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Publication Record


Inverted formin 2 regulates intracellular trafficking, placentation, and pregnancy outcome.
Lamm KYB, Johnson ML, Baker Phillips J, Muntifering MB, James JM, Jones HN, Redline RW, Rokas A, Muglia LJ
(2018) Elife 7:
MeSH Terms: Animals, Cell Differentiation, Cell Movement, Female, Mice, Mice, Knockout, Microfilament Proteins, Placentation, Pregnancy, Pregnancy Outcome, Trophoblasts
Show Abstract · Added March 21, 2018
Healthy pregnancy depends on proper placentation-including proliferation, differentiation, and invasion of trophoblast cells-which, if impaired, causes placental ischemia resulting in intrauterine growth restriction and preeclampsia. Mechanisms regulating trophoblast invasion, however, are unknown. We report that reduction of ( alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of in mice recapitulates maternal and fetal phenotypes of placental insufficiency. dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. fetuses are growth restricted and demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. Our data support a critical regulatory role for in trophoblast invasion-a necessary process for placentation-representing a possible future target for improving placentation and fetal outcomes.
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11 MeSH Terms
Differentiating Research, Quality Improvement, and Case Studies to Ethically Incorporate Pregnant Women.
Phillippi JC, Hartmann KE
(2018) J Midwifery Womens Health 63: 104-114
MeSH Terms: Delivery of Health Care, Female, Humans, Information Dissemination, Patient Participation, Perinatal Care, Pregnancy, Pregnancy Outcome, Pregnant Women, Publishing, Quality Improvement, Research
Show Abstract · Added February 21, 2019
Pregnant women have been called therapeutic orphans because data supporting common interventions, medications, health teaching, and models of care are meager. The generation of quality evidence benefits from proactive approaches that ensure ethical standards are met to protect participants. The purpose of this article is to differentiate among health care, quality improvement, and research and to discuss ethical involvement of women who are pregnant and potentially childbearing in these initiatives. Health care is provided to protect and improve individual health. Quality improvement aims to enhance delivery of care for all those receiving care in particular settings. Research, whether retrospective or prospective, is designed to contribute to generalizable knowledge. This review includes vignettes to distinguish between research, quality improvement, and case study dissemination and to highlight the value of publication of information with applicability beyond a single site. As a community, perinatal care providers will be able to contribute more evidence to guide care if they err on the side of seeking institutional review board approval for activities that examine the care and outcomes of pregnant women and the fetus. Traditional research activities, including clinical trials, remain crucial. However, to fill gaps in knowledge, we must expedite our ability to report informative cases, examine clinical data, share lessons learned during quality improvement campaigns, and publish and disseminate these findings. Accelerating improvements in care demands expansion of the evidence base.
© 2017 by the American College of Nurse-Midwives.
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12 MeSH Terms
Interpregnancy Interval After Pregnancy Loss and Risk of Repeat Miscarriage.
Sundermann AC, Hartmann KE, Jones SH, Torstenson ES, Velez Edwards DR
(2017) Obstet Gynecol 130: 1312-1318
MeSH Terms: Abortion, Spontaneous, Adult, Birth Intervals, Cohort Studies, Female, Humans, Maternal Age, Parity, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Tennessee
Show Abstract · Added February 21, 2019
OBJECTIVE - To assess whether interpregnancy interval length after a pregnancy loss is associated with risk of repeat miscarriage.
METHODS - This analysis includes pregnant women participating in the Right From the Start (2000-2012) community-based prospective cohort study whose most recent pregnancy before enrollment ended in miscarriage. Interpregnancy interval was defined as the time between a prior miscarriage and the last menstrual period of the study pregnancy. Miscarriage was defined as pregnancy loss before 20 weeks of gestation. Cox proportional hazard models were used to estimate crude and adjusted hazard ratios and 95% CIs for the association between different interpregnancy interval lengths and miscarriage in the study pregnancy. Adjusted models included maternal age, race, parity, body mass index, and education.
RESULTS - Among the 514 study participants who reported miscarriage as their most recent pregnancy outcome, 15.7% had a repeat miscarriage in the study pregnancy (n=81). Median maternal age was 30 years (interquartile range 27-34) and 55.6% of participants had at least one previous livebirth (n=286). When compared with women with interpregnancy intervals of 6-18 months (n=136), women with intervals of less than 3 months (n=124) had the lowest risk of repeat miscarriage (7.3% compared with 22.1%; adjusted hazard ratio 0.33, 95% CI 0.16-0.71). Neither maternal race nor parity modified the association. Attempting to conceive immediately was not associated with increased risk of miscarriage in the next pregnancy.
