Publications by authors named "Michael Varner"

357 Publications

Umbilical cord milking in non-vigorous infants: A cluster-randomized crossover trial.

Am J Obstet Gynecol 2022 Aug 12. Epub 2022 Aug 12.

Departments of George Washington University Biostatistics Center, Washington DC, United States of America.

Background: Delayed cord clamping (DCC) and umbilical cord milking (UCM) provide placental transfusion to vigorous newborns. Delayed cord clamping in non-vigorous newborns may not be provided due to perceived need for immediate resuscitation. UCM is an alternative since it can be performed more quickly than DCC and may confer similar benefits.

Objective: We hypothesized that UCM would reduce admission to the neonatal intensive care unit (NICU) compared with early cord clamping (ECC) in non-vigorous newborns born between 35-42 weeks' gestation.

Study Design: A pragmatic cluster-randomized crossover trial of infants born at 35-42 weeks' gestation from 10 medical centers in 3 countries between January 2019 and May 2021. Centers were randomized to UCM or ECC for approximately one year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if non-vigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to UCM or ECC according to their birth hospital randomization assignment. Baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the NICU for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy (HIE). Data were analyzed by intention to treat.

Results: Among 16,234 screened newborns, 1780 were eligible (905 UCM, 875 ECC) and 1730 had primary outcome data for analysis (97% of eligible; 872 UCM, 858 ECC) via either informed consent (606 UCM, 601 ECC) or waiver of informed consent (266 UCM, 257 ECC). The difference in the frequency of NICU admission using predefined criteria between the UCM (23%) and ECC (28%) groups did not reach statistical significance (modeled OR 0.69, 95% CI 0.41-1.14). UCM was associated with predefined secondary outcomes including a higher hemoglobin (modeled mean difference between UCM and ECC groups 0.68 g/dL, 95% CI 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude OR 0.72, 95%CI 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled OR 0.57, 95% CI 0.33-0.99) and therapeutic hypothermia (3% vs 4%, crude OR 0.57, 95% CI 0.33-0.99). Moderate-severe HIE was significantly less common with UCM (1% vs 3%, crude OR 0.48, 95% CI 0.24-0.96). No significant difference was observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude OR 0.81, 95% CI 0.62-1.06), or a serious adverse event composite of death before discharge.

Conclusions: Among non-vigorous infants born at 35-42 weeks' gestation, UCM did not reduce NICU admission for predefined criteria. However, infants in the UCM arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate to severe HIE and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that UCM in non-vigorous infants is feasible, safe and superior to ECC.
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http://dx.doi.org/10.1016/j.ajog.2022.08.015DOI Listing
August 2022

Quantitative longitudinal T2* mapping for assessing placental function and association with adverse pregnancy outcomes across gestation.

PLoS One 2022 19;17(7):e0270360. Epub 2022 Jul 19.

Department of Obstetrics and Gynecology, OHSU, Portland, Oregon, United States of America.

Existing methods for evaluating in vivo placental function fail to reliably detect pregnancies at-risk for adverse outcomes prior to maternal and/or fetal morbidity. Here we report the results of a prospective dual-site longitudinal clinical study of quantitative placental T2* as measured by blood oxygen-level dependent magnetic resonance imaging (BOLD-MRI). The objectives of this study were: 1) to quantify placental T2* at multiple time points across gestation, and its consistency across sites, and 2) to investigate the association between placental T2* and adverse outcomes. 797 successful imaging studies, at up to three time points between 11 and 38 weeks of gestation, were completed in 316 pregnancies. Outcomes were stratified into three groups: (UN) uncomplicated/normal pregnancy, (PA) primary adverse pregnancy, which included hypertensive disorders of pregnancy, birthweight <5th percentile, and/or stillbirth or fetal death, and (SA) secondary abnormal pregnancy, which included abnormal prenatal conditions not included in the PA group such as spontaneous preterm birth or fetal anomalies. Of the 316 pregnancies, 198 (62.6%) were UN, 70 (22.2%) PA, and 48 (15.2%) SA outcomes. We found that the evolution of placental T2* across gestation was well described by a sigmoid model, with T2* decreasing continuously from a high plateau level early in gestation, through an inflection point around 30 weeks, and finally approaching a second, lower plateau in late gestation. Model regression revealed significantly lower T2* in the PA group than in UN pregnancies starting at 15 weeks and continuing through 33 weeks. T2* percentiles were computed for individual scans relative to UN group regression, and z-scores and receiver operating characteristic (ROC) curves calculated for association of T2* with pregnancy outcome. Overall, differences between UN and PA groups were statistically significant across gestation, with large effect sizes in mid- and late- pregnancy. The area under the curve (AUC) for placental T2* percentile and PA pregnancy outcome was 0.71, with the strongest predictive power (AUC of 0.76) at the mid-gestation time period (20-30 weeks). Our data demonstrate that placental T2* measurements are strongly associated with pregnancy outcomes often attributed to placental insufficiency. Trial registration: ClinicalTrials.gov: NCT02749851.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295947PMC
July 2022

Umbilical Cord Collection and Drug Testing to Estimate Prenatal Substance Exposure in Utah.

Obstet Gynecol 2022 Aug 6;140(2):153-162. Epub 2022 Jul 6.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, the Department of Pathology, and the Department of Pediatrics, University of Utah Health, the Division of Maternal Fetal Medicine, Women and Newborns Clinical Program, Intermountain Healthcare, the Program for Addiction Research, Clinical Care, Knowledge and Advocacy (PARCKA), Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, and ARUP Laboratories, Salt Lake City, Utah.

Objective: Our primary objective was to estimate statewide prenatal substance exposure based on umbilical cord sampling. Our secondary objectives were to compare prevalence of prenatal substance exposure across urban, rural, and frontier regions, and to compare contemporary findings to those previously reported.

Methods: We performed a cross-sectional prevalence study of prenatal substance exposure, as determined by umbilical cord positivity for 49 drugs and drug metabolites, through the use of qualitative liquid chromatography-tandem mass spectrometry. All labor and delivery units in Utah (N=45) were invited to participate. Based on a 2010 study using similar methodology, we calculated that a sample size of at least 1,600 cords would have 90% power to detect 33% higher rate of umbilical cords testing positive for any substance. Deidentified umbilical cords were collected from consecutive deliveries at participating hospitals. Prevalence of prenatal substance exposure was estimated statewide and by rurality using weighted analysis.

Results: From November 2020 to November 2021, 1,748 cords (urban n=988, rural n=384, frontier n=376) were collected from 37 hospitals, representing 92% of hospitals that conduct 91% of births in the state. More than 99% of cords (n=1,739) yielded results. Statewide, 9.9% (95% CI 8.1-11.7%) were positive for at least one substance, most commonly opioids (7.0%, 95% CI 5.5-8.5%), followed by cannabinoid (11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) (2.5%, 95% CI 1.6-3.4%), amphetamines (0.9%, 95% CI 0.4-1.5), benzodiazepines (0.5%, 95% CI 0.1-0.9%), alcohol (0.4%, 95% CI 0.1-0.7%), and cocaine (0.1%, 95% CI 0-0.3%). Cord positivity was similar by rurality (urban=10.3%, 95% CI 8.3-12.3%, rural=7.1%, 95% CI 3.5-10.7%, frontier=9.2%, 95% CI 6.2-12.2%, P=.31) and did not differ by substance type. Compared with a previous study, prenatal exposure to any substance (6.8 vs 9.9%, P=.01), opioids (4.7 vs 7.0% vs 4.7%, P=.03), amphetamines (0.1 vs 0.9%, P=.01) and THC-COOH (0.5 vs 2.5%, P<.001) increased.

Conclusion: Prenatal substance exposure was detected in nearly 1 in 10 births statewide.
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http://dx.doi.org/10.1097/AOG.0000000000004868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373719PMC
August 2022

The association of race and ethnicity with severe maternal morbidity among individuals diagnosed with hypertensive disorders of pregnancy.

Am J Perinatol 2022 Jun 28. Epub 2022 Jun 28.

Obstetrics & Gynecology, University of Texas Health Sciences Center at Houston, Houston, United States.

Objective: To examine racial disparities in severe maternal morbidity in patients with hypertensive disorder of pregnancy (HDP).

