Delivery outcomes in the subsequent pregnancy following the conservative management of placenta accreta spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: Cesarean hysterectomy is generally presumed to decrease maternal morbidity and mortality secondary to placenta accreta spectrum disorder. Recently, uterine-sparing techniques have been introduced in conservative management of placenta accreta spectrum disorder to preserve fertility and potentially reduce surgical complications. However, despite patients often expressing the intention for future conception, few data are available regarding the subsequent pregnancy outcomes after conservative management of placenta accreta spectrum disorder. Thus, we aimed to perform a systematic review and meta-analysis to assess these outcomes. DATA SOURCES: PubMed, Scopus, and Web of Science databases were searched from inception to September 2022. STUDY ELIGIBILITY CRITERIA: We included all studies, with the exception of case studies, that reported the first subsequent pregnancy outcomes in individuals with a history of placenta accreta spectrum disorder who underwent any type of conservative management. METHODS: The R programming language with the "meta" package was used. The random-effects model and inverse variance method were used to pool the proportion of pregnancy outcomes. RESULTS: We identified 5 studies involving 1458 participants that were eligible for quantitative synthesis. The type of conservative management included placenta left in situ (n=1) and resection surgery (n=1), and was not reported in 3 studies. The rate of placenta accreta spectrum disorder recurrence in the subsequent pregnancy was 11.8% (95% confidence interval, 1.1-60.3; I2=86.4%), and 1.9% (95% confidence interval, 0.0-34.1; I2=82.4%) of participants underwent cesarean hysterectomy. Postpartum hemorrhage occurred in 10.3% (95% confidence interval, 0.3-81.4; I2=96.7%). A composite adverse maternal outcome was reported in 22.7% of participants (95% confidence interval, 0.0-99.4; I2=56.3%). CONCLUSION: Favorable pregnancy outcome is possible following successful conservation of the uterus in a placenta accreta spectrum disorder pregnancy. Approximately 1 out of 4 subsequent pregnancies following conservative management of placenta accreta spectrum disorder had considerable adverse maternal outcomes. Given such high incidence of adverse outcomes and morbidity, patient and provider preparation is vital when managing this population.

Hemolytic disease of the fetus and newborn in the sensitizing pregnancy where anti-D was incorrectly identified as RhIG.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is a potentially fatal complication in Rh-incompatible pregnancies and rarely occurs in the sensitizing pregnancy. Distinguishing RhIG from true anti-D identified is challenging. A case of severe HDFN in which a sample drawn at 28 weeks showed anti-D antibody (3+ strength) attributed to RhIG is described. RBC antibody testing early in pregnancy was negative. At birth, the infant was severely anemic and maternal anti-D titer was 1:256. This case represents a clinically significant anti-D in the sensitizing pregnancy that was missed due to confusion with RhIG. METHODS: To determine if agglutination strength could be helpful, a retrospective chart-review using both electronic and paper medical records was performed on 348 samples identified as RhIG and 52 true anti-D samples. The agglutination strength of antibody was recorded for each sample. RESULTS: For RhIG, there was an even distribution between the weak to moderate agglutination strength (w+, 1+, and 2+) results (35%, 26%, and 33%, respectively) and just 6% had a 3+ strength. Agglutination strength in patients with high titer (≥1:16) anti-D showed they often (44.4%) have 1+ or 2+ agglutination reactivity. CONCLUSIONS: These results show that agglutination strength alone does not provide reliable evidence to distinguish RhIG from high titer anti-D antibodies. We recommend that in cases where there is any uncertainty about whether the anti-D reactivity is due to RhIG, titers should be performed to rule out clinically significant anti-D antibody.

Clinical Presentation of Coronavirus Disease 2019 (COVID-19) in Pregnant and Recently Pregnant People.

