Increasing Preterm Delivery and Small for Gestational Age Trends in South Carolina during the COVID-19 Pandemic.

Preterm delivery (PTD) complications are a major cause of childhood morbidity and mortality. We aimed to assess trends in PTD and small for gestational age (SGA) and whether trends varied between race-ethnic groups in South Carolina (SC). We utilized 2015-2021 SC vital records linked to hospitalization and emergency department records. PTD was defined as clinically estimated gestation less than (<) 37 weeks (wks.) with subgroup analyses of PTD < 34 wks. and < 28 wks. SGA was defined as infants weighing below the 10th percentile for gestational age. This retrospective study included 338,532 (243,010 before the COVID-19 pandemic and 95,522 during the pandemic) live singleton births of gestational age ≥ 20 wks. born to 260,276 mothers in SC. Generalized estimating equations and a change-point during the first quarter of 2020 helped to assess trends. In unadjusted analyses, pre-pandemic PTD showed an increasing trend that continued during the pandemic (relative risk (RR) = 1.04, 95% CI: 1.02-1.06). PTD < 34 wks. rose during the pandemic (RR = 1.07, 95% CI: 1.02-1.12) with a significant change in the slope. Trends in SGA varied by race and ethnicity, increasing only in Hispanics (RR = 1.02, 95% CI: 1.00-1.04) before the pandemic. Our study reveals an increasing prevalence of PTD and a rise in PTD < 34 wks. during the pandemic, as well as an increasing prevalence of SGA in Hispanics during the study period.

Neutrophil-inflicted vasculature damage suppresses immune-mediated optic nerve regeneration.

In adult mammals, injured retinal ganglion cells (RGCs) fail to spontaneously regrow severed axons, resulting in permanent visual deficits. Robust axon growth, however, is observed after intra-ocular injection of particulate ß-glucan isolated from yeast. Blood-borne myeloid cells rapidly respond to ß-glucan, releasing numerous pro-regenerative factors. Unfortunately, the pro-regenerative effects are undermined by retinal damage inflicted by an overactive immune system. Here, we demonstrate that protection of the inflamed vasculature promotes immune-mediated RGC regeneration. In the absence of microglia, leakiness of the blood-retina barrier increases, pro-inflammatory neutrophils are elevated, and RGC regeneration is reduced. Functional ablation of the complement receptor 3 (CD11b/integrin-αM), but not the complement components C1q-/- or C3-/-, reduces ocular inflammation, protects the blood-retina barrier, and enhances RGC regeneration. Selective targeting of neutrophils with anti-Ly6G does not increase axogenic neutrophils but protects the blood-retina barrier and enhances RGC regeneration. Together, these findings reveal that protection of the inflamed vasculature promotes neuronal regeneration.

Impact on Neonatal Outcomes with Late Preterm and Early Term Delivery in Women with Diabetes.

OBJECTIVE: Late preterm and early term deliveries are common in pregnancies complicated by diabetes due to higher rates of obstetric complications including increased stillbirth risk. However, early delivery is associated with multiple neonatal adverse outcomes, which may be further increased by maternal diabetes. We examined whether there is an additive effect on adverse neonatal outcomes in the setting of maternal diabetes in the late preterm and early term periods. STUDY DESIGN: This was a retrospective cohort study of women with a singleton, nonanomalous pregnancy delivering at a single academic medical center in the late preterm (340/7-366/7 weeks) or early term (370/7-386/7 weeks) period between 2010 and 2019. Women were categorized by diabetes status: no diabetes, type 1 (T1DM), type 2 (T2DM), or gestational diabetes (GDM). Multivariate logistic regression was used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for risk of both mild and severe composite neonatal outcome with delivery in the late preterm or early term period using pregnancies without diabetes as the referent. RESULTS: A total of 8,072 pregnancies were included with T1DM, T2DM, and GDM complicating 1.8, 5.6, and 9.9% of pregnancies, respectively. Expected demographic differences were seen among groups including higher rates of non-Hispanic Black race, chronic hypertension, and higher body mass index in women with T2DM. The probability of severe composite adverse neonatal outcome was significantly increased in women with T1DM in the late preterm (aOR: 4.4; CI: 2.4-8.1) and early term (aOR: 1.6; CI: 1.1-2.3) periods, largely driven by the need for mechanical ventilation. The mild composite outcome was increased among all women with diabetes with early term delivery but highest in women with T1DM. CONCLUSION: Pregnancies complicated by diabetes, particularly T1DM, have higher rates of neonatal adverse outcomes independent of gestational age at delivery, which is an important consideration when late preterm or early term delivery is planned. KEY POINTS: · Diabetes in pregnancy increases risk of early delivery.. · Adverse neonatal outcomes are higher with diabetes, especially T1DM.. · Adverse neonatal outcomes are independent of gestational age..

