Recent Research Publications- September 2022
Implementation of a Maternal Child Knowledgebase.
Santillan DA, Santillan MK, Davis HA, Crooks M, Flanagan PJ, Ortman CE, Faro EZ, Hunter SK, Knosp BK.
AMIA Annu Symp Proc. 2022 May 23;2022:432-438.
To advance the application of clinical data to address maternal health we developed and implemented a Maternal Child Knowledgebase (MCK). The MCK integrates data from every pregnancy that received care at the University of Iowa Hospitals & Clinics (UIHC) and links information from the pregnancy episode to the delivery episode and between the mother and child. This knowledgebase contains integrated information regarding diagnoses, medications, mother and child vitals, hospital admissions, depression screenings, laboratory value results, and procedure information. It also collates information from the electronic health record (EPIC), the Social Security Death Index, and the Medication Administration Record into one knowledgebase. To enhance usability, we designed a custom viewer with several pre-designed queries and reports that eliminates the need for users to be proficient in SQL coding. The recent implementation of the MCK has supported multiple projects and reduced the number of Obstetrics-related data queries to the Biomedical Informatics group.
Green S, Ryckman KK, Anderson E,
Breastfeed Med. 2022 Jul 29. doi: 10.1089/bfm.2021.0355. Epub ahead of print.
- The rates of severe maternal morbidity (SMM) including blood transfusions after delivery are rising, yet little is known about the impact of these experiences on breastfeeding.
Materials and Methods: This is a single-institution retrospective cohort study examining breastfeeding rates at three time points for 1,857 first-time parents delivered at term between July 1, 2016 and June 30, 2019. Our exposure of interest was SMM, which was subdivided into SMM where transfusion was the only indicator (transfusion-only SMM) and SMM where another indicator (diagnostic or procedural) was met, which may also include transfusion (all-cause SMM). Association between transfusion-only SMM and all-cause SMM with feeding method was determined using multinomial regression modeling and adjusting for relevant sociodemographic characteristics.
- The majority of those with uncomplicated deliveries were exclusively breastfeeding at the 2- to 4-week and 2- to 3-month time points (59.6% and 53.6%, respectively), in contrast to 46.3% and 42.0% of those who had experienced transfusion-only SMM, and 40.9% and 30% of those who had experienced all-cause SMM. In adjusted models, receipt of a blood transfusion was found to be associated with greater risk of exclusive formula feeding at all time points. Experience of all-cause SMM was significantly associated with increased likelihood of exclusive formula feeding at hospital discharge and the 2- to 3-month time point.
- We identified that experience of all-cause SMM and transfusion-only SMM are independently associated with a lower likelihood of exclusive breastfeeding after adjusting for sociodemographic factors. Perinatal clinicians should be aware of these risks and offer increased support to these couplets.
Cardillo N, Devor EJ, Pedra Nobre S, Newtson A, Leslie K, Bender DP,
Smith BJ,
Cancers (Basel). 2022 Jul 21;14(14):3554.
Advanced high-grade serous (HGSC) ovarian cancer is treated with either primary surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval surgery. The decision to proceed with surgery primarily or after chemotherapy is based on a surgeon's clinical assessment and prediction of an optimal outcome. Optimal and complete cytoreductive surgery are correlated with improved overall survival. This clinical assessment results in an optimal surgery approximately 70% of the time. We hypothesize that this prediction can be improved by using biological tumor data to predict optimal cytoreduction. With access to a large biobank of ovarian cancer tumors, we obtained genomic data on 83 patients encompassing gene expression, exon expression, long non-coding RNA, micro RNA, single nucleotide variants, copy number variation, DNA methylation, and fusion transcripts. We then used statistical learning methods (lasso regression) to integrate these data with pre-operative clinical information to create predictive models to discriminate which patient would have an optimal or complete cytoreductive outcome. These models were then validated within The Cancer Genome Atlas (TCGA) HGSC database and using machine learning methods (TensorFlow). Of the 124 models created and validated for optimal cytoreduction, 21 performed at least equal to, if not better than, our historical clinical rate of optimal debulking in advanced-stage HGSC as a control. Of the 89 models created to predict complete cytoreduction, 37 have the potential to outperform clinical decision-making. Prospective validation of these models could result in improving our ability to objectively predict which patients will undergo optimal cytoreduction and, therefore, improve our ovarian cancer outcomes.
