A role for adverse childhood experiences and depression in preeclampsia.

Introduction: Adverse childhood experiences (ACEs) are a measure of childhood adversity and are associated with life-long morbidity. The impacts of ACEs on peripartum health including preeclampsia, a common and dangerous hypertensive disorder of pregnancy, remain unclear, however. Therefore, we aimed to determine ACE association with peripartum psychiatric health and prevalence of preeclampsia using a case-control design. Methods: Clinical data were aggregated and validated using a large, intergenerational knowledgebase developed at our institution. Depression symptoms were measured by standard clinical screeners: the Patient Health Questionnaire-9 (PHQ-9) and the Edinburgh Postnatal Depression Scale (EPDS). ACEs were assessed via survey. Scores were compared between participants with (N = 32) and without (N = 46) prior preeclampsia. Results: Participants with ACE scores ≥4 had significantly greater odds of preeclampsia than those with scores ≤ 3 (adjusted odds ratio = 6.71, 95% confidence interval:1.13-40.00; p = 0.037). Subsequent speculative analyses revealed that increased odds of preeclampsia may be driven by increased childhood abuse and neglect dimensions of the ACE score. PHQ-9 scores (3.73 vs. 1.86, p = 0.03), EPDS scores (6.38 vs. 3.71, p = 0.01), and the incidence of depression (37.5% vs. 23.9%, p = 0.05) were significantly higher in participants with a history of preeclampsia versus controls. Conclusions: Childhood sets the stage for life-long health. Our findings suggest that ACEs may be a risk factor for preeclampsia and depression, uniting the developmental origins of psychiatric and obstetric risk.

Care from Birth to Discharge of Infants Born at 22 to 23 Weeks' Gestation.

The clinical care of infants born at 22 weeks' gestation must be well-designed and standardized if optimal results are to be expected. Although several approaches to care in this vulnerable population are possible, protocols should be neither random nor inconsistent. We describe the approach taken at the University of Iowa Stead Family Children's Hospital neonatal intensive care unit with respect to preterm infants born at 22 weeks' gestation. We have chosen to present our standardize care plan with respect to prenatal, neurologic, nutritional, gastrointestinal, and skin management. Respiratory and cardiopulmonary care will be briefly reviewed, as these strategies have been published previously.

Proposed Solutions for Improving Maternal Health Care in Rural America.

Increasing hospital and labor & delivery (L&D) closures have led to declining access to hospital obstetric care in rural areas across the country. These closures increase the burden on women and families living in rural communities, who often must drive long distances for prenatal visits and delivery. The lack of maternal health care in rural America can also result in several adverse maternal and infant outcomes including premature birth, low birth weight, out of hospital births, maternal and infant morbidity and mortality, and increased risk of postpartum depression. The reasons for these closures are multifactorial, and include, workforce shortages, financial viability, low volume of patients, concerns over maintaining the knowledge base and skill sets of the obstetrical health care team required to provide high quality and safe care, as well as medical-legal concerns. The problems of providing and accessing quality maternal and obstetrical care in rural America have not happened overnight, Likewise, the solutions to these problems will also not occur overnight and must also address the multifactorial nature of the problem. However, there are several opportunities to improve access to maternal health care in rural communities. Programs, policies, and funding need to be designed and provided to make these opportunities a reality.

Implementation of a Maternal Child Knowledgebase.

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.

Barriers and solutions to developing and maintaining research networks during a pandemic: An example from the iELEVATE perinatal network.

Introduction: To improve maternal health outcomes, increased diversity is needed among pregnant people in research studies and community surveillance. To expand the pool, we sought to develop a network encompassing academic and community obstetrics clinics. Typical challenges in developing a network include site identification, contracting, onboarding sites, staff engagement, participant recruitment, funding, and institutional review board approvals. While not insurmountable, these challenges became magnified as we built a research network during a global pandemic. Our objective is to describe the framework utilized to resolve pandemic-related issues. Methods: We developed a framework for site-specific adaptation of the generalized study protocol. Twice monthly video meetings were held between the lead academic sites to identify local challenges and to generate ideas for solutions. We identified site and participant recruitment challenges and then implemented solutions tailored to the local workflow. These solutions included the use of an electronic consent and videoconferences with local clinic leadership and staff. The processes for network development and maintenance changed to address issues related to the COVID-19 pandemic. However, aspects of the sample processing/storage and data collection elements were held constant between sites. Results: Adapting our consenting approach enabled maintaining study enrollment during the pandemic. The pandemic amplified issues related to contracting, onboarding, and IRB approval. Maintaining continuity in sample management and clinical data collection allowed for pooling of information between sites. Conclusions: Adaptability is key to maintaining network sites. Rapidly changing guidelines for beginning and continuing research during the pandemic required frequent intra- and inter-institutional communication to navigate.