Remote Monitoring Compared With In-Office Surveillance of Blood Pressure in Patients With Pregnancy-Related Hypertension: A Randomized Controlled Trial.

OBJECTIVE: To compare the rate of blood pressure ascertainment within 10 days of postpartum discharge among individuals with hypertensive disorders of pregnancy randomized either to in-office blood pressure assessment or at-home monitoring. METHODS: This was a multisite randomized controlled trial of postpartum patients diagnosed with a hypertensive disorder of pregnancy before discharge between April 2021 and September 2021 and was performed at two academic training institutions. Patients were randomized to either an in-office blood pressure check or remote monitoring through a web-enabled smartphone platform. The primary outcome was the rate of any blood pressure ascertainment within 10 days of discharge. Secondary outcomes include rates of initiation of antihypertensive medication, readmission, and additional office or triage visits for hypertension. Assuming a 10-day postdischarge blood pressure ascertainment rate of 50% in the in-office arm, we estimated that 186 participants would provide 80% power to detect a 20% difference in the primary outcome between groups. RESULTS: One hundred ninety-seven patients were randomized (96 remote, 101 in-office). Patients with remote monitoring had higher rates of postpartum blood pressure ascertainment compared with in-office surveillance (91.7% [n=88] vs 58.4% [n=59]; P<.001). There were 11 (11.5%) patients in the intervention arm whose only qualifying blood pressure was a postdischarge in-person ascertainment, yielding a true remote monitoring uptake rate of 80.2%. In those with remote blood pressure uptake (n=77), the median number of blood pressure checks was 15 (interquartile range 6-26) and the median duration of remote monitoring use was 14 days (interquartile range 9-16). There were no differences in rates of readmission for hypertension (5.0% [n=5] vs 4.2% [n=4], P=.792) or initiation of antihypertensive medications after discharge (9.4% [n=9] vs 6.9% [n=7], P=.530). Rates of unscheduled visits were increased in the remote monitoring arm, but this did not reach statistical significance (5.0% [n=5] vs 12.5% [n=12], P=.059). When stratifying the primary outcome by race and randomization group, Black patients had lower rates of blood pressure ascertainment than White patients when assigned to in-office surveillance (41.2% [n=14] vs 69.5% [n=41], P=.007), but there was no difference in the remote management group (92.9% [n=26] vs 92.9% [n=52], P>.99). CONCLUSION: Remote monitoring can increase postpartum blood pressure ascertainment within 10 days of discharge for women with hypertensive disorders of pregnancy and has the potential to promote health equity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04823949.

Risk of Stillbirth in Pregnancies Complicated by Diabetes, Stratified by Fetal Growth.

OBJECTIVE: To compare stillbirth rates per week of expectant management stratified by birth weight in pregnancies complicated by gestational diabetes mellitus (GDM) or pregestational diabetes mellitus. METHODS: A national population-based retrospective cohort study of singleton, nonanomalous pregnancies complicated by pregestational diabetes or GDM was performed using national birth and death certificate data from 2014 to 2017. Stillbirth rates per 10,000 patients (stillbirth incidence at gestational age week/ongoing pregnancies-[0.5×live births at gestational age week]) were determined for each week of pregnancy from 34 to 39 completed weeks of gestation. Pregnancies were stratified by birth weight, categorized as having small-for-gestational-age (SGA), appropriate-for-gestational-age (AGA), or large-for-gestational-age (LGA) fetuses, assigned by sex-based Fenton criteria. Relative risk (RR) and 95% CI for stillbirth were calculated for each gestational age week compared with the GDM-related AGA group. RESULTS: We included 834,631 pregnancies complicated by either GDM (86.9%) or pregestational diabetes (13.1%) in the analysis, with a total of 3,033 stillbirths. Stillbirth rates increased with advancing gestational age for pregnancies complicated by both GDM and pregestational diabetes regardless of birth weight. Compared with pregnancies with AGA fetuses, those with both SGA and LGA fetuses were significantly associated with an increased risk of stillbirth at all gestational ages. Ongoing pregnancies at 37 weeks of gestation complicated by pregestational diabetes with LGA or SGA fetuses had respective stillbirth rates of 64.9 and 40.1 per 10,000 patients. Pregnancies complicated by pregestational diabetes had an RR of stillbirth of 21.8 (95% CI 17.4-27.2) for LGA fetuses and 13.5 (95% CI 8.5-21.2) for SGA fetuses compared with GDM-related AGA at 37 weeks of gestation. The greatest absolute risk of stillbirth was in pregnancies complicated by pregestational diabetes at 39 weeks of gestation with LGA fetuses (97/10,000). CONCLUSION: Pregnancies complicated by both GDM and pregestational diabetes affected by pathologic fetal growth have an increased risk of stillbirth with advancing gestational age. This risk is significantly higher with pregestational diabetes, especially pregestational diabetes with LGA fetuses.