Study Design: Secondary analysis of an observational study of 115,502 patients who had a live birth at ≥ 20 weeks in 25 hospitals in the US, 2008-2011. Only patients with HDP were included in this analysis. Race and ethnicity were categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB) and Hispanic. Associations were estimated between race and ethnicity and the primary outcome of severe maternal morbidity, defined as any of the following: blood transfusion ≥4 units, unexpected surgical procedure, need for a ventilator ≥ 12 hours, intensive care unit (ICU) admission, or failure of ≥ 1 organ system, were estimated by unadjusted logistic and multivariable backward logistic regressions. Multivariable models were run classifying HDP into 3 levels: 1) gestational hypertension; 2) preeclampsia (mild, severe or superimposed); and 3) eclampsia or HELLP.

Results: A total of 9,612 individuals with HDP were included. The frequency of the primary outcome, composite severe maternal morbidity, was higher in NHB patients compared with that in NHW or Hispanic patients (11.8% vs. 4.5% in NHW and 4.8% in Hispanic, p<0.001). This was driven by a higher frequency of blood transfusions and ICU admissions among NHB individuals. After adjusting for sociodemographic and clinical factors, hospital site, and the severity of HDP, the odds ratios of composite severe maternal morbidity did not differ between the groups (adjusted OR 1.26, 95% CI 0.95, 1.67 for NHB and adjusted OR 1.29, 95% CI 0.94, 1.77 for Hispanic, compared to NHW patients).

Conclusion: NHB patients with HDP had higher rates of the composite maternal morbidity compared with NHW, driven mainly by higher frequencies of blood transfusions and ICU admissions. However, once severity and other confounding factors were taken into account, the differences did not persist.
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http://dx.doi.org/10.1055/a-1886-5404DOI Listing
June 2022

DLK1: A novel biomarker of placental insufficiency in stillbirth and live birth.

Am J Perinatol 2022 Jun 16. Epub 2022 Jun 16.

Obstetrics & Gynecology, University of Utah School of Medicine, Salt Lake City, United States.

Objective Delta-like homolog 1 (DLK1) is a growth factor that is reduced in maternal sera in pregnancies with small for gestational age neonates. We sought to determine if DLK1 is associated with stillbirth (SB), with and without placental insufficiency. Study Design A nested case-control study was performed using maternal sera from a multicenter case-control study of SB and live birth (LB). SB and LB were stratified as placental insufficiency cases (small for gestational age <5% or circulatory lesions on placental histopathology) or normal placenta controls (appropriate for gestational age and no circulatory lesions). ELISA was used to measure DLK1. The mean difference in DLK1 was compared on the log scale in an adjusted linear regression model with pairwise differences, stratified by term/preterm deliveries among DLK1 results in the quantifiable range. In exploratory analysis, geometric means were compared among all data and the proportion of "low DLK1" (less than the median value for gestational age) were compared between groups and modeled using linear and logistic regression respectively. Results 234 SB and 234 LB were analyzed; 246 DLK1 values were quantifiable within the standard curve. Pairwise comparisons of case and control DLK1 geometric means showed no significant differences between groups. In exploratory analysis of all data, adjusted analysis revealed a significant difference for the LB comparison only (SB 71.9 pg/ml vs 99.1 pg/ml, p 0.097; LB 37.6 pg/ml vs 98.1 pg/ml, p 0.005). In exploratory analysis of "low DLK1", there was a significant difference between the odds ratio of having "low DLK1" between preterm cases and controls for both SB and LB. There were no significant differences in geometric means nor "low DLK1" between SB and LB. Conclusions In exploratory analysis, more placental insufficiency cases in preterm SB and LB had "low DLK1". However, low DLK1 levels were not associated with SB.
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http://dx.doi.org/10.1055/a-1877-6191DOI Listing
June 2022

ASSOCIATION OF MATERNAL BODY MASS INDEX AND MATERNAL MORBIDITY AND MORTALITY.

Am J Perinatol 2022 Jun 16. Epub 2022 Jun 16.

Oregon Health Sciences University, Portland, Portland, United States.

Objective: To assess the association of maternal BMI with a composite of severe maternal outcomes.

Study Design: Secondary analysis of a cohort of deliveries on randomly selected days at 25 hospitals from 2008-2011. Data on comorbid conditions, intrapartum events, and postpartum course were collected. The reference group (REF, BMI 18.5-29.9), obese (OB, BMI 30-39.9), morbidly obese (MO, BMI 40-49.9) and super morbidly obese (SMO, BMI  50) women were compared. The composite of severe maternal outcomes was defined as death, ICU admission, ventilator use, DVT/PE, sepsis, hemorrhage, DIC, unplanned operative procedure, or stroke. Patients in the REF group were matched 1:1 with those in all other obesity groups based on propensity score using the baseline characteristics of age, race-ethnicity, previous cesarean, pre-existing diabetes, chronic hypertension, parity, cigarette use, and insurance status. Multivariable Poisson regression was used to estimate adjusted relative risks (aRR) and 95% confidence intervals (CI) for the association between BMI and the composite outcome. Because cesarean delivery may be in the causal pathway between obesity and adverse maternal outcomes, models were then adjusted for mode of delivery to evaluate potential mediation.

Results: A total of 52,162 pregnant patients are included in the analysis. Risk of composite maternal outcomes was increased for SMO compared with REF, but not for OB and MO [OB aRR 1.06 95%CI (0.99-1.14); MO aRR 1.10 (95%CI 0.97-1.25); SMO aRR 1.32 95%CI (1.02-1.70)]. However, in the mediation analysis, cesarean appears to mediate 46% (95%CI 31% - 50%) of the risk of severe morbidity for SMO compared with REF.

Conclusion: Super morbid obesity is significantly associated with increased serious maternal morbidity and mortality; however, cesarean appears to mediate this association. Obesity and morbid obesity are not associated with maternal morbidity and mortality.
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http://dx.doi.org/10.1055/a-1877-8918DOI Listing
June 2022

Differential Gene Expression in Cord Blood of Infants Diagnosed with Cerebral Palsy: a Pilot Analysis of the BEAM Cohort.

Dev Neurosci 2022 Jun 15. Epub 2022 Jun 15.

The Beneficial Effects of Antenatal Magnesium (BEAM) clinical trial was conducted between 1997-2007, and demonstrated a significant reduction in cerebral palsy (CP) in preterm infants who were exposed to peripartum magnesium sulfate (MgSO4). However, the mechanism by which MgSO4 confers neuroprotection remains incompletely understood. Cord blood samples from this study were interrogated during an era when next generation sequencing was not widely accessible and few gene expression differences or biomarkers were identified between treatment groups. Our goal was to use bulk RNA deep sequencing to identify differentially expressed genes comparing the following four groups: newborns who ultimately developed CP treated with MgSO4 or placebo, and controls (newborns who ultimately did not develop CP) treated with MgSO4 or placebo. Those who died after birth were excluded. We found that MgSO4 upregulated expression of SCN5A only in the control group, with no change in gene expression in cord blood of newborns who ultimately developed CP. Regardless of MgSO4 exposure, expression of NPBWR1 and FTO were upregulated in cord blood of newborns who ultimately developed CP compared with controls. These data support that MgSO4 may not exert its neuroprotective effect through changes in gene expression. Moreover, NPBWR1 and FTO may be useful as biomarkers, and may suggest new mechanistic pathways to pursue in understanding the pathogenesis of CP. The small number of cases ultimately available for this secondary analysis, with male predominance and mild CP phenotype, is a limitation of the study. In addition, differentially expressed genes were not validated by qRT-PCR.
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http://dx.doi.org/10.1159/000525483DOI Listing
June 2022

Comparison of Cesarean Deliveries in a Multicenter U.S. Cohort Using the 10-Group Classification System.

Am J Perinatol 2022 Jun 3. Epub 2022 Jun 3.

Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon.

Objective:  We sought to (1) use the Robson 10-Group Classification System (TGCS), which classifies deliveries into 10 mutually exclusive groups, to characterize the groups that are primary contributors to cesarean delivery frequencies, (2) describe inter-hospital variations in cesarean delivery frequencies, and (3) evaluate the contribution of patient characteristics by TGCS group to hospital variation in cesarean delivery frequencies.

Study Design:  This was a secondary analysis of an observational cohort of 115,502 deliveries from 25 hospitals between 2008 and 2011. The TGCS was applied to the cohort and each hospital. We identified and compared the TGCS groups with the greatest relative contributions to cohort and hospital cesarean delivery frequencies. We assessed variation in hospital cesarean deliveries attributable to patient characteristics within TGCS groups using hierarchical logistic regression.