Cardiorespiratory management of infants born at 22 weeks' gestation: The Iowa approach.

The approach to clinical care of infants born at 22 weeks' gestation must be consistent and well-designed if optimal results are to be expected. Publications from several international centers have demonstrated that, although there may be variance in aspects of care in this vulnerable population, treatment should be neither random nor inconsistent. In designing a standardized approach, careful attention should be paid to the unique anatomy, physiology, and biochemistry of this vulnerable patient population. Emerging evidence, suggesting a link between cardiopulmonary health and longer-term sequela, highlights the importance of understanding the relationship between cardiorespiratory illnesses of the 22-week infant, treatments provided, and subsequent cardiopulmonary development. In this review we will provide an overview to our approach to cardiopulmonary assessment and treatment, with a particular emphasis on the importance of early recognition of atypical phenotypes, timely interventions with evidence-based treatments, and longitudinal monitoring.

Group B Streptococcus Screening and Treatment Adherence in Pregnancy: A Retrospective Cohort Study and Opportunities for Improvement.

Introduction: Pregnancy is a time of increased healthcare screening, and past adherence to evolving guidelines informs best practices. Although studies of Group B Streptococcus guideline adherence have focused primarily on treatment of Group B Streptococcus carriers, this study broadly evaluated long-term adherence to both Group B Streptococcus screening and treatment guidelines. Adherence was evaluated across provider types (obstetrics and gynecology, certified nurse midwives, and family medicine). Methods: We conducted a retrospective cohort study. Demographic and clinical information were extracted from all prenatal care and delivery patients at a single institution in a single year. Vancomycin prescriptions in pregnancy were tracked for 10 years to determine long-term adherence. Adherence was defined as no deviation from 2010 Group B Streptococcus screening and treatment guidelines. Results: Adherence occurred in 89% (1,610/1,810) of patients. Reasons for deviations from guidelines could not always be determined. There was no significant difference in maternal age, race, prenatal provider type, provider type at delivery, gestational age at delivery, delivery mode, or whether antibiotic sensitivities were performed between compliant and noncompliant groups. Significant differences in adherence were found between obstetric clinics (high-risk obstetrics clinic, maternal‒fetal medicine fellows clinic, continuity of care clinic, and faculty private clinic) (p<0.0001) and between the faculty family medicine clinic and resident family medicine clinic (p=0.001). Vancomycin prescription practice did not change significantly over the10-year period. Conclusions: High rates of adherence to Group B Streptococcus screening and treatment guidelines in pregnancy have positive implications for reducing antibiotic resistance. Given evolving guidelines, there is a need to periodically evaluate adherence and to re-educate providers about standard practices and best documentation practices.

The maternal early warning criteria: a proposal from the national partnership for maternal safety.

Case reviews of maternal death have revealed a concerning pattern of delay in recognition of hemorrhage, hypertensive crisis, sepsis, venous thromboembolism, and heart failure. Early-warning systems have been proposed to facilitate timely recognition, diagnosis, and treatment for women developing critical illness. A multidisciplinary working group convened by the National Partnership for Maternal Safety used a consensus-based approach to define The Maternal Early Warning Criteria, a list of abnormal parameters that indicate the need for urgent bedside evaluation by a clinician with the capacity to escalate care as necessary in order to pursue diagnostic and therapeutic interventions. This commentary reviews the evidence supporting the use of early-warning systems and describes The Maternal Early Warning Criteria, along with considerations for local implementation.

The maternal early warning criteria: a proposal from the national partnership for maternal safety.

Case reviews of maternal death have revealed a concerning pattern of delay in recognition of hemorrhage, hypertensive crisis, sepsis, venous thromboembolism, and heart failure. Early-warning systems have been proposed to facilitate timely recognition, diagnosis, and treatment for women developing critical illness. A multidisciplinary working group convened by the National Partnership for Maternal Safety used a consensus-based approach to define The Maternal Early Warning Criteria, a list of abnormal parameters that indicate the need for urgent bedside evaluation by a clinician with the capacity to escalate care as necessary in order to pursue diagnostic and therapeutic interventions. This commentary reviews the evidence supporting the use of early-warning systems, describes The Maternal Early Warning Criteria, and provides considerations for local implementation.

Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model.

Preeclampsia, a cardiovascular disorder of late pregnancy, is characterized as a low-renin hypertensive state relative to normotensive pregnancy. Because other nonpregnant low-renin hypertensive disorders often exhibit and are occasionally dependent on elevated arginine vasopressin (AVP) secretion, we hypothesized a possible use for plasma AVP measurements in the prediction of preeclampsia. Copeptin is an inert prosegment of AVP that is secreted in a 1:1 molar ratio and exhibits a substantially longer biological half-life compared with AVP, rendering it a clinically useful biomarker of AVP secretion. Copeptin was measured throughout pregnancy in maternal plasma from preeclamptic and control women. Maternal plasma copeptin was significantly higher throughout preeclamptic pregnancies versus control pregnancies. While controlling for clinically significant confounders (age, body mass index, chronic essential hypertension, twin gestation, diabetes mellitus, and history of preeclampsia) using multivariate regression, the association of higher copeptin concentration and the development of preeclampsia remained significant. Receiver operating characteristic analyses reveal that as early as the sixth week of gestation, elevated maternal plasma copeptin concentration is a highly significant predictor of preeclampsia throughout pregnancy. Finally, chronic infusion of AVP during pregnancy (24 ng per hour) is sufficient to phenocopy preeclampsia in C57BL/6J mice, causing pregnancy-specific hypertension, renal glomerular endotheliosis, proteinuria, and intrauterine growth restriction. These data implicate AVP release as a novel predictive biomarker for preeclampsia very early in pregnancy, identify chronic AVP infusion as a novel and clinically relevant model of preeclampsia in mice, and are consistent with a potential causative role for AVP in preeclampsia in humans.

"Collection of a lifetime: a practical approach to developing a longitudinal collection of women's healthcare biological samples".

OBJECTIVE: The objective is to develop a biorepository of samples that represent all stages of a women's life. Importantly, our goal is to collect longitudinal physical specimens as well as the associated short and long-term clinical information. STUDY DESIGN: The Women's Health Tissue Repository was established to encompass four tissue banks: Well Women Tissue Bank, Reproductive Endocrinology and Infertility Tissue Bank, Maternal Fetal Tissue Bank, and the long-established Gynecologic Malignancies Tissue Bank. Based on their health status, women being seen in Women's Health at the University of Iowa are recruited to contribute samples and grant access to their electronic medical record to the biorepository. Samples are coded, processed, and stored for use by investigators. RESULTS: The Maternal Fetal Tissue Bank was the first expansion of our department's biobanking efforts. Approximately 75% of the women approached consent to participate in the Maternal Fetal Tissue Bank. Enrollment has steadily increased. Samples have been used for over 20 projects in the first 3 years and are critical to 7 funded grants and 3 patent applications. CONCLUSION: Patient samples with corresponding clinical data are initially important to women's health research. Our model demonstrates that many research projects by faculty, fellows, and residents have benefited from the existence of the Women's Health Tissue Repository. While challenging to achieve, longitudinal sampling allows for the greatest opportunity to study normal and pathological changes throughout all phases of a women's life, including pregnancy. This bank facilitates and accelerates the development of novel research, technologies, and possible therapeutic options in women's health. The establishment of more longitudinal biorepositories based on our model would enhance women's health research.

The association between hospital obstetrical volume and maternal postpartum complications.

OBJECTIVE: The purpose of this study was to examine the relationship between delivery volume and maternal complications. STUDY DESIGN: We used administrative data to identify women who had been admitted for childbirth in 2006. Hospitals were stratified into deciles that were based on delivery volume. We compared composite complication rates across deciles. RESULTS: We evaluated 1,683,754 childbirths in 1045 hospitals. Decile 1 and 2 hospitals had significantly higher rates of composite complications than decile 10 (11.8% and 10.1% vs 8.5%, respectively; P < .0001). Decile 9 and 10 hospitals had modestly higher composite complications as compared with decile 6 (8.8% and 8.5% vs 7.6%, respectively; P < .0001). Sixty percent of decile 1 and 2 hospitals were located within 25 miles of the nearest greater volume hospital. CONCLUSION: Women who deliver at very low-volume hospitals have higher complication rates, as do women who deliver at exceedingly high-volume hospitals. Most women who deliver in extremely low-volume hospitals have a higher volume hospital located within 25 miles.