A Comparison of Vaginal and Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth.

OBJECTIVE: This study aimed to examine whether vaginal progesterone is noninferior to 17-α hydroxyprogesterone caproate (17OHP-C) in the prevention of recurrent preterm birth (PTB). STUDY DESIGN: This retrospective cohort study included singleton pregnancies among women with a history of spontaneous PTB who received prenatal care at a single tertiary center from 2011 to 2016. Pregnancies were excluded if progesterone was not initiated prior to 24 weeks or the fetus had a major congenital anomaly. The primary outcome was PTB <37 weeks. A priori, noninferiority was to be established if the upper bound of the adjusted two-sided 90% confidence interval (CI) for the difference in PTB fell below 9%. Inverse probability of treatment weighting (IPTW) was used to carefully control for confounding associated with choice of treatment and PTB. Adjusted differences in PTB proportions were estimated via IPTW regression, with standard errors adjustment for multiple pregnancies per woman. Secondary outcomes included PTB <34 and <28 weeks, spontaneous PTB, neonatal intensive care unit admission, and gestational age at delivery. RESULTS: Among 858 pregnancies, 41% (n = 353) received vaginal progesterone and 59% (n = 505) were given 17OHP-C. Vaginal progesterone use was more common later in the study period, and among women who established prenatal care later, had prior PTBs at later gestational ages, and whose race/ethnicity was neither non-Hispanic white nor non-Hispanic Black. Vaginal progesterone did not meet noninferiority criteria compared with 17-OHPC in examining PTB <37 weeks, with an IPTW adjusted difference of 3.4% (90% CI: -3.5, 10.3). For secondary outcomes, IPTW adjusted differences between treatment groups were generally small and CIs were wide. CONCLUSION: We could not conclude noninferiority of vaginal progesterone to 17OHP-C; however, women and providers may be willing to accept a larger difference (>9%) when considering the cost and availability of vaginal progesterone versus 17OHP-C. A well-designed randomized trial is needed. KEY POINTS: · Vaginal progesterone is not noninferior to 17OHP-C.. · PTB risk may be 10% higher with vaginal progesterone.. · Associations did not differ based on obesity status..

The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration.

Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood-nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1-/- mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand-receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/.

Fetal Autopsy Rates in the United States: Analysis of National Vital Statistics.

OBJECTIVE: To identify rates of fetal autopsy in the United States as well as demographic and clinical characteristics related to consent to autopsy after stillbirth. METHODS: This is a population-based retrospective cohort study using U.S. fetal death certificates for stillborn fetuses (20 weeks of gestation or more) delivered between January 2014 and December 2016. Multiple gestations were excluded. Fetal autopsy rates were calculated by gestational age, maternal age, self-reported race and ethnicity, education, and having at least one living child. Multivariate logistic regression to adjust for potential confounders was performed. RESULTS: There were 60,328 stillbirths meeting inclusion criteria. Overall, fetal autopsy was performed in 20.9% of stillbirths. Non-Hispanic Black women had the highest rate of fetal autopsy (22.9%, 95% CI 22.3-23.6%), compared with non-Hispanic White women (20.4%, 95% CI 20.0-20.9%) and Hispanic women (19.6%, 95% CI 19.0-20.3%) ( P <.001). After adjusting for potential confounders, maternal non-Hispanic Black race (adjusted odds ratio [aOR] 1.22, 95% CI 1.16-1.29), higher education (graduate degree: aOR 1.62, 95% CI 1.47-1.79), and higher gestational age (term: aOR 2.08, 95% CI 1.95-2.23) were associated with increased aORs for fetal autopsy. Maternal age 40 years or older (aOR 0.77 95% CI 0.63-0.92) and having at least one living child (aOR 0.74, 95% CI 0.71-0.78) were associated with a decreased aOR of having a fetal autopsy. Women of American Indian or Alaska Native decent had decreased uptake of fetal autopsy compared with non-Hispanic White women (aOR 0.72, 95% CI 0.58-0.90). CONCLUSION: Fetal autopsy rates are low throughout the United States. The reasons for low autopsy rates warrant further exploration to inform strategies to increase availability and uptake.

Identification of in vivo roles of ErbB4-JMa and its direct nuclear signaling using a novel isoform-specific knock out mouse.