Results:  A total of 115,211 patients were classifiable in the TGCS (99.7%). The cohort cesarean delivery frequency was 31.4% (hospital range: 19.1-39.3%). Term singletons in vertex presentation with a prior cesarean delivery (group 5) were the greatest relative contributor to cohort (34.8%) and hospital cesarean delivery frequencies (median: 33.6%; range: 23.8-45.5%). Nulliparous term singletons in vertex (NTSV) presentation (groups 1 [spontaneous labor] and 2 [induced or absent labor]: 28.9%), term singletons in vertex presentation with a prior cesarean delivery (group 5: 34.8%), and preterm singletons in vertex presentation (group 10: 9.8%) contributed to 73.2% of the relative cesarean delivery frequency for the cohort and were correlated with hospital cesarean delivery frequencies (Spearman's rho = 0.96). Differences in patient characteristics accounted for 34.1% of hospital-level cesarean delivery variation in group 2.

Conclusion:  The TGCS highlights the contribution of NTSV presentation to cesarean delivery frequencies and the impact of patient characteristics on hospital-level variation in cesarean deliveries among nulliparous patients with induced or absent labor.

Key Points: · We report on the cesarean delivery frequencies in a multicenter U.S.

Cohort: . · NTSV gestations (groups 1 and 2) are a primary driver of cesarean deliveries.. · Patient characteristics contributed most to hospital variation in cesarean deliveries in group 2..
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http://dx.doi.org/10.1055/s-0042-1748527DOI Listing
June 2022

Endometriosis diagnosis, staging and typology and adverse pregnancy outcome history.

Paediatr Perinat Epidemiol 2022 May 16. Epub 2022 May 16.

Department of Obstetrics and Gynecology University of Utah Health, Salt Lake City, Utah, USA.

Background: Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity.

Objectives: We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women.

Methods: Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), including the operative cohort: 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; and the population cohort: 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors.

Results: Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes.

Conclusions: While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.
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http://dx.doi.org/10.1111/ppe.12887DOI Listing
May 2022

Amniocentesis to diagnose congenital cytomegalovirus infection following maternal primary infection.

Am J Obstet Gynecol MFM 2022 07 6;4(4):100641. Epub 2022 May 6.

Washington University in St. Louis, MO (Dr Macones).

Background: Congenital cytomegalovirus infection following maternal primary cytomegalovirus infection affects approximately 0.4% of newborns in the United States but may be hard to diagnose prenatally.

Objective: To evaluate the current sensitivity and specificity of amniocentesis in detecting congenital cytomegalovirus infection.

Study Design: Secondary analysis of a multicenter randomized placebo-controlled trial designed to evaluate whether cytomegalovirus hyperimmune globulin reduces congenital cytomegalovirus infection in neonates of individuals diagnosed with primary cytomegalovirus infection before 24 weeks of gestation. At randomization, subjects had no clinical evidence of fetal infection. Eligible subjects were randomized to monthly infusions of cytomegalovirus hyperimmune globulin or placebo until delivery. Although not required by the trial protocol, amniocentesis following randomization was permitted. The fetuses and neonates were tested for the presence of cytomegalovirus at delivery. Comparisons were made between those with and without amniocentesis and between those with cytomegalovirus-positive and negative results, using chi-square or Fisher exact test for categorical variables and the Wilcoxon rank sum test or t test for continuous variables. A P value of <.05 was considered significant.

Results: From 2012 to 2018, 397 subjects were included, of whom 55 (14%) underwent amniocentesis. Cytomegalovirus results were available for 53 fetuses and neonates. Fourteen amniocenteses were positive (25%). Gestational age at amniocentesis was similar between those with and without cytomegalovirus present, as was the interval between maternal diagnosis and amniocentesis. The prevalence of fetal or neonatal infection was 26% (14/53). The neonates of all 12 subjects with a positive amniocentesis and available results had cytomegalovirus infection confirmed at delivery, as did 2 neonates from the group of 41 subjects with a negative amniocentesis, with a sensitivity of 86% (95% confidence interval, 57-98), specificity of 100% (95% confidence interval, 91-100), positive predictive value of 100% (95% confidence interval, 74-100), and negative predictive value of 95% (95% confidence interval, 83-99). Amniocentesis-positive pregnancies were delivered at an earlier gestational age (37.4 vs 39.6 weeks; P<.001) and had lower birthweights (2583±749 vs 3428±608 g, P=.004) than amniocentesis-negative pregnancies.

Conclusion: Amniocentesis results are an accurate predictor of congenital cytomegalovirus infection.
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http://dx.doi.org/10.1016/j.ajogmf.2022.100641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167787PMC
July 2022

Overall and sex-specific risk factors for subjective cognitive decline: findings from the 2015-2018 Behavioral Risk Factor Surveillance System Survey.

Biol Sex Differ 2022 04 12;13(1):16. Epub 2022 Apr 12.

Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, Illinois, USA.

Background: Prior research indicates that at least 35% of Alzheimer's disease and related dementia risk may be amenable to prevention. Subjective cognitive decline is often the first indication of preclinical dementia, with the risk of subsequent Alzheimer's disease in such individuals being greater in women than men. We wished to understand how modifiable factors are associated with subjective cognitive decline, and whether differences exist by sex.

Methods: Data were collected from men and women (45 years and older) who completed the U.S. Behavioral Risk Factor Surveillance System Cognitive Decline Module (2015-2018), n = 216,838. We calculated population-attributable fractions for subjective cognitive decline, stratified by sex, of the following factors: limited education, deafness, social isolation, depression, smoking, physical inactivity, obesity, hypertension, and diabetes. Our models were adjusted for age, race, income, employment, marital and Veteran status, and accounted for communality among risk factors.

Results: The final study sample included more women (53.7%) than men, but both had a similar prevalence of subjective cognitive decline (10.6% of women versus 11.2% of men). Women and men had nearly equivalent overall population-attributable fractions to explain subjective cognitive decline (39.7% for women versus 41.3% for men). The top three contributing risk factors were social isolation, depression, and hypertension, which explained three-quarters of the overall population-attributable fraction.

Conclusions: While we did not identify any differences in modifiable factors between men and women contributing to subjective cognitive decline, other factors including reproductive or endocrinological health history or biological factors that interact with sex to modify risk warrant further research.
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http://dx.doi.org/10.1186/s13293-022-00425-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004039PMC
April 2022

Prediction of Cerebral Palsy or Death among Preterm Infants Who Survive the Neonatal Period.

Am J Perinatol 2022 Mar 4. Epub 2022 Mar 4.

Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Objective:  To assess whether neonatal morbidities evident by the time of hospital discharge are associated with subsequent cerebral palsy (CP) or death.

Study Design:  This is a secondary analysis of data from a multicenter placebo-controlled trial of magnesium sulfate for the prevention of CP. The association between prespecified intermediate neonatal outcomes ( = 11) and demographic and clinical factors ( = 10) evident by the time of discharge among surviving infants ( = 1889) and the primary outcome of death or moderate/severe CP at age 2 ( = 73) was estimated, and a prediction model was created.

Results:  Gestational age in weeks at delivery (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.67-0.83), grade III or IV intraventricular hemorrhage (IVH) (OR: 5.3, CI: 2.1-13.1), periventricular leukomalacia (PVL) (OR: 46.4, CI: 20.6-104.6), and male gender (OR: 2.5, CI: 1.4-4.5) were associated with death or moderate/severe CP by age 2. Outcomes not significantly associated with the primary outcome included respiratory distress syndrome, bronchopulmonary dysplasia, seizure, necrotizing enterocolitis, neonatal hypotension, 5-minute Apgar score, sepsis, and retinopathy of prematurity. Using all patients, the receiver operating characteristic curve for the final prediction model had an area under the curve of 0.84 (CI: 0.78-0.89). Using these data, the risk of death or developing CP by age 2 can be calculated for individual surviving infants.

Conclusion:  IVH and PVL were the only neonatal complications evident at discharge that contributed to an individual infant's risk of the long-term outcomes of death or CP by age 2. A model that includes these morbidities, gestational age at delivery, and gender is predictive of subsequent neurologic sequelae.

Key Points: · Factors known at hospital discharge are identified which are independently associated with death or CP by age 2.. · A model was created and validated using these findings to counsel parents.. · The risk of death or CP can be calculated at the time of hospital discharge..
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http://dx.doi.org/10.1055/a-1788-6281DOI Listing
March 2022

Antenatal Steroids and Cord Blood T-cell Glucocorticoid Receptor DNA Methylation and Exon 1 Splicing.