CONCLUSION - An interpregnancy interval after pregnancy loss of less than 3 months is associated with the lowest risk of subsequent miscarriage. This implies counseling women to delay conception to reduce risk of miscarriage may not be warranted.
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MeSH Terms
Pregnancy outcomes in women with sickle-cell disease in low and high income countries: a systematic review and meta-analysis.
Boafor TK, Olayemi E, Galadanci N, Hayfron-Benjamin C, Dei-Adomakoh Y, Segbefia C, Kassim AA, Aliyu MH, Galadanci H, Tuuli MG, Rodeghier M, DeBaun MR, Oppong SA
(2016) BJOG 123: 691-8
MeSH Terms: Anemia, Sickle Cell, Developed Countries, Developing Countries, Female, Global Health, Humans, Models, Statistical, Odds Ratio, Pregnancy, Pregnancy Complications, Hematologic, Pregnancy Outcome
Show Abstract · Added July 20, 2016
BACKGROUND - Pregnancy in women with sickle-cell disease (SCD) is associated with increased adverse outcomes. Findings on the association between SCD and adverse pregnancy outcomes are conflicting, and the results do not address whether these associations are similar in both low- and high-income countries.
OBJECTIVES - We conducted a systematic review and meta-analysis to evaluate pregnancy outcomes associated with SCD.
SEARCH STRATEGY - The MEDLINE database was searched using medical subject headings (MeSH) and keywords for articles on pregnancy outcomes in women with SCD.
SELECTION CRITERIA - We used full research articles published in English that compared women with SCD with women who did not have SCD, as controls.
DATA COLLECTION AND ANALYSIS - Data were abstracted and analysed using comprehensive Meta-analysis 2.2. The primary outcomes were intrauterine growth restriction and perinatal mortality. Secondary outcomes were rates of caesarean sections, pre-eclampsia, eclampsia, postpartum haemorrhage, maternal mortality, prematurity, and low birthweight. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (95% CIs).
MAIN RESULTS - Sixteen studies met all of the selection criteria and were included in the analysis. SCD was associated with intrauterine growth restriction (pooled OR 2.79, 95% CI 1.85-4.21), perinatal mortality (pooled OR 3.76, 95% CI 2.34-6.06), and low birthweight (pooled OR 2.00, 95% CI 1.42-2.83). SCD was also associated with an increased risk of pre-eclampsia (pooled OR 2.05, 95% CI 1.47-2.85), maternal mortality (pooled OR 10.91, 95% CI 1.83-65.11, P = 0.009), and eclampsia (pooled OR 3.02, 95% CI 1.20-7.58).
CONCLUSION - Pregnancy in women with SCD is associated with increased risks of adverse perinatal and maternal outcomes in both low- and high-income countries.
TWEETABLE ABSTRACT - This meta-analysis showed worse pregnancy outcomes in women with sickle-cell disease compared with controls.
© 2015 Royal College of Obstetricians and Gynaecologists.
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High mobility group box 1 (HMGB1) protein in human uterine fluid and its relevance in implantation.
Bhutada S, Basak T, Savardekar L, Katkam RR, Jadhav G, Metkari SM, Chaudhari UK, Kumari D, Kholkute SD, Sengupta S, Sachdeva G
(2014) Hum Reprod 29: 763-80
MeSH Terms: Animals, Bodily Secretions, Cell Line, Embryo Implantation, Endometrium, Enzyme-Linked Immunosorbent Assay, Female, HMGB1 Protein, Humans, Immunohistochemistry, Menstrual Cycle, Pregnancy, Pregnancy Outcome, Rats, Uterus
Show Abstract · Added November 3, 2017
STUDY QUESTION - Does a differential abundance of high mobility group box 1 (HMGB1) protein in uterine fluid (UF) have a functional significance?
SUMMARY ANSWER - In rats, an excess of HMGB1 in UF during the receptive phase is detrimental to pregnancy.
WHAT IS KNOWN ALREADY - The identification of constituents of the human uterine secretome has been a subject of renewed interest, due to the advent of high throughput proteomic technologies. Proteomic-based investigations of human UF have revealed the presence of several proteins such as mucins, host defense proteins S100, heat shock protein 27 and haptoglobin, etc. The present study reports on the presence of HMGB1, a nuclear protein, in human UF. Activated macrophages/monocytes, natural killer cells, mature dendritic cells, pituicytes and erythroleukemic cells are also known to secrete HMGB1. Existing data suggest that extracellular HMGB1 plays a role in inflammation.