Like all receptor tyrosine kinases (RTKs), ErbB4 signals through a canonical signaling involving phosphorylation cascades. However, ErbB4 can also signal through a non-canonical mechanism whereby the intracellular domain is released into the cytoplasm by regulated intramembrane proteolysis (RIP) and translocates to the nucleus where it regulates transcription. These different signaling mechanisms depend on the generation of alternative spliced isoforms, a RIP cleavable ErbB4-JMa and an uncleavable ErbB4-JMb. Non-canonical signaling by ErbB4-JMa has been implicated in the regulation of brain, heart, mammary gland, lung, and immune cell development. However, most studies on non-canonical ErbB4 signaling have been performed in vitro due to the lack of an adequate mouse model. We created an ErbB4-JMa specific knock out mouse and demonstrate that RIP-dependent, non-canonical signaling by ErbB4-JMa is required for the regulation of GFAP expression during cortical development. We also show that ErbB4-JMa signaling is not required for the development of the heart, mammary glands, sensory ganglia. Furthermore, we identify genes whose expression during cortical development is regulated by ErbB4, and show that the expression of three of them, CRYM and DBi, depend on ErbB4-JMa whereas WDFY1 relies on ErbB4-JMb. Thus, we provide the first animal model to directly study the roles of ErbB4-JMa and non-canonical ErbB4 signaling in vivo.

Latency of late preterm steroid administration to delivery and risk of neonatal hypoglycemia.

BACKGROUND: Late preterm antenatal corticosteroid administration has been associated with an increased risk of neonatal hypoglycemia. The mechanism is thought to be secondary to transient fetal hyperinsulinemia, which may be more likely if delivery occurs during peak antenatal corticosteroid levels. OBJECTIVE: This study aimed to investigate whether there is a latency interval between antenatal corticosteroid administration and delivery that places neonates at the greatest risk of hypoglycemia. STUDY DESIGN: This was a retrospective matched cohort study of pregnant women who received antenatal corticosteroid vs unexposed women between 34 0/7 and 36 6/7 weeks of gestation from 2016 to 2019. Unexposed women were those who did not receive antenatal corticosteroid matched according to gestational age at delivery, diabetes mellitus status, and maternal body mass index from 2010 to 2015. Latency periods from initial steroid administration to delivery were defined in grouped intervals until ≥72 hours. The primary outcome was neonatal hypoglycemia, defined as a neonatal glucose level of <40 mg/dL within 24 hours of life. Poisson regression was used to generate an adjusted relative risk of hypoglycemia for each latency period adjusting for confounders. RESULTS: A total of 812 women were included in the analysis (406 exposed and 406 unexposed). Women who received antenatal corticosteroids were more likely to be nulliparous (P=.009); moreover, the women were well matched on pregnancy complications and baseline demographics. Neonatal hypoglycemia was more frequently identified in women receiving antenatal corticosteroids than in women not receiving antenatal corticosteroids (42% vs 26%; P<.001). Severe hypoglycemia, defined as a glucose level of <20 mg/dL, was significantly more common in patients receiving antenatal corticosteroids than in patients not receiving antenatal corticosteroids (8.4% vs 2.7%; P<.001). Latency time intervals of 12 to 71 hours from antenatal corticosteroid administration were significantly associated with neonatal hypoglycemia in exposed women compared with unexposed women after adjustment; within this time frame, the highest risk was 24 to 47 hours after antenatal corticosteroid administration (adjusted relative risk, 2.09; 95% confidence interval, 1.29-3.38). CONCLUSION: In the late preterm period, the risk of neonatal hypoglycemia is the greatest in the latency period of 12 to 71 hours between steroid administration and delivery. Neonates exposed to antenatal corticosteroids were more likely to experience severe hypoglycemia within 24 hours of life than unexposed neonates.

Impact of pre-pregnancy obesity on cesarean delivery rates in nulliparous pregnant people undergoing induction of labor.

OBJECTIVE: To evaluate the impact of pre-pregnancy obesity on the cesarean delivery rate in nulliparous pregnant people undergoing induction of labor. STUDY DESIGN: This is a retrospective cohort study of nulliparous pregnant people with a normal weight and obesity who underwent induction of labor between 37 and 41 weeks gestation at a single institution from 2012 to 2018. Weight category was based on pre-pregnancy body mass index. The primary outcome was rate of cesarean delivery. Additional demographic and clinical characteristics were analyzed. A chi square test was used to compare the cesarean delivery rates. Multivariate logistic regression was used to generate adjusted odds ratios (aOR) and 95% confidence intervals (CI) controlling for potential cofounders. RESULTS: Of the 557 pregnancies identified, 88/285 (31%) of pregnant people with a normal weight had a cesarean delivery while 165/263 (63%) of pregnant people with obesity had a cesarean delivery (cOR 3.8, 95% CI 2.6-5.4). After adjustment, pregnant people with obesity remained more likely to have a cesarean delivery compared to pregnant people with a normal weight (aOR 2.7, 95% CI 1.8-4.0). Further, cesarean delivery was more likely in those with an unfavorable modified Bishop score (aOR 3.4, 95% CI 1.8-6.5) and gestational weight gain above the Institute of Medicine recommendation (aOR 2.6, 95% CI 1.8-3.9). The rate of cesarean delivery was not different by class of obesity (p = .32). CONCLUSION: Pre-pregnancy obesity is associated with higher cesarean delivery rates in nulliparous pregnant people undergoing induction of labor compared with normal pre-pregnancy body mass index. Gestational weight gain above the Institute of Medicine recommendations and having an unfavorable modified Bishop score at the time of induction are associated with increased cesarean delivery rates.