OBJECTIVE: To describe the clinical presentation, symptomology, and disease course of coronavirus disease 2019 (COVID-19) in pregnancy. METHODS: The PRIORITY (Pregnancy CoRonavIrus Outcomes RegIsTrY) study is an ongoing nationwide prospective cohort study of people in the United States who are pregnant or up to 6 weeks postpregnancy with known or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed the clinical presentation and disease course of COVID-19 in participants who tested positive for SARS-CoV-2 infection and reported symptoms at the time of testing. RESULTS: Of 991 participants enrolled from March 22, 2020, until July 10, 2020, 736 had symptoms of COVID-19 at the time of testing; 594 tested positive for SARS-CoV-2 infection and 142 tested negative in this symptomatic group. Mean age was 31.3 years (SD 5.1), and 37% will nulliparous. Ninety-five percent were outpatients. Participants who tested positive for SARS-CoV-2-infection were a geographically diverse cohort: 34% from the Northeast, 25% from the West, 21% from the South, and 18% from the Midwest. Thirty-one percent of study participants were Latina, and 9% were Black. The average gestational age at enrollment was 24.1 weeks, and 13% of participants were enrolled after pregnancy. The most prevalent first symptoms in the cohort of patients who tested positive for SARS-CoV-2 infection were cough (20%), sore throat (16%), body aches (12%), and fever (12%). Median time to symptom resolution was 37 days (95% CI 35-39). One quarter (25%) of participants who tested positive for SARS-CoV-2 infection had persistent symptoms 8 or more weeks after symptom onset. CONCLUSION: COVID-19 has a prolonged and nonspecific disease course during pregnancy and in the 6 weeks after pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04323839.

Early pregnancy prediction of gestational diabetes mellitus risk using prenatal screening biomarkers in nulliparous women.

AIMS: To evaluate the clinical utility of first and second trimester prenatal screening biomarkers for early pregnancy prediction of gestational diabetes mellitus (GDM) risk in nulliparous women. METHODS: We conducted a population-based cohort study of nulliparous women participating in the California Prenatal Screening Program from 2009 to 2011 (n = 105,379). GDM was ascertained from hospital discharge records or birth certificates. Models including maternal characteristics and prenatal screening biomarkers were developed and validated. Risk stratification and reclassification were performed to assess clinical utility of the biomarkers. RESULTS: Decreased levels of first trimester pregnancy-associated plasma protein A (PAPP-A) and increased levels of second trimester unconjugated estriol (uE3) and dimeric inhibin A (INH) were associated with GDM. The addition of PAPP-A only and PAPP-A, uE3, and INH to maternal characteristics resulted in small, yet significant, increases in area under the receiver operating characteristic curve (AUC) (maternal characteristics only: AUC 0.714 (95% CI 0.703-0.724), maternal characteristics + PAPP-A: AUC 0.718 (95% CI 0.707-0.728), maternal characteristics + PAPP-A, uE3, and INH: AUC 0.722 (0.712-0.733)); however, no net improvement in classification was observed. CONCLUSIONS: PAPP-A, uE3, and INH have limited clinical utility for prediction of GDM risk in nulliparous women. Utility of other readily accessible clinical biomarkers in predicting GDM risk warrants further investigation.

Association of Mood and Anxiety Disorders and Opioid Prescription Patterns Among Postpartum Women.

BACKGROUND AND OBJECTIVES: Postpartum women represent a large population with opioid exposure who also have an increased risk of experiencing mood and anxiety disorders. However, the effect that mood and anxiety disorders have on opioid use postpartum has received little attention in the literature. Therefore, the objective of this study was to examine the association of mood and anxiety disorders with filling opioid prescriptions within the first 3 months postpartum. METHODS: A retrospective cohort study (n = 25 279) was completed using claims data for a sample of privately insured women who gave birth in the state of Iowa. The interactive effects of mood and anxiety disorders and delivery mode on filling at least one and two or more opioid prescriptions were examined in logistic regression models. RESULTS: The presence of mood and anxiety disorders among women who delivered vaginally increased their odds of filling at least one opioid fill by nearly 50% (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.35-1.63) and by 20% (OR: 1.20, 95% CI: 1.00-1.43) among women with cesarean delivery. DISCUSSION AND CONCLUSION: Postpartum women with mood and anxiety disorders were more likely to fill opioid prescriptions postpartum compared to women without these conditions. SCIENTIFIC SIGNIFICANCE: This study extends prior research by examining the intersection of risk of mood and anxiety disorders and opioid use postpartum. Findings from this study support the need for future research to identify the drivers of increased opioid use among postpartum women with mood and anxiety disorders. (Am J Addict 2020;29:463-470).