Reprod Sci 2022 05 10;29(5):1513-1523. Epub 2022 Feb 10.

Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.

Antenatal administration of glucocorticoids such as betamethasone (BMZ) during the late preterm period improves neonatal respiratory outcomes. However, glucocorticoids may elicit programming effects on immune function and gene regulation. Here, we test the hypothesis that exposure to antenatal BMZ alters cord blood immune cell composition in association with altered DNA methylation and alternatively expressed Exon 1 transcripts of the glucocorticoid receptor (GR) gene in cord blood CD4 T-cells. Cord blood was collected from 51 subjects in the Antenatal Late Preterm Steroids Trial: 27 BMZ, 24 placebo. Proportions of leukocytes were compared between BMZ and placebo. In CD4+ T-cells, methylation at CpG sites in the GR promoter regions and expression of GR mRNA exon 1 variants were compared between BMZ and placebo. BMZ was associated with an increase in granulocytes (51.6% vs. 44.7% p = 0.03) and a decrease in lymphocytes (36.8% vs. 43.0% p = 0.04) as a percent of the leukocyte population vs. placebo. Neither GR methylation nor exon 1 transcript levels differed between groups. BMZ is associated with altered cord blood leukocyte proportions, although no associated alterations in GR methylation were observed.
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http://dx.doi.org/10.1007/s43032-022-00859-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010373PMC
May 2022

An evaluation of seasonal maternal-neonatal morbidity related to trainee cycles.

Am J Obstet Gynecol MFM 2022 05 2;4(3):100583. Epub 2022 Feb 2.

Department of Obstetrics & Gynecology, University of Texas Health Science Center at Houston, McGovern Medical School-Children's Memorial Hermann Hospital, Houston, TX (Dr Blackwell).

Background: The existence of the "July phenomenon" (worse outcomes related to the presence of new physician trainees in teaching hospitals) has been debated in the literature and media. Previous studies of the phenomenon in obstetrics are limited by the quality and detail of data.

Objective: To evaluate whether the months of June to August, when transitions in trainees occur, are associated with increased maternal and neonatal morbidity.

Study Design: Secondary analysis of an observational cohort of 115,502 mother-infant pairs that delivered at 25 hospitals from March 2008 to February 2011. Inclusion criteria were an individual who had a singleton, nonanomalous live fetus at the onset of labor, and delivered at a hospital with trainees. The primary outcomes were composites of maternal and neonatal morbidity. We evaluated the outcomes by academic quarter during which the delivery occurred, beginning July 1, and by duration of the academic year as a continuous variable. To account for clustering in outcomes at a given delivery location, we applied hierarchical logistic regression with adjustment for hospital as a random effect.

Results: Of 115,502 deliveries, 99,929 met the inclusion criteria. Race and ethnicity, insurance, body mass index, drug use, and the availability of 24/7 maternal-fetal medicine, anesthesia, and neonatology varied by quarter. In adjusted analysis, the frequency of the composite maternal and neonatal morbidity did not differ by quarter. No differences in composite morbidity were observed when using day of the year as a continuous variable (maternal morbidity adjusted odds ratio, 1.00; 95% confidence interval, 0.99-1.00 and neonatal morbidity adjusted odds ratio, 1.00; 95% confidence interval, 1.00-1.01) and after adjustment for hospital as a random effect. Odds of major surgical complications in quarter 2 were twice those in quarter 1. Neonatal injury and intensive care unit were less frequent in later quarters.

Conclusion: Maternal and neonatal morbidity in teaching hospitals was not associated with the academic quarter during which delivery occurred, and there was no evidence of a "July phenomenon".
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http://dx.doi.org/10.1016/j.ajogmf.2022.100583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081218PMC
May 2022

Noninvasive Prediction of Congenital Cytomegalovirus Infection After Maternal Primary Infection.

Obstet Gynecol 2022 03;139(3):400-406

Departments of Obstetrics and Gynecology, Brown University, Providence, Rhode Island, University of Texas Medical Branch at Galveston, Galveston, Texas, Northwestern University, Chicago, Illinois, Columbia University, New York, New York, University of Utah Health Sciences Center, Salt Lake City, Utah, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, University of Alabama at Birmingham, Birmingham, Alabama, The Ohio State University, Columbus, Ohio, Duke University, Durham, North Carolina University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, Case Western Reserve University, Cleveland, Ohio, University of Texas Health Science Center at Houston and Children's Memorial Hermann Hospital, Houston, Texas, Stanford University, Stanford, California, University of Texas Southwestern Medical Center, Dallas, Texas University of Pennsylvania, Philadelphia, Pennsylvania, University of Pittsburgh, Pittsburgh, Pennsylvania, Madigan Army Medical Center, Joint Base Lewis-McChord, Washington, and Washington University in St. Louis, St. Louis, Missouri; the Departments of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, and Duke University, Durham, North Carolina; the George Washington University Biostatistics Center, Washington, DC; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

Objective: To develop and internally validate a noninvasive method for the prediction of congenital cytomegalovirus (CMV) infection after primary maternal CMV infection.

Methods: We conducted a secondary analysis of a multicenter randomized placebo-controlled trial of CMV hyperimmune globulin to prevent congenital infection. Women were eligible if they had primary CMV infection, defined as detectable plasma CMV-specific immunoglobulin (Ig)M and CMV-specific IgG with avidity less than 50% before 24 weeks of gestation or IgG seroconversion before 28 weeks, and were carrying a singleton fetus without ultrasonographic findings suggestive of CMV infection. Antibody assays were performed in a single reference laboratory. Congenital infection was defined as CMV detection in amniotic fluid, neonatal urine or saliva, or postmortem tissue. Using backward elimination, we developed logit models for prediction of congenital infection using factors known at randomization. The performance of the model was assessed using leave-one-out cross-validation (a method of internal validation).

Results: Of 399 women enrolled in the trial, 344 (86%) had informative data for this analysis. Congenital infection occurred in 68 pregnancies (20%). The best performing model included government-assisted insurance, IgM index 4.5 or higher, IgG avidity less than 32%, and whether CMV was detectable by polymerase chain reaction in maternal plasma at the time of randomization. Cross-validation showed an average area under the curve of 0.76 (95% CI 0.70-0.82), indicating moderate discriminatory ability. More parsimonious one-, two-, and three-factor models performed significantly less well than the four-factor model. Examples of prediction with the four-factor model: for a woman with government-assisted insurance, avidity less than 32%, IgM index 4.5 or higher, and detectable plasma CMV, probability of congenital infection was 0.69 (95% CI 0.53-0.82); for a woman with private insurance, avidity 32% or greater, IgM index less than 4.5, and undetectable plasma CMV, probability of infection was 0.03 (95% CI 0.02-0.07).

Conclusion: We developed models to predict congenital CMV infection in the presence of primary maternal CMV infection and absence of ultrasonographic findings suggestive of congenital infection. These models may be useful for patient counseling and decision making.
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http://dx.doi.org/10.1097/AOG.0000000000004691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857032PMC
March 2022

Neonatal Birthweight, Infant Feeding, and Childhood Metabolic Markers.

Am J Perinatol 2022 04 16;39(6):584-591. Epub 2021 Dec 16.

University of Texas Health Science Center at Houston-Children's Memorial Hermann Hospital, Houston, Texas.

Objective: Antenatal and early neonatal nutritional environment may influence later metabolic health. Infants of mothers with gestational diabetes mellitus (GDM) have higher risk for childhood obesity and metabolic syndrome (MetS). Leptin and adiponectin are known biomarkers for MetS and may guide interventions to reduce later obesity. We sought to examine the relationship between birthweight, early infancy feeding practices, and biomarkers for MetS in offspring of women with mild GDM.

Study Design: Secondary analysis of a prospective observational follow-up study on the offspring of women who participated in a multicenter randomized treatment trial on mild GDM. Children were evaluated by research coordinators and biospecimens collected at the age of 5 to 10. Plasma concentrations of leptin and adiponectin were compared between large for gestational age (LGA) and average birthweight (AGA) infants, and according to whether solid foods were introduced early (<6 months of age) or at the recommended age (≥6 months of age). Multivariable analysis adjusted for fetal sex, race/ethnicity, and maternal body mass index.