AUGS-PERFORM: A New Patient-Reported Outcome Measure to Assess Quality of Prolapse Care.
O'Shea M, Boyles S, Jacobs K, McFatrich M, Sung V, Weinfurt K, Siddiqui NY.
Female Pelvic Med Reconstr Surg. 2022 Aug;28(8):468-478. doi: 10.1097/SPV.0000000000001225. Epub 2022 Jun 22.
Patient-reported outcomes (PRO) are important for measuring quality of care, particularly for interventions aimed at improving symptom bother such as procedures for pelvic organ prolapse. We aimed to create a concise yet comprehensive PRO measurement tool to assess pelvic organ prolapse care in high-volume clinical environments.
Methods: The relevant concepts to measure prolapse treatment quality were first established through literature review, qualitative interviews, and a patient and provider-driven consensus-building process. Extant items mapping to these concepts, or domains, were identified from an existing pool of patient-reported symptoms and condition-specific and generic health-related quality of life measures. Item classification was performed to group items assessing similar concepts while eliminating items that were redundant, inconsistent with domains, or overly complex. A consensus meeting was held in March 2020 where patient and provider working groups ranked the remaining candidate items in order of relevance to measure prolapse treatment quality. After subsequent expert review, the revised candidate items underwent cognitive interview testing and were further refined.
- Fifteen relevant PRO instruments were initially identified, and 358 items were considered for inclusion. After 2 iterative consensus reviews and 4 rounds of cognitive interviewing with 19 patients, 11 final candidate items were identified. These items map 5 consensus-based domains that include awareness and bother from prolapse, physical function, physical discomfort during sexual activity, pain, and urinary/defecatory symptoms.
- We present a concise set of candidate items that were developed using rigorous patient-centered methodology and a national consensus process, including urogynecologic patients and providers.
Bradley CS, Gallop R, Sutcliffe S, Kreder KJ, Lai HH, Clemens JQ, Naliboff BD; Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.
Urology. 2022 Aug 9:S0090-4295(22)00654-9. doi: 10.1016/j.urology.2022.07.045. Epub ahead of print
- To characterize Urologic Chronic Pelvic Pain Syndrome (UCPPS) pain and urinary symptom trajectories with up to 9 years of follow-up and evaluate whether initial 1-year trajectories are associated with longer-term changes.
Materials and methods: Data were analyzed from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Network's prospective observational protocols including the Epidemiology and Phenotyping Study (EPS; baseline to Year 1), EPS Extension (EXT; Years 1-5), and Symptom Patterns Study (SPS: 3-year study; Years 3-9). Adults with Interstitial Cystitis/Bladder Pain Syndrome or Chronic Prostatitis/Chronic Pelvic Pain Syndrome provided patient-reported assessments biweekly (EPS), every 4 months (EXT), or quarterly (SPS). Primary outcomes were composite pain (0-28) and urinary (0-25) severity scores. Multi-phase mixed effects models estimated outcomes over time, adjusted for baseline severity and stratified by EPS symptom trajectory.
Results: 163 participants (52% women; mean ± SD age 46.4 ± 16.1 years) completed EPS and enrolled in EXT; 67 also enrolled in SPS. Median follow-up was 4.6 years (range 1.3-9.0). After 1 year: 27.6%, 44.8% and 27.6% and 27.0%, 38.0% and 35.0% were improved, stable or worse in pain and urinary symptom severity, respectively. On average, pain and urinary symptom scores did not change further during EXT and SPS periods.
- Women and men with UCPPS showed remarkable stability in pain and urinary symptom severity for up to 9 years, irrespective of their initial symptom trajectory, suggesting UCPPS is a chronic condition with stable symptoms over multiple years of follow-up.
Kowalski JT, Wiseman JB, Smith AR, Helmuth ME, Cameron A, DeLancey JOL, Hendrickson WK, Jelovsek JE, Kirby A, Kreder K, Lai HH, Mueller M, Siddiqui N, Bradley CS.
Am J Obstet Gynecol. 2022 Aug 5:S0002-9378(22)00594-4. doi: 10.1016/j.ajog.2022.07.038. Epub ahead of print.