STUDY DESIGN, SIZE, DURATION - The human part of this study was cross-sectional in design. UF and endometrial tissues were collected from regularly cycling women in the early secretory (i.e. pre-receptive phase, Day 2 post-ovulation, n = 7) or secretory phase (i.e. receptive phase, Day 6 post-ovulation, n = 7) of their menstrual cycles. Samples were also collected from cycling rats in the proestrous (n = 8) or metestrous (n = 8) phase of their estrous cycles. Uteri were also collected from HMGB1-treated pregnant (n = 7) and untreated pseudo-pregnant (n = 7) rats and from pregnant rats at Day 3-5 post-coitum (p.c.) (n = 18, 3 each for six-time points).
PARTICIPANTS/MATERIALS, SETTING, METHODS - In each group of human samples, four samples were used for isobaric tag for relative and absolute quantification (iTRAQ) analysis and three samples were used for immunoblotting experiments to determine the abundance of HMGB1 in pre-receptive and receptive phase UF samples. HMGB1 levels in rat UF and endometrial tissue samples were estimated by ELISA and immunohistochemical studies, respectively. The expression of inflammation-associated molecules, such as nuclear factor kappa B (NFκB), receptor for advanced glycation end products (RAGEs), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), was analyzed by immunohistochemistry in HMGB1-treated and pseudo-pregnant rats.
MAIN RESULTS AND THE ROLE OF CHANCE - HMGB1 was identified as one of the differentially abundant proteins in the list generated by 8-plex iTRAQ analysis of receptive and pre-receptive phase UF samples. In both humans and rats, secreted and cellular levels of HMGB1 showed a similar pattern, i.e. significantly (P < 0.05) lower abundance in the receptive phase compared with that in the pre-receptive phase. A significant (P < 0.05) decline was also observed in the endometrial expression of HMGB1 on the day of implantation in pregnant rats. Exogenous administration of recombinant HMGB1, on Day 3 p.c., led to pregnancy failure, whereas administration of recombinant leukemia inhibitory factor or saline had no effect on pregnant rats. Further investigations revealed morphological changes in the endometrium, an increase in the expression of luminal epithelial NFκB and significantly (P < 0.05) higher expression levels of endometrial RAGE, TNF-α and IL-6 in HMGB1-treated rats, compared with untreated pseudo-pregnant rats.
LIMITATIONS, REASONS FOR CAUTION - The mechanisms, contributing to a decline in the cellular and extracellular levels of HMGB1 during the receptive phase, remain to be ascertained.
WIDER IMPLICATIONS OF THE FINDINGS - An excess of HMGB1 in the UF may be associated with infertility in women.
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15 MeSH Terms
Racial differences in risk of spontaneous abortions associated with periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure.
Velez Edwards DR, Hartmann KE
(2014) Ann Epidemiol 24: 111-115.e1
MeSH Terms: Abortion, Spontaneous, Adult, African Americans, Anti-Inflammatory Agents, Non-Steroidal, European Continental Ancestry Group, Female, Gestational Age, Healthcare Disparities, Humans, Incidence, Interviews as Topic, Nonprescription Drugs, Pregnancy, Pregnancy Outcome, Pregnancy Trimester, First, Prevalence, Proportional Hazards Models, Prospective Studies, Regression Analysis, Risk Factors, Socioeconomic Factors, United States, Young Adult
Show Abstract · Added March 5, 2014
PURPOSE - Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most common medications reported in pregnancy. NSAIDs directly impact prostaglandin pathways and have been proposed as potential risk factors for spontaneous abortions (SABs, gestation <20 weeks). SAB risk and drug response across several medications differ by race; therefore, we evaluated whether associations between NSAIDs and SAB risk differ by race.
METHODS - Women were enrolled in the Right from the Start (2004-2010) prospective cohort. Data regarding over-the-counter NSAIDs up to the sixth week of pregnancy were obtained from interviews. Race was self-reported. Cox proportional hazards regression models were used to estimate the association between NSAID exposure and SAB, adjusted for confounders.