Development and validation of a clinical model for preconception and early pregnancy risk prediction of gestational diabetes mellitus in nulliparous women.

Implementation of dietary and lifestyle interventions prior to and early in pregnancy in high risk women has been shown to reduce the risk of gestational diabetes mellitus (GDM) development later in pregnancy. Although numerous risk factors for GDM have been identified, the ability to accurately identify women before or early in pregnancy who could benefit most from these interventions remains limited. As nulliparous women are an under-screened population with risk profiles that differ from their multiparous counterparts, development of a prediction model tailored to nulliparous women may facilitate timely preventive intervention and improve maternal and infant outcomes. We aimed to develop and validate a model for preconception and early pregnancy prediction of gestational diabetes mellitus based on clinical risk factors for nulliparous women. A risk prediction model was built within a large California birth cohort including singleton live birth records from 2007-2012. Model accuracy was assessed both internally and externally, within a cohort of women who delivered at University of Iowa Hospitals and Clinics between 2009-2017, using discrimination and calibration. Differences in predictive accuracy of the model were assessed within specific racial/ethnic groups. The prediction model included five risk factors: race/ethnicity, age at delivery, pre-pregnancy body mass index, family history of diabetes, and pre-existing hypertension. The area under the curve (AUC) for the California internal validation cohort was 0.732 (95% confidence interval (CI) 0.728, 0.735), and 0.710 (95% CI 0.672, 0.749) for the Iowa external validation cohort. The model performed particularly well in Hispanic (AUC 0.739) and Black women (AUC 0.719). Our findings suggest that estimation of a woman's risk for GDM through model-based incorporation of risk factors accurately identifies those at high risk (i.e., predicted risk >6%) who could benefit from preventive intervention encouraging prompt incorporation of this tool into preconception and prenatal care.

Telemedicine Applications in Obstetrics and Gynecology.

This article reviews principles to consider when setting up a telemedicine (TM) program to provide care to women in the field of obstetrics and gynecology. There are different types of TM encounters and clinical applications vary widely. The consensus among patients and providers is that TM is convenient to provide needed subspecialty medical care when it is not available locally. These programs are clinically successful, but economic and cost-effectiveness data are lacking. Federal reimbursement policy is limited for TM. State policy on coverage and reimbursement varies significantly from state to state and is the main driver on whether TM programs are successful.

Genetic Characterization of Ten-Eleven-Translocation Methylcytosine Dioxygenase Alterations in Human Glioma.

The molecular mechanisms leading to brain tumors still remain unclear. Nevertheless, there is increasing evidence that epigenetic effects play crucial roles in tumor development and progression. Thereby, 5-hydroxymethylcytosine (5hmC) represents a further base modification of cytosine besides 5-methylcytosine (5mC). In addition to the role of 5hmC as an intermediate in demethylation, 5hmC is of reasonable importance for cellular control. Previous studies showed that loss of 5hmC is a hallmark of human malignancies, e.g. in glioma, melanoma, and myeloid tumors. In myeloid malignancies studies showed that loss of 5hmC was due to mutations within ten-eleven-translocation (TET) genes, enzymes being responsible for conversion of 5mC to 5hmC. Nevertheless, till date there are no genetic characterization data of TET enzymes available for glioma. In this study, we genetically characterized TET2 and TET3 alterations in 50 human gliomas (WHO-Grade II-IV) and in 19 healthy brain samples. We identified 7 genetic alterations within TET2 (p.V218M, p.G355N, p.P363L, p.L1721W, p.P1723S, p.I1762V, p.H1778R). Additionally, we performed quantification of 5hmC amount and added functional prediction analysis of identified TET alterations to evaluate the biological impact of these alterations on the hydroxymethylome. An analysis of TET3 showed no non-synonymous alterations. In summary, we did not find correlations of TET alterations with 5hmC amount. Thus, our data emphasize that, in contrast to leukemia, loss of 5hmC in glioma is not caused by TET gene alterations. Moreover, other disturbances, such as disrupted gene expressions or functional inhibitions of TET proteins may be responsible for the aberrant epigenome of human glioma.