Results: Leptin and adiponectin were measured in 336 plasma samples. In bivariate analysis, compared with AGA children, LGA children had lower leptin (5.0 ng/mL [3.6-6.0] vs. 5.8 ng/mL [4.5 = 6.6],  = 0.01) and similar adiponectin (6.3 µg/mL [5.1-7.9] vs. 6.4 µg/mL [5.3-8.6],  = 0.49) concentrations. Maternal/child characteristics were similar between the early/delayed solid feeding groups. Leptin and adiponectin concentrations were similar in the early fed and delayed feeding groups (5.8 ng/mL [4.6-6.7] vs. 5.6 ng/mL [4.2-6.6],  = 0.50 and 6.4 µg/mL [5.4-8.1] vs. 6.4 µg/mL [5.1-8.8],  = 0.85, respectively). After controlling for covariates, children who were LGA and AGA at birth had similar leptin concentrations.

Conclusion: Birthweight and early infancy feeding practice are not associated with alterations in leptin and adiponectin in children of women with mild GDM.

Key Points: · Adipocytokines are markers of metabolic status.. · Children of women with mild GDM may be at risk for MetS.. · Biomarkers similar in LGA and AGA groups.. · Biomarkers similar in early and delayed solid-fed groups.. · Nonhuman milk does not modify effect of feeding practice..
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http://dx.doi.org/10.1055/s-0041-1740056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106839PMC
April 2022

How good are medical and death records for identifying dementia?

Alzheimers Dement 2021 Dec 7. Epub 2021 Dec 7.

Department of Psychology, Utah State University, Logan, Utah, USA.

Introduction: Retrospective studies using administrative data may be an efficient way to assess risk factors for dementia if diagnostic accuracy is known.

Methods: Within-individual clinical diagnoses of Alzheimer's disease (AD) and all-cause dementia in ambulatory (outpatient) surgery, inpatient, Medicare administrative records and death certificates were compared with research diagnoses among participants of Cache County Study on Memory, Health, and Aging (CCSMHA) (1995-2008, N = 5092).

Results: Combining all sources of clinical health data increased sensitivity for identifying all-cause dementia (71%) and AD (48%), while maintaining relatively high specificity (81% and 93%, respectively). Medicare claims had the highest sensitivity for case identification (57% and 40%, respectively).

Discussion: Administrative health data may provide a less accurate method than a research evaluation for identifying individuals with dementing disease, but accuracy is improved by combining health data sources. Assessing all-cause dementia versus a specific cause of dementia such as AD will result in increased sensitivity, but at a cost to specificity.
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http://dx.doi.org/10.1002/alz.12526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170837PMC
December 2021

Directly Measured Costs of Severe Maternal Morbidity Events during Delivery Admission Compared with Uncomplicated Deliveries.

Am J Perinatol 2022 04 2;39(6):567-576. Epub 2021 Dec 2.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, Utah.

Objective: To estimate the actual excess costs of care for delivery admissions complicated by severe maternal morbidity (SMM) compared with uncomplicated deliveries.

Study Design: This is a retrospective cohort study of all deliveries between October 2015 and September 2018 at a single tertiary academic center. Pregnant individuals ≥ 20 weeks' gestation who delivered during a hospital admission (i.e., a "delivery admission") were included. The primary exposure was SMM, as defined by Centers for Disease Control and Prevention (CDC) criteria, CDC criteria excluding blood transfusion, or by validated hospital-defined criteria (intensive care unit admission or ≥ 4 units of blood products). Potential SMM events identified via administrative and blood bank data were reviewed to confirm SMM events had occurred. Primary outcome was total actual costs of delivery admission derived from time-based accounting and acquisition costs in the institutional Value Driven Outcomes database. Cost of delivery admissions with SMM events was compared with the cost of uncomplicated delivery using adjusted generalized linear models, with separate models for each of the SMM definitions. Relative cost differences are reported due to data restrictions.

Results: Of 12,367 eligible individuals, 12,361 had complete cost data. Two hundred and eighty individuals (2.3%) had confirmed SMM events meeting CDC criteria. CDC criteria excluding transfusion alone occurred in 1.0% ( = 121) and hospital-defined SMM in 0.6% ( = 76). In adjusted models, SMM events by CDC criteria were associated with a relative cost increase of 2.45 times (95% confidence interval [CI]: 2.29-2.61) the cost of an uncomplicated delivery. SMM by CDC criteria excluding transfusion alone was associated with a relative increase of 3.26 (95% CI: 2.95-3.60) and hospital-defined SMM with a 4.19-fold (95% CI: 3.64-4.83) increase. Each additional CDC subcategory of SMM diagnoses conferred a relative cost increase of 1.60 (95% CI: 1.43-1.79).

Conclusion: SMM is associated with between 2.5- and 4-fold higher cost than uncomplicated deliveries.

Key Points: · Severe maternal morbidity as defined by CDC criteria confers a 2.5-fold increase in delivery hospitalization costs.. · Intensive care unit admission or ≥ 4 units of blood products confer a fourfold increase in cost.. · Costs of maternal morbidity may motivate SMM review..
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http://dx.doi.org/10.1055/s-0041-1740237DOI Listing
April 2022

Oral Glucose Tolerance Test in Pregnancy and Subsequent Maternal Hypertension.

Am J Perinatol 2021 Nov 16. Epub 2021 Nov 16.

Departments of Obstetrics and Gynecology, University of Texas Health Science Center at Houston-Children's Memorial Hermann Hospital, Houston, Texas.

Objective:  The aim of the study is to evaluate whether values and the shape of the glucose curve during the oral glucose tolerance test (OGTT) in pregnancy identify women at risk of developing hypertension (HTN) later in life.

Methods:  This category includes the secondary analysis of a follow-up from a mild gestational diabetes mellitus (GDM) study that included a treatment trial for mild GDM ( = 458) and an observational cohort of participants with abnormal 1-hour glucose loading test only (normal OGTT,  = 430). Participants were assessed at a median of 7 (IQR 6-8) years after their index pregnancy, and trained staff measured their blood pressure (systolic blood pressure [SBP]; diastolic blood pressure [DBP]). The association between values and the shape of the glucose curve during OGTT in the index pregnancy and the primary outcome defined as elevated BP (SBP ≥120, DBP ≥80 mm Hg, or receiving anti-HTN medications), and secondary outcome defined as stage 1 or higher (SBP ≥130, DBP ≥80 mm Hg, or receiving anti-HTN medications) at follow-up were evaluated using multivariable regression, adjusting for maternal age, body mass index, and pregnancy-associated hypertension during the index pregnancy.

Results:  There was no association between fasting, 1-hour OGTT, and the outcomes. However, the 2-hour OGTT value was positively associated (adjusted odds ratio [aRR] per 10-unit increase 1.04, 95% CI 1.01-1.08), and the 3-hour was inversely associated (aRR per 10-unit increase 0.96, 95% CI 0.93-0.99) with the primary outcome. When the shape of the OGTT curve was evaluated, a monophasic OGTT response (peak at 1 hour followed by a decline in glucose) was associated with increased risk of elevated BP (41.3vs. 23.5%, aRR 1.66, 95% CI 1.17-2.35) and stage 1 HTN or higher (28.5 vs. 14.7%, aRR 1.83, 95% CI 1.15-2.92), compared with a biphasic OGTT response.

Conclusion:  Among persons with mild GDM or lesser degrees of glucose intolerance, the shape of the OGTT curve during pregnancy may help identify women who are at risk of HTN later in life, with biphasic shape to be associated with lower risk.

Key Points: · The shape of the Oral Glucose Tolerance Test curve may help identify patients who are at risk of having elevated BP or HTN 5 to 10 years following pregnancy.. · The 2-hour Oral Glucose Tolerance Test values is positively associated with elevated BP 5 to 10 years following pregnancy.. · This supports the concept of pregnancy as a window to future health and represents a potential novel biomarker for maternal cardiovascular health screening..
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http://dx.doi.org/10.1055/s-0041-1740007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9108113PMC
November 2021

Association between Hypertensive Disorders of Pregnancy and Long-Term Neurodevelopmental Outcomes in the Offspring.

Am J Perinatol 2022 07 29;39(9):921-929. Epub 2021 Dec 29.

Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Objective: The long-term impact of hypertensive disorders of pregnancy (HDP) exposure on offspring health is an emerging research area. The objective of this study was to evaluate the association between a maternal diagnosis of HDP (gestational hypertension and preeclampsia) and adverse neurodevelopmental outcomes in the offspring.