Association of change in haemoglobin A1c with adverse perinatal outcomes in women with pregestational diabetes.

AIMS: To determine whether a net decline in glycosylated haemoglobin (HbA1c ) from early to late pregnancy is associated with lower risk of adverse perinatal outcomes at delivery among women with pregestational diabetes. METHODS: A retrospective analysis from 2012 to 2016 at a tertiary care centre. The exposure was the net change in HbA1c from early (<20 weeks gestation) to late pregnancy (≥20 weeks gestation). Primary outcomes were large for gestational age (LGA) and neonatal hypoglycaemia. The association between outcomes per 6 mmol/mol (0.5%) absolute decrease in HbA1c was evaluated using modified Poisson regression, and adjusted for age, body mass index, White Class, early HbA1c and haemoglobin and gestational age at HbA1c measurement and delivery. RESULTS: Among 347 women with pregestational diabetes, HbA1c was assessed in early (9 weeks [IQR 7,13]) and late pregnancy (31 weeks [IQR 29,34]). Mean HbA1c decreased from early (59 mmol/mol [7.5%]) to late (47 mmol/mol [6.5%]) pregnancy. Each 6 mmol/mol (0.5%) absolute decrease in HbA1c was associated with a 12% reduced risk of LGA infant (30%, aRR:0.88; 95% CI:0.81,0.95), and a 7% reduced risk of neonatal hypoglycaemia (35%, aRR:0.93; 95% CI:0.87,0.99). Preterm birth (36%, aRR:0.93; 95% CI:0.89,0.98) and neonatal intensive care unit admission (55%, aRR:0.95; 95% CI:0.91,0.98) decreased with a net decline in HbA1c , but not caesarean delivery, pre-eclampsia, shoulder dystocia and respiratory distress syndrome. CONCLUSIONS: Women with pregestational diabetes with a reduction in HbA1c may have fewer infants born LGA or with neonatal hypoglycaemia. Repeated assessment of HbA1c may provide an additional measure of glycaemic control.

Indication Creep of Antenatal Late Preterm Steroids.

OBJECTIVE: While antenatal corticosteroids (ACS) administered in the late preterm period have been shown to reduce respiratory morbidity, this finding was demonstrated in a well-designed randomized controlled trial (the Antenatal Betamethasone for Women at Risk for Late Preterm Delivery [ALPS]) with strict inclusion/exclusion criteria that may differ from clinical practice. The aim of this study was to investigate whether there has been indication creep since use of late preterm ACS became standard of care. STUDY DESIGN: Retrospective cohort study of pregnant women who received late preterm ACS between 2016 and 2019 were identified and separated into epochs of 2016 to 2017 and 2018 to 2019 based on year of exposure. The primary outcome was rate of inappropriate ACS exposure, defined as nonadherence to the inclusion/exclusion criteria of the ALPS trial. Secondary outcomes were rates of nonoptimal ACS exposure (delivery >7 days from ACS or term delivery). Logistic regression was used to generate adjusted odds ratios (aORs) between epochs for the primary outcome adjusting for confounders. RESULTS: There were 660 women who received late preterm ACS during the study period with 229 (34.6 %) deemed inappropriate exposures. The most common reason for inappropriate treatment was preterm premature rupture of membrane (PPROM; 29.0%) with exclusionary cervical examination or contraction frequency. No difference was observed in inappropriate ACS exposure between epochs (aOR = 0.83, 95% confidence interval [CI]: 0.59-1.2). However, there was a reduction in nonoptimal exposure over time (aOR = 0.67, 95% CI: 0.47-0.97) . Women receiving inappropriate ACS were more likely to deliver at term if indicated for maternal/fetal status (50.0 vs. 19.5%, p < 0.001) and preterm labor (66.0 vs. 41.9%; p = 0.015). Further, inappropriate exposure in preterm labor had higher rates of exposure latency >7 days (62.3 vs. 39.1%, p = 0.006) with a longer latency to delivery (3 vs. 16 days; p < 0.001). CONCLUSION: Over one-third of women received late preterm ACS for an indication that could be classified as indication creep. Depending on indication, inappropriate administration is associated with higher rates of nonoptimal exposure. KEY POINTS: · There is potential for indication creep of ACS administration.. · One third of late preterm ACS exposures in our study were inappropriate.. · Utilizing clinical criteria can aid in identifying patients who best benefit from late preterm ACS..

Obstetric History and Risk of Short Cervix in Women with a Prior Preterm Birth.