Efficacy of polymeric encapsulated C5a peptidase-based group B streptococcus vaccines in a murine model.

OBJECTIVE: The purpose was to examine in mice the efficacy of various polymeric-encapsulated C5a peptidase vaccine formulations in eliciting a long-term immune response and preventing group B streptococcus (GBS) infection. STUDY DESIGN: C5a peptidase was encapsulated in semipermeable microspheres of poly(lactide-coglycolide) (PLGA). Female ICR mice were immunized with 0, 10, or 30 µg of encapsulated C5a peptidase within 2 different formulations of PLGA polymers. Booster doses were given at weeks 4 and 8. Antibody responses were measured by enzyme-linked immunosorbent assay at weeks 4, 8, 11, and 40. Vaginal challenges with GBS types 1a, III, and V were performed at week 12. RESULTS: Thirty microgram doses of the 75:25 and 50:50 PLGA formulations generate the highest and most sustained C5a peptidase-specific immune responses. Mice that received encapsulated C5a peptidase were significantly protected from vaginal colonization compared with mice that received empty microspheres. CONCLUSION: Encapsulated C5a peptidase elicited significant immune responses and protection against a GBS challenge. C5a peptidase microsphere encapsulation has potential as a GBS vaccine.

Cell encapsulation as a potential nondietary therapy for maternal phenylketonuria.

OBJECTIVE: The objective of this work was to determine whether cells overexpressing phenylalanine (Phe) hydroxylase (PAH) can significantly reduce Phe in vitro for potential use as a therapy for preventing maternal phenylketonuria. STUDY DESIGN: Human 293T and WRL68 cell lines were transiently and stably transfected to overexpress PAH. Cells were encapsulated within microspheres of sodium alginate. Timed measurements of Phe in media were performed using tandem mass spectrometry. RESULTS: Both nonencapsulated and encapsulated transiently transfected cells overexpressing PAH significantly reduced the Phe concentration in media by approximately 50% in comparison to mock-transfected cells. Cell line clones stably expressing PAH significantly decreased the Phe concentration in the media by up to 85% compared with media alone. CONCLUSION: Both unencapsulated and encapsulated cells overexpressing PAH significantly reduce Phe in vitro. Studies using phenylketonuria model mice will be important in determining the ability of our therapy to prevent the teratogenic effects of elevated maternal Phe in maternal phenylketonuria.

From molecules to medicine: a future cure for preeclampsia?

In the United States, preeclampsia (PreE) affects 5-7% of all pregnancies, yet represents 15% of all maternal-fetal morbidity and mortality. PreE causes fetal growth restriction, oligohydramnios, fetal death, and maternal seizures, stroke, cerebrovascular hemorrhage and death. It has immediate and potentially long-term effects on both the fetus and mother. To date, the molecular pathogenesis of PreE is largely unknown. Multiple pathways, including dysfunctional angiogenesis, inappropriate placentation, oxidative stress and an altered immunological milieu have been proposed as key players in the development of PreE. In addition, genetic factors in all of these pathways are essential components in the etiology of this disease. This review introduces the clinical presentation of PreE and its particular disease phenotype that has prompted some of the molecular investigations of its etiology. Evidence of the many molecular pathways involved in the pathogenesis of PreE, as well as the therapeutic investigations targeting these pathways, is presented.

Protective immunization in mice against group B streptococci using encapsulated C5a peptidase.

OBJECTIVE: The purpose of the study was to test whether C5a peptidase encapsulated within a biodegradable polymer can act as a vaccine and elicit an immune response to prevent group B streptococci (GBS) infection in mice and provide protection to pups. STUDY DESIGN: C5a peptidase was encapsulated in semipermeable microspheres of poly(lactide-co-glycolide). Female ICR mice were immunized with encapsulated C5a peptidase, free C5a peptidase, or empty microparticles. Booster doses were given at days 21 and 42. Antibody responses were measured by enzyme-linked immunosorbent assay. Challenge with GBS type III was performed 4 days after the final booster in the vaginal vault of adult mice and intraperitoneally 48 hours after the birth for pups. RESULTS: Encapsulated C5a peptidase elicited a systemic immunoglobulin (Ig) G antibody response after intramuscular and intranasal administration. Unencapsulated C5a peptidase elicited a smaller systemic response. In addition to the strong IgG response, a secretory IgA response was observed in the vaginal mucosa after intranasal vaccination. No evidence of GBS colonization was found in vaccinated mice. Eighty-seven percent and 81% of the pups from intramuscularly and intranasally vaccinated dams survived a 90% lethal dose (LD90) GBS challenge vs 9% born to nonvaccinated dams. CONCLUSION: Encapsulated C5a peptidase elicited significant immune responses and protection against GBS challenge. C5a peptidase microsphere encapsulation has potential as a GBS vaccine.