Background: The association of pelvic organ prolapse with overactive bladder and other lower urinary tract symptoms, and the natural history of those symptoms are not well characterized. Previous cross-sectional studies demonstrated conflicting relationships between prolapse and lower urinary tract symptoms.
Objective: This study primarily aimed to determine the baseline association between lower urinary tract symptoms and prolapse and to assess longitudinal differences in symptoms over 12 months in women with and without prolapse. Secondary aims were to explore associations between lower urinary tract symptoms and prolapse treatment. We hypothesized that: (1) prolapse is associated with the presence of lower urinary tract symptoms, (2) lower urinary tract symptoms are stable over time in patients with and without prolapse, and (3) prolapse treatment is associated with lower urinary tract symptom improvement.
Study design: Women enrolled in the Symptoms of Lower Urinary Tract Dysfunction Research Network Observational Cohort Study with adequate 12-month follow-up data were included. Prolapse and lower urinary tract symptom treatment during follow-up was guided by standard of care. Outcome measures included the Lower Urinary Tract Symptoms Tool total severity score (in addition to overactive bladder, obstructive, and stress urinary incontinence subscales) and Urogenital Distress Inventory-6 Short Form. Prolapse (yes or no) was defined primarily when Pelvic Organ Prolapse Quantification System points Ba, C or Bp were >0 (beyond the hymen). Mixed-effects models with random effects for patient slopes and intercepts were fitted for each lower urinary tract symptom outcome and prolapse predictor, adjusted for other covariates. The study had >90% power to detect differences as small as 0.4 standard deviation for less prevalent group comparisons (eg, prolapse vs not).
- : A total of 371 women were analyzed, including 313 (84%) with no prolapse and 58 (16%) with prolapse. Women with prolapse were older (64.6±8.8 vs 55.3±14.1 years; P<.001) and more likely to have prolapse surgery (28% vs 1%; P<.001) and pessary treatment (26% vs 4%; P<.001) during the study. Average baseline Lower Urinary Tract Symptoms Tool total severity scores were lower (fewer symptoms) for participants with prolapse compared with those without (38.9±14.0 vs 43.2±14.0; P=.036), but there were no differences in average scores between prolapse groups for other scales. For all urinary outcomes, average scores were significantly lower (improved) at 3 and 12 months compared with baseline (all P<.05). In mixed-effects models, there were no statistically significant interactions between pelvic organ prolapse measurement and visit and time-dependent prolapse treatment groups (P>.05 for all regression interaction coefficients). The Lower Urinary Tract Symptoms Tool obstructive severity score had a statistically significant positive association with Pelvic Organ Prolapse Quantification System Ba, Bp, and point of maximum vaginal descent. The Lower Urinary Tract Symptoms Tool total severity scale had a statistically significant negative association with Pelvic Organ Prolapse Quantification System Ba and point of maximum vaginal descent. No other associations between prolapse and lower urinary tract symptoms were significant (P>.05 for all regression coefficients). Symptom differences between prolapse groups were small: all regression coefficients (interpretable as additive percentage change in each score) were between -5 and 5 (standard deviation of outcomes ranged from 14.0-32.4).
Conclusion: Among treatment-seeking women with urinary symptoms, obstructive symptoms were positively associated with prolapse, and overall lower urinary tract symptom severity was negatively associated with prolapse. Lower Urinary Tract Symptoms Tool scores improved over 12 months regardless of prolapse status, including in those with treated prolapse, untreated prolapse, and without prolapse.
Andreev VP, Helmuth ME, Liu G, Smith AR, Merion RM, Yang CC, Cameron AP, Jelovsek JE, Amundsen CL, Helfand BT,DeLancey JOL, Griffith JW, Glaser AP, Gillespie BW, Clemens JQ, Lai HH; LURN Study Group.
PLoS One. 2022 Jun 10;17(6):e0268547.