Loss of 5-hydroxymethylcytosine and intratumoral heterogeneity as an epigenomic hallmark of glioblastoma.

Glioblastoma (GBM) is the most malignant neoplasm with predominant astrocytic differentiation and the most frequent primary brain tumor of the adult. Here, we investigated 170 human GBM specimens deriving from 162 patients, as well as 66 healthy control tissue specimens deriving from 27 patients, and analyzed the amount of 5-hydroxymethylcytosine (5hmC) in GBMs compared to normal brain and tumor infiltration zones. Additionally, we correlated the amount of 5hmC with two different proliferation markers, Ki67 and H3S10p. Genetic characterization of GBMs enabled us to analyze the effect of isocitrate dehydrogenase 1 (IDH1) mutations, O6-methylguanin-DNA-methyltransferase (MGMT) promoter methylation, and loss of heterozygosity of chromosome 1p and 19q (LOH1p/19q) on 5hmC amount. We found that GBMs show a tremendous loss of 5hmC, and we observed that even the infiltration zones show reduced amounts of 5hmC. Interestingly, the amount of 5hmC was inversely proportional to the two investigated proliferation markers, Ki67 and H3S10p. Correlation of 5hmC amount and molecular genetic markers of GBMs showed that there are no correlations of 5hmC amount and IDH1 mutations, MGMT promoter methylation, and LOH1p/19q. Furthermore, we evaluated the intratumoral distribution of 5hmC in compact and infiltrating areas and found that the quantification of the 5hmC amount is a useful tool in evaluation of tumor infiltration. In summary, our data emphasize that GBMs show a disturbed hydroxymethylome that is disrupted by IDH1 independent pathways, and that loss of 5hmC shows astonishing intratumoral heterogeneity.

Identification of Stably Expressed lncRNAs as Valid Endogenous Controls for Profiling of Human Glioma.

BACKGROUND: Recent research indicates that long non-coding RNAs (lncRNA) represent a new family of RNAs that is of fundamental importance for controlling transcription and translation. Thereby, there is increasing evidence that lncRNAs are also important in tumourigenesis. Thereby valid expression profiling using quantitative PCR requires suitable, stably expressed normalisers to achieve reliable and reproducible data. However, no systematic analysis of suitable references in lncRNA studies in human glioma has been performed yet. METHODS: In this study, we investigated 90 lncRNAs in 30 tissue specimen for the expression stability in human diffuse astrocytoma (WHO-Grade II), anaplastic astrocytoma (WHO-Grade III) and glioblastoma (WHO-Grade IV) both alone as well as in comparison with normal white matter. Our identification procedure included a rigorous bioinformatical selection process that resulted in the inclusion of only highly abundant, equally expressed lncRNAs for further analysis. Additionally, lncRNAs were classified according to their stability value using the NormFinder algorithm. RESULTS: We identified 24 appropriate normalisers suitable for studies in diffuse astrocytoma, 22 for studies in anaplastic astrocytoma and 12 for studies in glioblastoma. Comparing all three glioma entities 7 lncRNAs showed stable expression levels. Addition of normal brain tissue resulted in only 4 suitable lncRNAs. CONCLUSIONS: Our findings indicate that 4 lncRNAs (HOXA6as, H19 upstream conserved 1 and 2, Zfhx2as and BC200) are suitable as normalisers in glioma and normal brain. These lncRNAs may thus be regarded as universal references being applicable for the accurate normalisation of lncRNA expression profiling in various glioma (WHO-Grades II-IV) alone and in combination with brain tissue. This enables to perform valid longitudinal studies, e.g. of glioma before and after malignisation to identify changes of lncRNA expressions probably driving malignant transformation.

Breaking bad news to a pregnant woman with a fetal abnormality on ultrasound.