Study Design: This was a secondary analysis of two parallel multicenter clinical trials of thyroxine therapy for subclinical hypothyroid disorders in pregnancy. Women with singleton nonanomalous gestations diagnosed with subclinical hypothyroidism or hypothyroxinemia were randomized to thyroxine therapy or placebo. The primary outcome was child intelligence quotient (IQ) at 5 years of age. Secondary outcomes included several neurodevelopmental measures, including the Bayley-III cognitive, motor, and language scores at 12 and 24 months, Differential Ability Scales-II (DAS-II) scores at 36 months, the Conners' rating scales-revised at 48 months, and scores from the Child Behavior Checklist at 36 and 60 months. Thyroxine therapy did not influence neurodevelopment in either of the primary studies. Associations between neurodevelopment outcomes and maternal HDP were examined using univariable and multivariable analyses.

Results: A total of 112 woman-child dyads with HDP were compared with 1,067 woman-child dyads without HDP. In univariable analysis, mean maternal age (26.7 ± 5.9 vs. 27.8 ± 5.7 years,  = 0.032) and the frequency of nulliparity (45.5 vs. 31.0%,  = 0.002) differed significantly between the two groups. Maternal socioeconomic characteristics did not differ between the groups. After adjusting for potential confounders, there were no significant differences in any primary or secondary neurodevelopment outcome between offspring exposed to HDP and those unexposed. However, when dichotomized as low or high scores, we found higher rates of language delay (language scores <85: -1 standard deviation) at 2 years of age among offspring exposed to HDP compared with those unexposed (46.5 vs. 30.5%, adjusted odds ratio = 2.22, 95% confidence interval [CI]: 1.44-3.42).

Conclusion: In this cohort of pregnant women, HDP diagnosis was associated with language delay at 2 years of age. However, other long-term neurodevelopmental outcomes in offspring were not associated with HDP.

Key Points: · No differences were found in neurodevelopment between offspring exposed to HDP and controls.. · Higher rates of language delay at 2 years of age were found in offspring exposed to HDP.. · The results did not differ when analysis was stratified by preterm birth..
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http://dx.doi.org/10.1055/a-1692-0659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081295PMC
July 2022

Fetal Tachycardia in the Setting of Maternal Intrapartum Fever and Perinatal Morbidity.

Am J Perinatol 2021 Oct 20. Epub 2021 Oct 20.

Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio.

Objective:  The fetal consequences of intrapartum fetal tachycardia with maternal fever or clinical chorioamnionitis are not well studied. We evaluated the association between perinatal morbidity and fetal tachycardia in the setting of intrapartum fever.

Study Design:  Secondary analysis of a multicenter randomized control trial that enrolled 5,341 healthy laboring nulliparous women ≥36 weeks' gestation. Women with intrapartum fever ≥ 38.0°C (including those meeting criteria for clinical chorioamnionitis) after randomization were included in this analysis. Isolated fetal tachycardia was defined as fetal heart rate (FHR) ≥160 beats per minute for at least 10 minutes in the absence of other FHR abnormalities. FHR abnormalities other than tachycardia were excluded from the analysis. The primary outcome was a perinatal composite (5-minute Apgar's score ≤3, intubation, chest compressions, or mortality). Secondary outcomes included low arterial cord pH (pH < 7.20), base deficit ≥12, and cesarean delivery.

Results:  A total of 986 (18.5%) of women in the trial developed intrapartum fever, and 728 (13.7%) met criteria to be analyzed; of these, 728 women 336 (46.2%) had maternal-fetal medicine (MFM) reviewer-defined fetal tachycardia, and 349 of the 550 (63.5%) women during the final hour of labor had validated software (PeriCALM) defined fetal tachycardia. After adjusting for confounders, isolated fetal tachycardia was not associated with a significant difference in the composite perinatal outcome (adjusted odds ratio [aOR] = 3.15 [0.82-12.03]) compared with absence of tachycardia. Fetal tachycardia was associated with higher odds of arterial cord pH <7.2, aOR = 1.48 (1.01-2.17) and of infants with a base deficit ≥ 12, aOR = 2.42 (1.02-5.77), but no significant difference in the odds of cesarean delivery, aOR = 1.33 (0.97-1.82).

Conclusion:  Fetal tachycardia in the setting of intrapartum fever or chorioamnionitis is associated with significantly increased fetal acidemia defined as a pH <7.2 and base excess ≥12 but not with a composite perinatal morbidity.

Key Points: · The perinatal outcomes associated with fetal tachycardia in the setting of maternal fever are undefined.. · Fetal tachycardia was not significantly associated with perinatal morbidity although the sample size was limited.. · Fetal tachycardia was associated with an arterial cord pH <7.2 and base deficit of 12 or greater..
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http://dx.doi.org/10.1055/a-1675-0901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018887PMC
October 2021

Outcomes in Twins Compared With Singletons Subsequent to Preterm Prelabor Rupture of Membranes.

Obstet Gynecol 2021 11;138(5):725-731

Departments of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, McGovern Medical School-Children's Memorial Hermann Hospital, Houston, Texas, Northwestern University, Chicago, Illinois, MetroHealth Medical Center-Case Western Reserve University, Cleveland, Ohio, Columbia University, New York, New York, University of Utah Health Sciences Center, Salt Lake City, Utah, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, University of Pittsburgh, Pittsburgh, Pennsylvania, The Ohio State University, Columbus, Ohio, University of Alabama at Birmingham, Birmingham, Alabama, University of Texas Medical Branch at Galveston, Galveston, Texas, Brown University, Providence, Rhode Island, and the George Washington University Biostatistics Center, Washington, DC; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

Objective: To compare maternal and neonatal outcomes after preterm prelabor rupture of membranes (PROM) from 23 to 34 weeks of gestation in twin compared with singleton gestations.

Methods: We conducted a secondary analysis of an obstetric cohort of 115,502 individuals and their singleton or twin neonates born in 25 hospitals nationwide (2008-2011). Those with preterm PROM from 23 0/7 through 33 6/7 weeks of gestation were included; neonates with major fetal anomalies were excluded. The coprimary outcomes for this analysis were composite maternal morbidity (chorioamnionitis, blood transfusion, postpartum endometritis, wound infection, sepsis, venous thromboembolism, intensive care unit admission, or death) and composite major neonatal morbidity (persistent pulmonary hypertension, intraventricular hemorrhage grade III or IV, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II or III, bronchopulmonary dysplasia, stillbirth subsequent to admission, or neonatal death before discharge). Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs) with 95% CIs for twin compared with singleton gestations.

Results: Of 1,531 (1.3%) individuals who met eligibility criteria for this analysis, 218 (14.2%) had twin gestations. The median gestational age at preterm PROM was similar between those with twins and singletons (31.2 weeks [interquartile range 27.4-32.9] vs 30.6 weeks [interquartile range 26.9-32.7], P=.23); however, those with twin gestations had a shorter median latency period (2.0 days [interquartile range 1.0-5.0] vs 3.0 days [interquartile range 2.0-8.0], P<.001). After adjustment for potential confounders, odds of experiencing composite maternal morbidity (17.9% vs 19.3%, adjusted OR 0.97, 95% CI 0.66-1.42) or composite neonatal morbidity (20.4% vs 20.5%, OR 0.97, 95% CI 0.72-1.31) did not differ between groups.

Conclusion: In a large, diverse cohort, the likelihood of composite maternal or neonatal morbidity per fetus after preterm PROM was similar for twin and singleton gestations.
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http://dx.doi.org/10.1097/AOG.0000000000004561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542618PMC
November 2021

Attitudes Toward COVID-19 Illness and COVID-19 Vaccination among Pregnant Women: A Cross-Sectional Multicenter Study during August-December 2020.

Am J Perinatol 2022 01 1;39(1):75-83. Epub 2021 Oct 1.

Centers for Disease Control and Prevention, Atlanta, Georgia.

Objective: The aim of the study was to evaluate pregnant women's attitudes toward COVID-19 illness and vaccination and identify factors associated with vaccine acceptability.

Study Design: This was a cross-sectional survey among pregnant women enrolled in a prospective COVID-19 cohort study in Salt Lake City, UT, Birmingham, AL, and New York, NY, from August 9 to December 10, 2020. Women were eligible if they were 18 to 50 years old and <28 weeks of gestation. Upon enrollment, women completed surveys regarding concerns about COVID-19 illness and likelihood of getting COVID-19 vaccine if one were available during pregnancy. Vaccine acceptability was defined as a response of "very likely" or "somewhat likely" on a 4-point Likert scale. Factors associated with vaccine acceptability were assessed with multivariable logistic regression.