We present a methodology for subtyping of persons with a common clinical symptom complex by integrating heterogeneous continuous and categorical data. We illustrate it by clustering women with lower urinary tract symptoms (LUTS), who represent a heterogeneous cohort with overlapping symptoms and multifactorial etiology. Data collected in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN), a multi-center observational study, included self-reported urinary and non-urinary symptoms, bladder diaries, and physical examination data for 545 women. Heterogeneity in these multidimensional data required thorough and non-trivial preprocessing, including scaling by controls and weighting to mitigate data redundancy, while the various data types (continuous and categorical) required novel methodology using a weighted Tanimoto indices approach. Data domains only available on a subset of the cohort were integrated using a semi-supervised clustering approach. Novel contrast criterion for determination of the optimal number of clusters in consensus clustering was introduced and compared with existing criteria. Distinctiveness of the clusters was confirmed by using multiple criteria for cluster quality, and by testing for significantly different variables in pairwise comparisons of the clusters. Cluster dynamics were explored by analyzing longitudinal data at 3- and 12-month follow-up. Five clusters of women with LUTS were identified using the developed methodology. None of the clusters could be characterized by a single symptom, but rather by a distinct combination of symptoms with various levels of severity. Targeted proteomics of serum samples demonstrated that differentially abundant proteins and affected pathways are different across the clusters. The clinical relevance of the identified clusters is discussed and compared with the current conventional approaches to the evaluation of LUTS patients. The rationale and thought process are described for the selection of procedures for data preprocessing, clustering, and cluster evaluation. Suggestions are provided for minimum reporting requirements in publications utilizing clustering methodology with multiple heterogeneous data domains.
Selective Serotonin Reuptake Inhibitor Use in Pregnancy and Protective Mechanisms in Preeclampsia.
Vignato JA, , Davis HA, Pierce GL, Knosp BA,
Reprod Sci. 2022 Aug 19. doi: 10.1007/s43032-022-01065-z. Epub ahead of print. P
Depression and preeclampsia share risk factors and are bi-directionally associated with increased risk for each other. Despite epidemiological evidence linking selective serotonin reuptake inhibitors (SSRIs) in pregnancy to preeclampsia, serotonin (5-HT) and vasopressin (AVP) secretion mechanisms suggest that SSRIs may attenuate preeclampsia risk. However, there is a need to clarify the relationship between SSRIs and preeclampsia in humans to determine therapeutic potential. This retrospective cohort study included clinical data from 9558 SSRI-untreated and 9046 SSRI-treated pregnancies. In a subcohort of 233 pregnancies, early pregnancy (< 20 weeks) maternal plasma copeptin, an inert and stable AVP prosegment secreted 1:1 with AVP, was measured by enzyme-linked immunosorbent assay. Diagnoses and depression symptoms (Patient Health Questionnaire-9 [PHQ-9]) were identified via medical records review. Descriptive, univariate, and multivariate regression analyses were conducted (α = 0.05). SSRI use was associated with decreased preeclampsia after controlling for clinical confounders (depression severity, chronic hypertension, diabetes, body mass index, age) (OR = 0.9 [0.7-1.0], p = 0.05). Moderate-to-severe depression symptoms were associated with significantly higher copeptin secretion than mild-to-no depression symptoms (240 ± 29 vs. 142 ± 10 ng/mL, p < 0.001). SSRIs significantly attenuated first trimester plasma copeptin (78 ± 22 users vs. 240 ± 29 ng/ml non-users, p < 0.001). In preeclampsia, SSRI treatment was associated with significantly lower copeptin levels (657 ± 164 vs. 175 ± 134 ng/mL, p = 0.04). Interaction between SSRI treatment and preeclampsia was also significant (p = 0.04). SSRIs may modulate preeclampsia risk and mechanisms, although further studies are needed to investigate the relationships between 5-HT and AVP in depression and preeclampsia.
Selective serotonin reuptake inhibitors and preeclampsia: A quality assessment and meta-analysis.
Gumusoglu SB, Schickling BM, Vignato JA, Santillan DA, Santillan MK.
Pregnancy Hypertens. 2022 Aug 6;30:36-43. doi: 10.1016/j.preghy.2022.08.001. Epub ahead of print.