RESULTS - Among 2493 pregnancies, 12% were African American and 88% were Caucasian. NSAID exposure was reported by 40% (n = 124) of African Americans and 43% (n = 945) of Caucasians. Race-stratified analyses showed protection from SAB among African Americans (adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI], 0.73-0.96) but no effect in Caucasians (aHR, 1.01; 95% CI 0.88-1.16).
CONCLUSIONS - Our findings suggest that risk for SAB due to over-the-counter NSAIDs in early pregnancy is modified by race. Further investigation of dose, timing in gestation, and indication may help to further reconcile the relationship between race, NSAIDs, and SAB.
Copyright © 2014 Elsevier Inc. All rights reserved.
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23 MeSH Terms
Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion.
Edwards DR, Aldridge T, Baird DD, Funk MJ, Savitz DA, Hartmann KE
(2012) Obstet Gynecol 120: 113-22
MeSH Terms: Abortion, Spontaneous, Adult, Anti-Inflammatory Agents, Non-Steroidal, Female, Gestational Age, Humans, Nonprescription Drugs, Pregnancy, Pregnancy Outcome, Pregnancy Trimester, First, Proportional Hazards Models, Prospective Studies, Risk, Ultrasonography, Prenatal
Show Abstract · Added March 5, 2014
OBJECTIVE - To estimate the association between over-the-counter nonsteroidal anti-inflammatory drug (NSAID) exposure during the early first trimester and risk for spontaneous abortion (gestation before 20 weeks of gestation) in a prospective cohort.
METHODS - Women were enrolled in the Right from the Start study (2004-2010). Exposure data regarding over-the-counter NSAID use from the last menstrual period (LMP) through the sixth week of pregnancy were obtained from intake and first-trimester interviews. Pregnancy outcomes were self-reported and verified by medical records. Gestational age was determined from the LMP. Stage of development before loss was determined from study ultrasonography. Cox proportional hazards regression models were used to estimate the association between NSAID exposure and pregnancy outcome taking into account candidate confounders.
RESULTS - Among 2,780 pregnancies, 367 women (13%) experienced a spontaneous abortion. NSAID exposure was reported by 1,185 (43%) women. NSAID exposure was not associated with spontaneous abortion risk in unadjusted models (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.82-1.24) or models adjusted for maternal age (adjusted HR 1.00, 95% CI 0.81-1.23).
CONCLUSION - Our findings suggest that use of nonprescription over-the-counter NSAIDs in early pregnancy does not put women at increased risk of spontaneous abortion.
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14 MeSH Terms
Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies.
Hayes RM, Wu P, Shelton RC, Cooper WO, Dupont WD, Mitchel E, Hartert TV
(2012) Am J Obstet Gynecol 207: 49.e1-9
MeSH Terms: Adult, Antidepressive Agents, Cohort Studies, Depression, Drug Utilization, Female, Humans, Infant, Low Birth Weight, Infant, Newborn, Logistic Models, Medicaid, Multivariate Analysis, Obstetric Labor, Premature, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Premature Birth, Respiratory Distress Syndrome, Newborn, Retrospective Studies, Seizures, Serotonin Uptake Inhibitors, Tennessee, United States
Show Abstract · Added March 7, 2014
OBJECTIVE - The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes.
STUDY DESIGN - We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995-2007.
RESULTS - Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2-2.3), 3.7 (95% CI, 2.8-4.6), and 4.9 (95% CI, 3.9-5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7-2.8); 2.8 (95% CI, 1.9-5.5); and 4.9 (95% CI, 2.6-9.5) for filling 1, 2, and ≥3 prescriptions, respectively.
CONCLUSION - Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions.
Copyright © 2012 Mosby, Inc. All rights reserved.
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23 MeSH Terms
The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy.
Urbanek M, Hayes MG, Lee H, Freathy RM, Lowe LP, Ackerman C, Jafari N, Dyer AR, Cox NJ, Dunger DB, Hattersley AT, Metzger BE, Lowe WL
(2012) PLoS One 7: e32958
MeSH Terms: Asian Continental Ancestry Group, Blood Glucose, C-Peptide, Cohort Studies, European Continental Ancestry Group, Fasting, Female, Genetic Predisposition to Disease, Glucose Tolerance Test, Glycated Hemoglobin A, Humans, Hyperglycemia, Inflammation, Interleukin-6, Interleukin-8, Polymorphism, Single Nucleotide, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Receptors, Adiponectin, Receptors, Leptin, Resistin, Signal Transduction, Thailand, Tumor Necrosis Factor-alpha
Show Abstract · Added February 22, 2016
BACKGROUND - Since mediators of inflammation are associated with insulin resistance, and the risk of developing diabetes mellitus and gestational diabetes, we hypothesized that genetic variation in members of the inflammatory gene pathway impact glucose levels and related phenotypes in pregnancy. We evaluated this hypothesis by testing for association between genetic variants in 31 inflammatory pathway genes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort, a large multiethnic multicenter study designed to address the impact of glycemia less than overt diabetes on pregnancy outcome.
