascular (CV) risk is high in children with chronic kidney disease (CKD), and further compounded in those who are overweight. Children with CKD have a unique body habitus not accurately assessed by body mass index (BMI). Waist-to-height ratio (WHr), a better predictor of CV risk in populations with short stature, has not been investigated in children with CKD. METHODS: Analysis of 1723 visits of 593 participants enrolled in the Chronic Kidney Disease in Children (CKiD) study was conducted. CKiD participants had BMI and WHr measured and classified as follows: (1) lean (WHr ≤ 0.49, BMI < 85th percentile); (2) WHr-overweight (WHr > 0.49, BMI < 85th percentile); (3) BMI-overweight (WHr ≤ 0.49, BMI ≥ 85th percentile); or (4) overweight by both BMI and WHr. Left ventricular mass index (LVMI), fasting lipids, fibroblast growth factor 23 (FGF23), blood pressure, and glucose were measured as markers of CV risk. Linear mixed-effects regression was used to evaluate differences in CV markers between overweight and lean groups. RESULTS: Participants were 12.2 years old, 60% male, and 17% African-American. Approximately 15% were overweight by WHr but not by BMI. Overweight status by WHr-only or both WHr and BMI was associated with lower high-density lipoprotein (HDL) and higher LVMI, triglycerides, and non-HDL cholesterol compared to lean. CV markers of participants overweight by BMI-only were similar to those of lean children. CONCLUSIONS: WHr-adiposity is associated with an adverse CV risk profile in children with CKD. A significant proportion of children with central adiposity are missed by BMI. WHr should be utilized as a screening tool for CV risk in this population.

Pharmacokinetics of Human Plasma-Derived Antithrombin in Pediatric Patients Supported on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.

Exploratory factor analysis yields grouping of brain injury biomarkers significantly associated with outcomes in neonatal and pediatric ECMO.

In this two-center prospective cohort study of children on ECMO, we assessed a panel of plasma brain injury biomarkers using exploratory factor analysis (EFA) to evaluate their interplay and association with outcomes. Biomarker concentrations were measured daily for the first 3 days of ECMO support in 95 participants. Unfavorable composite outcome was defined as in-hospital mortality or discharge Pediatric Cerebral Performance Category > 2 with decline ≥ 1 point from baseline. EFA grouped 11 biomarkers into three factors. Factor 1 comprised markers of cellular brain injury (NSE, BDNF, GFAP, S100ß, MCP1, VILIP-1, neurogranin); Factor 2 comprised markers related to vascular processes (vWF, PDGFRß, NPTX1); and Factor 3 comprised the BDNF/MMP-9 cellular pathway. Multivariable logistic models demonstrated that higher Factor 1 and 2 scores were associated with higher odds of unfavorable outcome (adjusted OR 2.88 [1.61, 5.66] and 1.89 [1.12, 3.43], respectively). Conversely, higher Factor 3 scores were associated with lower odds of unfavorable outcome (adjusted OR 0.54 [0.31, 0.88]), which is biologically plausible given the role of BDNF in neuroplasticity. Application of EFA on plasma brain injury biomarkers in children on ECMO yielded grouping of biomarkers into three factors that were significantly associated with unfavorable outcome, suggesting future potential as prognostic instruments.