Results: Of 939 pregnant women eligible for the main cohort study, 915 (97%) consented to participate. Among these 915 women, 39% self-identified as White, 23% Black, 33% Hispanic, and 4% Other. Sixty-two percent received an influenza vaccine last season. Seventy-two percent worried about getting sick with COVID-19. If they were to get sick, 92% worried about harm to their pregnancy and 80% about harm to themselves. Only 41% reported they would get a vaccine. Of women who were unlikely to get vaccinated, the most frequently cited concern was vaccine safety for their pregnancy (82%). Non-Hispanic Black and Hispanic women had lower odds of accepting a vaccine compared with non-Hispanic White women (adjusted odds ratios [aOR] 0.4, 95% CI 0.2-0.6 for both). Receipt of influenza vaccine during the previous season was associated with higher odds of vaccine acceptability (aOR 2.1, 95% CI 1.5-3.0).

Conclusion: Although most pregnant women worried about COVID-19 illness, <50% were willing to get vaccinated during pregnancy. Racial and ethnic disparities in plans to accept COVID-19 vaccine highlight the need to prioritize strategies to address perceived barriers among groups at high risk for COVID-19.

Key Points: · Less than half of pregnant patients stated they would get a COVID-19 vaccine.. · Protecting their baby was the most common reason for acceptance and refusal of the COVID-19 vaccine.. · Patients of minority race/ethnicity and those without prior influenza vaccination were less likely to accept the COVID-19 vaccine..
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http://dx.doi.org/10.1055/s-0041-1735878DOI Listing
January 2022

Intrapartum Fetal Electrocardiogram in Small- and Large-for-Gestational Age Fetuses.

Am J Perinatol 2021 12 31;38(14):1465-1471. Epub 2021 Aug 31.

Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Objective: This study aimed to evaluate whether intrapartum fetal electrocardiogram (ECG) tracings with ST-elevation or depression occur more frequently in each stage of labor in small-for-gestational age (SGA) or large-for-gestational age (LGA), as compared with appropriate-for-gestational age (AGA) fetuses.

Study Design: We conducted a secondary analysis of a large, multicenter trial in which laboring patients underwent fetal ECG waveform-analysis. We excluded participants with diabetes mellitus and major fetal anomalies. Birth weight was categorized as SGA (<10th percentile), LGA (>90th percentile), or AGA (10-90th percentile) by using a gender and race/ethnicity specific nomogram. In adjusted analyses, the frequency of ECG tracings with ST-depression or ST-elevation without depression was compared according to birthweight categories and labor stage.

Results: Our study included 4,971 laboring patients in the first stage and 4,074 in the second stage. During the first stage of labor, there were no differences in the frequency of ST-depression in SGA fetuses compared with AGA fetuses (6.7 vs. 5.5%; adjusted odds ratio [aOR]: 1.41, 95% confidence interval [CI]: 0.93-2.13), or in ST-elevation without depression (35.8 vs. 34.1%; aOR: 1.17, 95% CI: 0.94-1.46). During the second stage, there were no differences in the frequency of ST-depression in SGA fetuses compared with AGA fetuses (1.6 vs. 2.0%; aOR: 0.69, 95% CI: 0.27-1.73), or in ST-elevation without depression (16.2 vs. 18.1%; aOR: 0.90, 95% CI: 0.67-1.22). During the first stage of labor, there were no differences in the frequency of ST-depression in LGA fetuses compared with AGA fetuses (6.3 vs. 5.5%; aOR: 0.97, 95% CI: 0.60-1.57), or in ST-elevation without depression (33.1 vs. 34.1%; aOR: 0.80, 95% CI: 0.62-1.03); during the second stage of labor, the frequency of ST-depression in LGA compared with AGA fetuses (2.5 vs. 2.0%, aOR: 1.36, 95% CI: 0.61-3.03), and in ST-elevation without depression (15.5 vs. 18.1%; aOR: 0.83, 95% CI: 0.58-1.18) were similar as well.

Conclusion: The frequency of intrapartum fetal ECG tracings with ST-events is similar among SGA, AGA, and LGA fetuses.

Key Points: · SGA and LGA neonates are at increased risk of cardiac dysfunction.. · Fetal ECG has been used to evaluate fetal response to hypoxia.. · Fetal ST-elevation and ST-depression occur during hypoxia.. · Frequency of intrapartum ST-events is similar among SGA, AGA and LGA fetuses..
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http://dx.doi.org/10.1055/s-0041-1735285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608729PMC
December 2021

Incidence and Clinical Characteristics of and Risk Factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Among Pregnant Individuals in the United States.

Clin Infect Dis 2022 07;74(12):2218-2226

New York-Presbyterian Hospital, New York, New York, USA.

Background: Data about the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among pregnant individuals are needed to inform infection-prevention guidance and counseling for this population.

Methods: We prospectively followed a cohort of pregnant individuals during August 2020-March 2021 at 3 US sites. The 3 primary outcomes were incidence rates of any SARS-CoV-2 infection, symptomatic infection, and asymptomatic infection, during pregnancy during periods of SARS-CoV-2 circulation. Participants self-collected weekly midturbinate nasal swabs for SARS-CoV-2 reverse transcription-polymerase chain reaction testing, completed weekly illness symptom questionnaires, and submitted additional swabs with coronavirus disease 2019 (COVID-19)-like symptoms. An overall SARS-CoV-2 infection incidence rate weighted by population counts of women of reproductive age in each state was calculated.

Results: Among 1098 pregnant individuals followed for a mean of 10 weeks, 9% (99/1098) had SARS-CoV-2 infections during the study. Population-weighted incidence rates of SARS-CoV-2 infection were 10.0 per 1000 (95% confidence interval, 5.7-14.3) person-weeks for any infection, 5.7 per 1000 (1.7-9.7) for symptomatic infections, and 3.5 per 1000 (0-7.1) for asymptomatic infections. Among 96 participants with SARS-CoV-2 infections and symptom data, the most common symptoms were nasal congestion (72%), cough (64%), headache (59%), and change in taste or smell (54%); 28% had measured or subjective fever. Median symptom duration was 10 (interquartile range, 6-16) days.

Conclusions: Pregnant individuals in this study had a 1% risk of SARS-CoV-2 infection per week, underscoring the importance of COVID-19 vaccination and other prevention measures during pregnancy while SARS-CoV-2 is circulating in the community.
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http://dx.doi.org/10.1093/cid/ciab713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513407PMC
July 2022

Intrapartum Resuscitation Interventions for Category II Fetal Heart Rate Tracings and Improvement to Category I.

Obstet Gynecol 2021 09;138(3):409-416

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD; the Departments of Obstetrics and Gynecology, the University of Texas Medical Branch at Galveston, Galveston, Texas, the University of Utah Health Sciences Center, Salt Lake City, Utah, the University of Texas McGovern Medical School at UT Health, Houston, Texas, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, the University of Alabama at Birmingham, Birmingham, Alabama, Columbia University, New York, New York, Northwestern University, Chicago, Illinois, The Ohio State University, Columbus, Ohio, MetroHealth Medical Center-Case Western Reserve University, Cleveland, Ohio, Brown University, Providence, Rhode Island, Stanford University, Stanford, California, Wayne State University, Detroit, Michigan, and the University of Pittsburgh, Pittsburgh, Pennsylvania; and the George Washington University Biostatistics Center, Washington, DC.

Objective: To evaluate intrapartum resuscitation interventions and improvement in category II fetal heart rate (FHR) tracings.

Methods: This secondary analysis of a randomized trial of intrapartum fetal electrocardiographic ST-segment analysis included all participants with category II FHR tracings undergoing intrauterine resuscitation: maternal oxygen, intravenous fluid bolus, amnioinfusion, or tocolytic administration. Fetal heart rate pattern-recognition software was used to confirm category II FHR tracings 30 minutes before intervention and to analyze the subsequent 60 minutes. The primary outcome was improvement to category I within 60 minutes. Secondary outcomes included FHR tracing improvement to category I 30-60 minutes after the intervention and composite neonatal outcome.