RESULTS - Fasting, 1-hour, and 2-hour glucose, fasting and 1-hour C-peptide, and HbA1c levels were measured in blood samples obtained from HAPO participants during an oral glucose tolerance test at 24-32 weeks gestation. We tested for association between 458 SNPs mapping to 31 genes in the inflammatory pathway and metabolic phenotypes in 3836 European ancestry and 1713 Thai pregnant women. The strongest evidence for association was observed with TNF alpha and HbA1c (rs1052248; 0.04% increase per allele C; p-value = 4.4×10(-5)), RETN and fasting plasma glucose (rs1423096; 0.7 mg/dl decrease per allele A; p-value = 1.1×10(-4)), IL8 and 1 hr plasma glucose (rs2886920; 2.6 mg/dl decrease per allele T; p-value = 1.3×10(-4)), ADIPOR2 and fasting C-peptide (rs2041139; 0.55 ug/L decrease per allele A; p-value = 1.4×10(-4)), LEPR and 1-hour C-peptide (rs1171278; 0.62 ug/L decrease per allele T; p-value = 2.4×10(-4)), and IL6 and 1-hour plasma glucose (rs6954897; -2.29 mg/dl decrease per allele G, p-value = 4.3×10(-4)).
CONCLUSIONS - Based on the genes surveyed in this study the inflammatory pathway is unlikely to have a strong impact on maternal metabolic phenotypes in pregnancy although variation in individual members of the pathway (e.g. RETN, IL8, ADIPOR2, LEPR, IL6, and TNF alpha,) may contribute to metabolic phenotypes in pregnant women.
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25 MeSH Terms
Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
Winther JF, Olsen JH, Wu H, Shyr Y, Mulvihill JJ, Stovall M, Nielsen A, Schmiegelow M, Boice JD
(2012) J Clin Oncol 30: 27-33
MeSH Terms: Adolescent, Antineoplastic Agents, Child, Chromosome Aberrations, Cohort Studies, Congenital Abnormalities, Denmark, Female, Genetic Diseases, Inborn, Germ-Line Mutation, Gonads, Humans, Infant Mortality, Infant, Newborn, Male, Neoplasms, Pregnancy, Pregnancy Outcome, Radiotherapy, Radiotherapy Dosage, Registries, Risk Assessment, Risk Factors, Stillbirth, Survivors
Show Abstract · Added March 10, 2014
PURPOSE - Preconception radiation and chemotherapy have the potential to produce germ cell mutations leading to genetic disease in the next generation. Dose-response relationships were evaluated between cancer treatments and untoward pregnancy outcomes.
PATIENTS AND METHODS - A case-cohort study was conducted involving 472 Danish survivors of childhood and adolescent cancer and their 1,037 pregnancies. Adverse outcomes included 159 congenital malformations, six chromosomal abnormalities, seven stillbirths, and nine neonatal deaths. Preconception radiation doses to the gonads, uterus, and pituitary gland and administered chemotherapy were quantified based on medical records and related to adverse outcomes using a generalized estimating equation model.
RESULTS - No statistically significant associations were found between genetic disease in children and parental treatment with alkylating drugs or preconception radiation doses to the testes in male and ovaries in female cancer survivors. Specifically, the risk of genetic disease was similar among the children of irradiated survivors when compared with nonirradiated survivors (relative risk [RR], 1.02; 95% CI, 0.59 to 1.44; P = .94). A statistically significant association between abdomino-pelvic irradiation and malformations, stillbirths, and neonatal deaths was not seen in the children of female survivors overall (P = .07) or in the children of mothers receiving high uterine doses (mean, 13.5 Gy; max, 100 Gy; RR, 2.3; 95% CI, 0.95 to 5.56).
CONCLUSION - Mutagenic chemotherapy and radiotherapy doses to the gonads were not associated with genetic defects in children of cancer survivors. However, larger studies need to be conducted to further explore potential associations between high-dose pelvic irradiation and specific adverse pregnancy outcomes.
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25 MeSH Terms