Serotonin modulates vascular, immune, and neurophysiology and is dysregulated in preeclampsia. Despite biological plausibility that selective serotonin reuptake inhibitors (SSRIs) prevent preeclampsia pathophysiology, observational studies have indicated increased risk and providers may be hesitant. The objective of this meta-analysis and quality assessment was to evaluate the evidence linking SSRI use in pregnancy to preeclampsia/gestational hypertension. PubMed was searched through June 5, 2020 manually and using combinations of terms: "preeclampsia", "serotonin", and "SSRI". This review followed MOOSE guidelines. Inclusion criteria were: 1) Observational cohort or population study, 2) exposure defined as SSRI use during pregnancy, 3) cases defined as preeclampsia or gestational hypertension, and 4) human participants. Studies were selected that addressed the hypothesis that gestational SSRI use modulates preeclampsia and/or gestational hypertension risk. Review Manager Web was used to synthesize study findings. Articles were read and scored (Newcastle-Ottawa Quality Assessment Scale) for quality by two independent reviewers. Publication bias was assessed using a funnel plot and the Egger test. Of 179 screened studies, nine were included. The pooled risk ratio (random effects model) was 1.43 (95 % CI: 1.15-1.78, P < 0.001; range 0.96-4.86). Two studies were rated as moderate quality (both with total score of 6); others were high quality. Heterogeneity was high (I2 = 88 %) and funnel asymmetry was significant (p < 0.00001). Despite evidence for increased preeclampsia risk with SSRIs, shared risk factors and other variables are poorly controlled. Depression treatment should not be withheld due to perceived gestational hypertension risk. Mechanistic evidence for serotonin modulation in preeclampsia demonstrates a need for future research.
Dataset describing maternal prenatal restraint stress effects on immune factors in mice.
Gumusoglu SB, Maurer SV, Stevens HE.
Data Brief. 2022 Jun 3;43:108348.
Maternal immune dysregulation, caused by gestational psychological stress, infection, and other perturbations, results in altered offspring neurodevelopment and increases risk for psychiatric disorders. Prior work has found that multiple cytokines play critical roles in shaping offspring neurodevelopment after gestational stress, though how maternal psychological stress impacts maternal, placental, and fetal cytokine levels more broadly remains unclear. The purpose of the present study was to assess changes to IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, IFNγ, and TNFα in a widely-used mouse prenatal restraint stress model. After repetitive restraint stress on gestational days 12-14, stressed dams had increased serum levels of IL-1β, IL-6, and IL-10. Embryonic day 14 IL-2 and IL-1β levels were decreased in prenatally stressed male fetal forebrain, while placental IL-2 was decreased by stress regardless of offspring sex. Placental and fetal forebrain IL-2 levels were negatively correlated. These data provide important insights into the immune changes that occur with prenatal restraint stress.
Vaginal Leptothrix: An Innocent Bystander?
Vieira-Baptista P, Lima-Silva J, Preti M, Sousa C, Caiano F, Bornstein J.
Microorganisms. 2022 Aug 15;10(8):1645.
Leptothrix are long bacteria of rare occurrence; although these bacteria have been implicated in causing vaginal symptoms identical to candidiasis, studies on prevalence and effect on overall vaginal health are lacking. In this study, we evaluated data of women referred to a private clinic for treating vulvovaginal symptoms (n = 1847) and reassessed data of our previous and ongoing studies (n = 1773). The overall rate of leptothrix was 2.8% (102/3620), and the mean age of affected women was 38.8 ± 10.65 years (range 18-76). The majority of the women with leptothrix had normal vaginal flora (63.7% [65/102]). Leptothrix was associated with a higher risk of candidiasis (relative risk (RR) 1.90, 95% confidence interval (CI) 1.1600-3.1013; p = 0.010) and a lower risk of bacterial vaginosis (RR 0.55, 95% CI, 0.3221-0.9398; p = 0.029) and cytolytic vaginosis (RR 0.11, 95% CI, 0.0294-0.4643; p = 0.002). No cases of trichomoniasis were observed. Human immunodeficiency virus infection increased the risk of leptothrix (RR 3.0, 95% CI, 1.6335-5.7245; p = 0.000). Among the women evaluated for vulvovaginal symptoms, 2.4% (45/1847) had leptothrix, and in 26.7% (12/45), leptothrix was considered the causative entity. This study suggests that leptothrix occurrence is rare; it remains unresolved if it can be a cause of vulvar symptoms.
Sharp AJ,
Proc Obstet Gynecol. 2022;11(2): Article 4 [ 5 p.].
We present a case of a full thickness epidermal burn resulting from an all-natural clay-based heating pad over a cesarean incision silver dressing to bring awareness to the risks associated with nonpharmacologic management of post cesarean pain. There is limited guidance on nonpharmacological management of post cesarean pain. It is important that providers are able to advise their patients about their options, including to be wary of using heating pads on post-cesarean dressings, especially with pain in the early post-partum period.