Can myoglobin expression in pancreatic beta cells improve insulin secretion under hypoxia? An exploratory study with transgenic porcine islets.

The feasibility of myoglobin (Mb)-facilitated oxygen transport in improving porcine islet survival under hypoxia was investigated. Discrete groups of islets were transfected with replication-defective adenoviral vector Ad5 respiratory syncitial virus (RSV) to induce expression of Mb or green fluorescent protein (GFP). Native islets served as the controls. In vitro studies at 37 degrees C assessed islet insulin secretion efficacy: (i) to a glucose challenge from 30 to 300 mg/dL at fixed pO2; and (ii) at variable oxygen tensions ranging from 5 to 40 mm Hg over 12 h. The transfection was effective in initiating islet expression of Mb or GFP. Low Mb-expression levels equivalent to 2% the Mb concentration in a muscle cell (0.25 ng of Mb per islet) were documented, with no statistical improvement in insulin secretion. A surprising side note is that insulin secretion was impaired in islets expressing GFP. Improved Mb expression is essential to determine the feasibility of enhancing islet survival under hypoxia.

Characterizing short-term release and neovascularization potential of multi-protein growth supplement delivered via alginate hollow fiber devices.

Multi-protein (10-250 kDa) endothelial cell growth supplement (ECGS) contains growth factors of varying sizes resulting in advanced release rates from diffusion-based drug delivery devices. As a result, the biochemical stimulus provided by ECGS for neovascularization in the critical initial stages of cell transplantation in artificial organs may differ from that for single growth factor delivery. In this study, both in vitro and in vivo studies were conducted with ECGS to correlate in vitro release of multiple angiogenic growth factors to vascularization potential in vivo. The short-term release of ECGS from calcium alginate gels supported in the lumen of polypropylene (PP) hollow fibers was investigated in vitro for up to 142 h. The overall time constant increased from 2, 2.2 and 6.3 h as the alginate concentration was increased from 1.5%, 2% and 3%, respectively. However, time constants for individual species ranged from 1.5 to 77 h. The in vivo bioactivity of released ECGS was assessed for up to 21 days using a Lewis rat model implanted with 1.5% calcium alginate gels supported in PP and polysulfone hollow fibers. For the ECGS-releasing PP hollow fiber system, a two-fold increase in neovascularization with respect to the control was observed for the period between 7 and 17 days post-implantation at the device-tissue interface (p<0.05).

Cyclic changes in glycemia assessed by continuous glucose monitoring system during multiple complete menstrual cycles in women with type 1 diabetes.

Many women with diabetes notice changes in glucose control perimenstrually. To describe the pattern of changes in glucose control throughout the complete menstrual cycle, and the reproducibility of these changes, we performed a pilot study evaluating glycemic profiles continuously for three cycles in four women with type 1 diabetes. All participants had hemoglobin A1c <7.5% and regular menstrual periods off oral contraceptives. They used Medtronic MiniMed (Northridge, CA) Continuous Glucose Monitoring System (CGMS) devices continuously for three complete menstrual cycles, checked capillary glucose measurements six times daily, changed their own sensors every 3 days, and were seen seven times per menstrual cycle to download data and draw blood. Prolonged monitoring was safely carried out over three consecutive menstrual cycles. We observed two different patterns of glycemic control in relation to the menstrual cycle in these women. The first pattern, seen in two women, was characterized by increased frequency of hyperglycemia in the luteal phase. One of these women also had a hyperglycemic peak in the follicular phase. In the other two women, no characteristic cycle-related pattern was noted. The glucose profiles appeared reproducible between cycles in all women, but varied between women. Thus the menstrual cycle has a reproducible effect on glucose control in a subset of women with type 1 diabetes. Prolonged use of continuous glucose monitoring was safe in the subjects studied, and is the first method clinically available to monitor glucose control over prolonged periods in individuals with diabetes.