OBJECTIVE: We aimed to assess the relationship between obstetric history and incidence of short cervical length (CL) at <24 weeks gestational age (GA) in women with a prior spontaneous preterm birth (PTB). STUDY DESIGN: Women with a singleton gestation and a history of spontaneous PTB on progesterone who received prenatal care at a single center from 2011 to 2016 were included. Those who did not undergo screening or had a history-indicated cerclage were excluded. The associations between short CL (<25 mm) before 24 weeks and obstetrical factors including: number of prior PTBs, history of term birth, and GA of earliest spontaneous PTB were estimated through modified Poisson regression, adjusting for confounding factors. Multiple pregnancies for the same woman were accounted for through robust sandwich standard error estimation. RESULTS: Among 773 pregnancies, 29% (n = 224) had a CL <25 mm before 24 weeks. The number of prior PTBs was not associated with short CL, but a prior full-term delivery conferred a lower risk of short CL (absolute risk reduction or aRR 0.79, 95% CI 0.63-1.00). Earliest GA of prior spontaneous PTB was associated with short CL. The strongest association was observed in women with a prior PTB at 160/7 to 236/7weeks (aRR 1.98, 95% CI: 1.46-2.70), compared with those with deliveries at 340/7 to 366/7 weeks. Yet, even women whose earliest PTB was 340/7 to 366/7 weeks remained at risk for a short CL, as 21% had a CL <25 mm. The number of prior PTBs did not modify the effect of GA of the earliest prior PTB (interaction test: p = 0.70). CONCLUSION: GA of earliest spontaneous PTB, but not the number of prior PTBs, is associated with short CL. Nevertheless, women with a history of later PTBs remain at sufficiently high risk of having a short CL at <24 weeks gestation that we cannot recommend modifications to existing CL screening guidelines in this group of women. KEY POINTS: · Prior 16 to 236/7 weeks birth is a key risk factor for CL <25 mm.. · One in five women with prior late PTB had a short CL.. · Number of PTBs is a less important risk factor..

Small Molecule Targeting of Oxysterol-Binding Protein (OSBP)-Related Protein 4 and OSBP Inhibits Ovarian Cancer Cell Proliferation in Monolayer and Spheroid Cell Models.

The development of precision drugs for the selective treatment of ovarian cancer will require targeting proliferative factors selectively expressed in ovarian tumors or targeting unique physiological microenvironments specific for ovarian tumors. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 (ORP4) is a potential druggable precision target in ovarian cancer cells. ORP4 has limited expression in normal tissues and was recently recognized to be a cancer-specific driver of cellular proliferation, including in patient-isolated leukemias. We demonstrate that ORP4 is strongly expressed in a panel of ovarian cancer cell lines. The antiproliferative natural product compound OSW-1 targets ORP4 and OSBP. Our results demonstrate that the OSW-1 compound has high antiproliferative potency in both monolayer and three-dimensional ovarian cancer spheroid models, especially compared to the standard-of-care agents cisplatin and paclitaxel. OSW-1 compound treatment induces a loss of ORP4 expression after 48 h, which is coincident with the cytotoxic effects of OSW-1. The absence of extracellular lipids markedly potentiated the cytotoxicity of OSW-1, which was reversed by addition of extracellular free cholesterol. OSBP, but not ORP4, is reported to transport cholesterol and other lipids between organelles. Our results indicate that the targeting of ORP4 is responsible for the antiproliferative activity of the OSW-1 compound, but that in the absence of exogenously supplied cholesterol, which might be similar to the in vivo ovarian cancer microenvironment, possible OSW-1 targeting of OSBP further potentiates the anticancer activity of the compound. Overall, ORP4 and potentially OSBP are revealed as potential druggable targets for the development of novel treatments for ovarian cancer.

Optimal antenatal corticosteroid exposure in women with history of preterm birth and asymptomatic short cervical length.