Ultrasound is a common procedure performed in pregnancy. Most obstetric patients have an ultrasound between 18 and 20 weeks' gestation. While there is debate regarding the utility of this ultrasound, it has become a routine part of prenatal care. Discovery of a fetal anomaly on ultrasound is most commonly an unexpected, emotionally devastating event for pregnant women. Counseling these women about the ultrasound findings requires empathy and sensitivity. This task falls on the physicians caring for pregnant women: maternal-fetal medicine specialists, radiologists, generalist obstetricians, and family medicine physicians. Their training regarding breaking bad news is varied. Therefore, the purpose of this article is to provide a framework to break bad news of an anomalous fetus for physicians caring for pregnant women using the SPIKES protocol. The SPIKES acronym stands for setting, perception, invitation, knowledge, empathize, summary, and strategy.

Long non-coding RNA normalisers in human brain tissue.

The family of long non-coding RNA (lncRNA) is of increasing scientific interest as there is emerging evidence, that lncRNAs are of essential importance for transcriptional and translational control, genomic imprinting and regulation of normal development as well as neuronal plasticity. As the generation of reliable expression profiles requires adequate normalisers, it is of fundamental importance to determine suitable references for lncRNA studies. However, to date no systematic analysis of potential lncRNA normalisers has been performed on human postmortem brain tissue samples. In this study, we investigated three different brain regions (cortex, white matter, and cerebellum) of human postmortem tissue and analysed the expression stability of 90 lncRNAs. Bioinformatical analysis was performed to identify stably expressed lncRNAs. Subsequently, lncRNAs were classified according to their stability values using the NormFinder algorithm. We identified 30 suitable normalisers in cortex, 22 in white matter, and 41 in cerebellum. In addition, there were 13 suitable normalisers for studies comparing cortex and white matter, 25 for studies comparing cortex and cerebellum and 7 for studies comparing white matter and cerebellum. 5 lncRNAs (LUST, IGF2AS (family), 7SK, HOXA6as, NDM29) showed stable expression in all investigated brain regions. A subsequent analysis of the influence of postmortem intervals (PMI) on expression of lncRNAs revealed that expression levels of the newly identified 5 universal lncRNA normalisers are stable within PMI of up to 27 h. Thus, these 5 lncRNAs may be applicable as references for accurate normalisation of lncRNA profiling in multiple brain regions during long PMI, enabling the generation of highly reproducible datasets in lncRNA studies of the human brain.

Severe lead poisoning caused by use of health supplements presenting as acute abdominal pain during pregnancy.

BACKGROUND: The public and some health care providers regard complementary and alternative medications as safe. There is no scientific basis for that belief, but there is evidence of poor quality control and toxicity of some remedies. CASE: A white pregnant woman presented with diffuse, acute abdominal pain ultimately diagnosed as lead poisoning due to the use of traditional Asian Indian health supplements. CONCLUSION: Use of traditional medicines may extend beyond the ethnic group in which the traditional medicine originated. When symptoms warrant, poisoning with lead or other heavy metals should be considered in the differential diagnosis.

Activity and subcellular distribution of cathepsins in primary human monocytes.

Cathepsins (Cat) in antigen presenting cells (APC) control antigen processing as well as major histocompatibility complex class II transport and function. The set of active Cat and the subcellular architecture of the class II antigen presentation compartment are largely unknown in primary human APC, including peripheral blood monocytes. We used novel chemical tools to visualize Cat in an activity-dependent manner. Primary human monocytes contained active CatS, -B, and -H, while CatL was absent. Expression and activity patterns of Cat in human myelo-monocytoid cell lines were distinct from those found in primary cells. On a subcellular scale, the bulk of active Cat was concentrated in lysosomes in primary monocytes. In late endosomes, only active CatS was found in sizable amounts, colocalizing with C-terminal processing of the class II invariant chain and with cystatin C, the major endogenous Cat inhibitor. Late endosomes of human peripheral blood monocytes contain a well-controlled proteolytic machinery distinct from lysosomes, which is likely to play a key role in class II function.