Results: Of 11,108 randomized participants, 2,251 (20.3%) had at least one qualifying intervention for category II FHR tracings: 63.7% improved to category I within 60 minutes and 50.5% improved at 30-60 minutes. Only 3.4% underwent cesarean delivery and 4.1% an operative vaginal delivery for nonreassuring fetal status within 60 minutes after the intervention. Oxygen administration was the most common intervention (75.4%). Among American College of Obstetricians and Gynecologists-defined subgroups that received oxygen, the absent FHR accelerations and absent-minimal FHR variability subgroup (n=332) was more likely to convert to category I within 60 minutes than the FHR accelerations or "moderate FHR variability" subgroup (n=1,919) (77.0% vs 63.0%, odds ratio [OR] 2.0, 95% CI 1.4-2.7). The incidence of composite neonatal adverse outcome for category II tracings was 2.9% (95% CI 2.2-3.7%) overall; 2.8% (95% CI 2.0-3.8%) for improvement to category I within 60 minutes (n=1,433); and 3.2% (95% CI 2.1-4.6%) for no improvement within 60 minutes (n=818). However, the group with improvement had 29% lower odds for higher level neonatal care (11.8% vs 15.9%, OR 0.71, 95% CI 0.55-0.91).

Conclusion: Nearly two thirds of category II FHR tracings improved to category I within 60 minutes of intervention with a relatively low overall rate of the composite neonatal adverse outcome.

Funding Source: Funded in part by Neoventa Medical.
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http://dx.doi.org/10.1097/AOG.0000000000004508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506980PMC
September 2021

Relationship Between Maternal Economic Vulnerability and Childhood Neurodevelopment at 2 and 5 Years of Life.

Obstet Gynecol 2021 09;138(3):379-388

Departments of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois, the University of Texas-Southwestern, Dallas, Texas, the University of Utah Health Sciences Center, Salt Lake City, Utah, Wayne State University, Detroit, Michigan, Columbia University, New York, New York, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, the University of Texas Medical Branch at Galveston, Galveston, Texas, the University of Alabama at Birmingham, Birmingham, Alabama, Brown University, Providence, Rhode Island, the University of Texas-Houston, Houston, Texas, The Ohio State University, Columbus, Ohio, Case Western Reserve University, Cleveland, Ohio, Oregon Health Sciences University, Portland, Oregon, the University of Pittsburgh, Pittsburgh, Pennsylvania; and the George Washington University Biostatistics Center, Washington, DC.

Objective: To assess the relationship between economic vulnerability during pregnancy and childhood neurodevelopment.

Methods: This is a secondary analysis of two parallel multicenter, randomized, controlled trials of administration of levothyroxine to pregnant individuals with subclinical hypothyroidism or hypothyroxinemia in the United States. All participants who delivered a live, nonanomalous neonate and completed the WPPSI-III (Weschler Preschool & Primary Scale of Intelligence) at 5 years of life and the Bayley-III (Bayley Scales of Infant Development) test at 2 years were included. The primary outcome is WPPSI-III score. Secondary outcome included Bayley-III subtest scores. Multivariable analyses were used to assess the relationships between economic vulnerability during the index pregnancy-defined as a household income less than 200% of the estimated federal poverty level, part-time or no employment, and use of government insurance-and the prespecified outcomes. Tests of interaction were performed to assess whether the magnitude of association differed according to whether participants were married or completed more than a high school education. A sensitivity analysis was performed to limit the income criteria for economic vulnerability to household income of less than 100% of the estimated federal poverty level.

Results: Of 955 participants who met inclusion criteria, 406 (42.5%) were considered economically vulnerable. In bivariate analysis, the WPPSI-III score and Bayley-III subtest scores were significantly lower among children of the economically vulnerable. For the WPPSI-III, Bayley-III cognitive subtest, and Bayley-III language subtest scores, the associations between economic vulnerability and lower childhood neurodevelopmental scores were primarily seen only among those who were married or completed more than a high school education (P for interaction<.05). A similar pattern was noted when restricting the income criteria for economic vulnerability to less than 100% of the federal poverty level.

Conclusion: Economic vulnerability during pregnancy is associated with an increased risk of adverse neurodevelopmental outcomes in their children at 2 and 5 years of life, particularly among those who are married or completed more than a high school education.
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http://dx.doi.org/10.1097/AOG.0000000000004503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376769PMC
September 2021

A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection.

N Engl J Med 2021 07;385(5):436-444

From the Department of Obstetrics and Gynecology, Brown University, Providence, RI (B.L.H., D.J.R., D.A.); George Washington University Biostatistics Center, Washington, DC (R.G.C., L.M.F.); the University of Texas Medical Branch, Galveston (G.R.S.), the University of Texas Health Science Center at Houston, Children's Memorial Hermann Hospital, Houston (S.P.C.), and the University of Texas Southwestern Medical Center, Dallas (B.M.C.); Northwestern University, Chicago (M.J.D., G.M.); Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD (U.M.R.); Columbia University, New York (C.G.-B.); the University of Utah Health Sciences Center, Salt Lake City (M.W.V.); the University of North Carolina at Chapel Hill, Chapel Hill (W.H.G.), and Duke University, Durham (G.K.S.) - both in North Carolina; the Department of Pediatrics (R.P.), University of Alabama at Birmingham (A.T.N.T.), Birmingham; Ohio State University, Columbus (M.M.C.), the University of Colorado School of Medicine, Anschutz Medical Campus, Aurora (R.S.G.); Case Western Reserve University, Cleveland (E.K.C.); Stanford University, Stanford, CA (Y.Y.E.-S.); the University of Pennsylvania, Philadelphia (S.P.), and the University of Pittsburgh, Pittsburgh (H.N.S.); Madigan Army Medical Center, Joint Base Lewis-McChord, WA (P.G.N.); and Washington University, St. Louis (G.A.M.).

Background: Primary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection.

Methods: In this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks' gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed.

Results: From 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P = 0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo.

Conclusions: Among pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks' gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.).
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http://dx.doi.org/10.1056/NEJMoa1913569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363945PMC
July 2021

Respiratory Viral Infections and Infection Prevention Practices Among Women With Acute Respiratory Illness During Delivery Hospitalizations During the 2019-2020 Influenza Season.

J Infect Dis 2022 01;225(1):50-54

Division of Child and Adolescent Health, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York,USA.

Background: We conducted a cross-sectional study of pregnant women with acute respiratory illness during delivery hospitalizations during influenza season to describe clinical testing for respiratory viruses and infection prevention practices.

Methods: Women had nasal swabs tested for influenza and other respiratory viruses. Among 91 enrolled women, 22 (24%) had clinical testing for influenza.

Results: Based on clinical and study testing combined, 41 of 91 (45%) women had samples positive for respiratory viruses. The most common virus was influenza (17 of 91, 19%); 53% (9 of 17) of influenza virus infections were identified through study testing alone. Only 16% of women were on droplet precautions.

Conclusions: Peripartum respiratory infections may be underrecognized.
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http://dx.doi.org/10.1093/infdis/jiab292DOI Listing
January 2022

Model-Based Re-Examination of the Effectiveness of Tumor/Immunohistochemistry and Direct-to-Sequencing Protocols for Lynch Syndrome Case Finding in Endometrial Cancer.

JCO Oncol Pract 2021 11 22;17(11):e1785-e1793. Epub 2021 Apr 22.

Genomic Medicine Institute, Geisinger, Danville, PA.

Purpose: Despite widespread provision of Lynch syndrome (LS) screening programs, questions remain about the most effective and efficient protocol for LS case finding. The purpose of this study was to explore the performance of the two protocols widely shown to be the most efficient and effective, respectively: immunohistochemical (IHC) staining of tumor and direct-to-sequencing (DtS) in endometrial cancer populations.

Methods: Simulation models were developed to explore performance of the IHC and DtS protocols, updated to reflect current evidence. Analyses explicitly account for protocol complexity and failure points, as well as decreased sequencing costs. Key outcomes are percent of LS cases identified, total protocol costs and efficiency, and break-even analyses of sequencing costs. All costs are in 2020 US dollars (USD).

Results: Under plausible conditions, the IHC protocol is expected to identify 40%-78% of LS cases and DtS protocol from 49% to 97%. When the key variable is fixed for both protocols at 50%, 75%, and 100%, the DtS protocol is 9%, 12%, and 16% better at case finding, respectively, than the IHC protocol. The break-even cost of sequencing is about $488 USD when the outcome is total direct testing protocol costs; it is about $670 USD when the outcome is cost per LS case detected.

Conclusion: This study quantifies the plausible differences in the clinical effectiveness and cost-effectiveness of the two LS case-finding protocols. We demonstrate the large influence of success in proceeding to sequencing and potential impact of decreasing sequencing prices.
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http://dx.doi.org/10.1200/OP.20.00988DOI Listing
November 2021
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