BACKGROUND: A proposed benefit of cervical length assessment after 24 weeks' gestation in women with a history of preterm birth is to aid in the timing of antenatal corticosteroids in otherwise asymptomatic women. OBJECTIVE: We sought to investigate whether the use of an ultrasonographic short cervical length as an indication for antenatal corticosteroids in asymptomatic women results in optimal exposure compared with women receiving antenatal corticosteroids for preterm labor symptoms. STUDY DESIGN: Retrospective cohort study of all women with a previous spontaneous preterm birth and a singleton gestation who underwent serial cervical length assessment at a large academic tertiary medical center from 2011 to 2016. Patients were included in the analysis if they received antenatal corticosteroids for either an asymptomatic short cervical length or symptoms of preterm labor. The primary outcome was optimal antenatal corticosteroids exposure (latency to delivery of ≤7 days). PROPOSED CHANGE IN RESULTS: Poisson regression with robust error variance was used to calculate incidence rate ratios (IRR) and confidence intervals (CI) for primary and secondary outcomes adjusting for primary and secondary outcomes adjusting for race, earliest previous preterm birth, and current cerclage. RESULTS: There were 287 women meeting inclusion criteria, among whom 166 (57.8%) received antenatal corticosteroids for a short cervical length and 121 (42.2%) for preterm labor symptoms. Women who received antenatal corticosteroids for a short cervical length were less likely to have optimal exposure (1.2% vs 19.0%; incidence rate ratios, 0.06; confidence interval, 0.02-0.27) compared with women with preterm labor symptoms. They were also more likely to have exposure with eventual term delivery (43.2% vs 33.4%; incidence rate ratios, 1.6; confidence interval, 1.2-2.0). Importantly, women who received antenatal corticosteroids for a short cervical length were significantly less likely to receive either an initial or rescue antenatal corticosteroids course within 7 days of a preterm delivery of less than 34 weeks' gestation (42.9% vs 76.9%; incidence rate ratios, 0.52; confidence interval, 0.35-0.75). CONCLUSION: Women with a previous preterm birth who receive antenatal corticosteroids for an asymptomatic short cervical length are less likely to have optimal exposure than women with symptoms of preterm labor. These data challenge the practice of cervical length surveillance for the sole indication of timing antenatal corticosteroids administration.

Dichorionic twin-specific vs singleton growth references for diagnosis of fetal growth restriction.

BACKGROUND: Fetal growth restriction is associated with an increased risk for adverse neonatal outcomes. The Hadlock singleton growth reference is widely used to determine the estimated fetal weight percentile for both twin and singleton gestations. The Eunice Kennedy Shriver National Institute of Child Health and Human Development's twin-specific growth reference accounts for the different growth trajectory that twins follow during gestation. There is a lack of research comparing these different growth references in their ability to identify fetal growth restriction that is associated with adverse neonatal outcomes in dichorionic twin gestations. OBJECTIVE: This study aimed to compare a twin-specific growth reference (the Eunice Kennedy Shriver National Institute of Child Health and Human Development's twin-specific growth reference) and a singleton growth reference (Hadlock) in their ability to identify fetal growth restriction associated with adverse neonatal outcomes in dichorionic twin gestations. STUDY DESIGN: This was a retrospective cohort study of dichorionic twin gestations at ≥32 weeks' gestation delivered at a single institution between 2004 and 2019 with the serial growth ultrasounds and neonatal outcomes data available for analysis. Using their last growth ultrasound before delivery, twins were classified into the following 3 categories: fetal growth restriction according to both the Hadlock and Eunice Kennedy Shriver National Institute of Child Health and Human Development references, fetal growth restriction according to the Hadlock reference only, and no fetal growth restriction according to either reference, with fetal growth restriction defined as an estimated fetal weight of <10th percentile for gestational age. Multivariable generalized linear mixed models were used to assess the adverse neonatal outcomes via pair-wise comparisons between the groups, with a random-effects component to account for twin-pair correlations. RESULTS: A total of 1460 dichorionic twin infants were included with 8.1% (n=118) of cases classified as fetal growth restricted by both the Eunice Kennedy Shriver National Institute of Child Health and Human Development and Hadlock references, 8.8% (n=129) of cases classified as fetal growth restricted by the Hadlock reference only, and 83.1% (n=1213) of cases classified as no fetal growth restriction by either reference. Compared with twins with no fetal growth restriction by either reference, twins with fetal growth restriction by both references were more likely to experience mild (adjusted odds ratio, 2.38; confidence interval, 1.38-4.13) or severe (adjusted odds ratio, 2.82; confidence interval, 1.16-6.88) composite neonatal morbidity. Compared with twins with fetal growth restriction according to the Hadlock reference only, twins with fetal growth restriction according to both references were more likely to experience mild (adjusted odds ratio, 2.03; confidence interval, 1.00-4.14) but not severe (adjusted odds ratio, 3.70; confidence interval, 0.72-18.90) composite neonatal morbidity. Composite neonatal morbidity was not different between twins with fetal growth restriction according to the Hadlock reference only and those with no fetal growth restriction by either growth reference. CONCLUSION: The Eunice Kennedy Shriver National Institute of Child Health and Human Development's twin-specific growth reference better identifies the risk for adverse neonatal outcomes in dichorionic twin gestations diagnosed with fetal growth restriction. The use of the Hadlock singleton growth reference more than doubles the number of dichorionic twins identified with fetal growth restriction who seem to be at a low-risk for neonatal morbidity, leading to unnecessary maternal anxiety, increased antenatal testing, and possibly iatrogenic preterm delivery.

The Importance of Clinical Presentation in Risk and Management of Recurrent Preterm Birth.

OBJECTIVE: This study aimed to compare the risk of recurrent spontaneous preterm birth (sPTB), as well as cerclage efficacy, between groups stratified by phenotype of the index sPTB. STUDY DESIGN: This is a retrospective cohort study of women with a history of sPTB. Included were women with a history of singleton sPTB who received progesterone in a subsequent pregnancy. Multifetal gestations and abdominal cerclage were excluded. Exposure groups were based upon the presenting symptom that preceded their first sPTB and included painless cervical dilation (PCD), preterm premature rupture of membranes (PPROM), and painful dilation (preterm labor [PTL]). Primary outcome was delivery <34 weeks in a subsequent pregnancy. Secondary outcomes included delivery <28 and <37 weeks. Rates were compared using the Chi-square test. Multivariable Poisson regression was used to adjust for confounders. RESULTS: A total of 723 women were included. A total of 114 (16%) presented with PCD, 305 (42%) with PPROM, and 304 (42%) with PTL in their first sPTB. Cerclage in subsequent pregnancy was highest in the PCD group (42%) when compared with the PPROM (16%) and PTL (12%) groups. Rates of sPTB <34 and 37 weeks were similar among the groups. After adjusting for confounders, PCD was found to significantly increase the risk of recurrent sPTB <28 weeks (incidence rate ratio: 3.46 [1.09-11.0]; p = 0.04). Of the 121 women who underwent cerclage, there were no significant differences in rates of sPTB between the clinical presentation groups. CONCLUSION: PCD as a specific phenotype of sPTB impacts recurrence of delivery before 28 weeks, but not at later gestational ages. In contrast, there was no significant association between clinical presentation of index sPTB and gestational latency in women who also underwent cerclage placement in a subsequent pregnancy. Our data suggest that clinical presentation is important with regards to recurrence of early sPTB, but not sPTB at later gestational ages. KEY POINTS: · Phenotype is critical to understanding PTB.. · Phenotype is associated with recurrent PTB.. · Painless dilation is associated with recurrent PTB..

The use of longitudinal hemoglobin A1c values to predict adverse obstetric and neonatal outcomes in pregnancies complicated by pregestational diabetes.

BACKGROUND: Although an elevated early pregnancy hemoglobin A1c has been associated with both spontaneous abortion and congenital anomalies, it is unclear whether A1c assessment is of value beyond the first trimester in pregnancies complicated by pregestational diabetes. OBJECTIVE: We sought to investigate the prognostic ability of longitudinal A1c assessment to predict obstetric and neonatal adverse outcomes based on degree of glycemic control in early and late pregnancy. MATERIALS AND METHODS: This was a retrospective cohort study of all pregnancies complicated by pregestational diabetes from January 2012 to December 2016 at The Ohio State University Wexner Medical Center with both an early A1c (<20 weeks' gestation) and late A1c (>26 weeks' gestation) available for analysis. Patients were categorized by good (early and late A1c <6.5%), improved (early A1c >6.5% and late A1c <6.5%) and poor (late A1c >6.5%) glycemic control. A multivariate regression model was used to calculate adjusted odds ratios (aOR) for each identified obstetric and neonatal outcome, controlling for maternal age, body mass index, race/ethnicity, type of diabetes, and gestational age at delivery compared to good control as the referent group. RESULTS: A total of 341 patients met inclusion criteria during the study period. The median A1c values improved from early to late gestation in the good (5.7% [interquartile range [IQR], 5.4-6.1%] versus 5.4%; [IQR 5.2-5.7%]), improved (7.5% [IQR, 6.7-8.5] versus 5.9% [IQR, 5.6-6.1%]) and poor (8.3% [IQR, 7.1-9.6%] versus 7.3% [IQR, 6.8-7.9%]) glycemic control groups. There were no statistically significant differences in the rate of adverse outcomes between the good and improved groups except for an increased rate of neonatal intensive care unit admissions in the improved group (aOR, 3.7; confidence interval [CI], 1.9-7.3). In contrast, the poor control group had an increased rate of shoulder dystocia (aOR, 6.8; CI, 1.4-34.0), preterm delivery (aOR, 3.9; CI, 2.1-7.3), neonatal intensive care unit admission (aOR, 2.8; CI, 1.4-5.3), respiratory distress syndrome (aOR, 3.0; CI, 1.1-8.0), hypoglycemia (aOR, 3.2; CI, 1.5-6.9), large for gestational age weight at birth (aOR, 2.7; CI, 1.5-4.9), neonatal length of stay >4 days (aOR, 3.1; CI, 1.6-6.0) and preeclampsia (aOR, 2.4; CI, 1.2-4.6). There were no differences in rates of cesarean delivery, umbilical artery pH <7.1, or Apgar score <7 at 5 minutes after regression analysis. CONCLUSION: Antenatal hemoglobin A1c values are useful for objective risk stratification of patients with pregestational diabetes. Strict glycemic control throughout pregnancy with a late pregnancy A1c target of <6.5% leads to reduced rates of obstetric and neonatal adverse outcomes independent of early pregnancy glucose control.