Examining the impact of trimester of diagnosis on COVID-19 disease progression in pregnancy.

BACKGROUND: COVID-19 infection is associated with increased morbidity in pregnancy and adverse maternal and neonatal outcomes. Little is currently known about how the timing of infection during pregnancy affects these outcomes. OBJECTIVE: This study aimed to evaluate the effect of trimester of COVID-19 infection on disease progression and severity in pregnant patients. STUDY DESIGN: This was a prospective cohort study of pregnant patients diagnosed with COVID-19 infection who delivered at a single urban hospital. Universal testing for SARS-CoV-2 was performed at hospital admission and for symptomatic patients in inpatient, emergency department, and outpatient settings. Disease severity was defined as asymptomatic, mild, moderate, severe, or critical on the basis of National Institutes of Health criteria. We evaluated disease progression from asymptomatic to symptomatic infection and from asymptomatic or mild infection to moderate, severe, or critical illness, and stratified by trimester of COVID-19 diagnosis. Primary outcomes included progression of COVID-19 disease severity and a composite obstetrical outcome, which included delivery at <37 weeks, preeclampsia with severe features, abruption, excess blood loss at delivery (>500 mL for vaginal or >1000 mL for cesarean delivery), and stillbirth. RESULTS: From March 18, 2020 to September 30, 2021, 1326 pregnant patients were diagnosed with COVID-19 and delivered at our institution, including 103 (8%) first-, 355 (27%) second-, and 868 (65%) third-trimester patients. First-trimester patients were older and had more medical comorbidities; 86% of patients in all trimesters were Hispanic. Among patients admitted within 14 days of a positive test, 3 of 18 (17%) first-trimester, 20 of 47 (43%) second-trimester, and 34 of 574 (6%) third-trimester patients were admitted for the indication of COVID-19 illness. Across all trimesters, 1195 (90%) of 1326 COVID-19 infections were asymptomatic or mild, and 45 (10%) of 436 initially asymptomatic patients developed symptoms. Of patients with asymptomatic or mild symptoms at diagnosis, 4 (4%) of 93 first-, 18 (5%) of 337 second-, and 49 (6%) of 836 third-trimester patients developed moderate, severe, or critical illness (P=.80). There was no significant difference in composite obstetrical outcome with respect to trimester of COVID-19 diagnosis (24% first-trimester, 28% second-trimester, 28% third-trimester patients; P=.69). CONCLUSION: Moderate, severe, or critical illness develops in almost 10% of pregnant patients. The frequency of COVID-19 disease progression in pregnancy does not differ by trimester of diagnosis.

The interplay of additivity, dominance, and epistasis on fitness in a diploid yeast cross.

In diploid species, genetic loci can show additive, dominance, and epistatic effects. To characterize the contributions of these different types of genetic effects to heritable traits, we use a double barcoding system to generate and phenotype a panel of ~200,000 diploid yeast strains that can be partitioned into hundreds of interrelated families. This experiment enables the detection of thousands of epistatic loci, many whose effects vary across families. Here, we show traits are largely specified by a small number of hub loci with major additive and dominance effects, and pervasive epistasis. Genetic background commonly influences both the additive and dominance effects of loci, with multiple modifiers typically involved. The most prominent dominance modifier in our data is the mating locus, which has no effect on its own. Our findings show that the interplay between additivity, dominance, and epistasis underlies a complex genotype-to-phenotype map in diploids.

An evidence-based definition of anemia for singleton, uncomplicated pregnancies.

BACKGROUND: The definition for anemia in pregnancy is outdated, derived from Scandinavian studies in the 1970's to 1980's. To identity women at risk of blood transfusion, a common cause of Severe Maternal Morbidity, a standard definition of anemia in pregnancy in a modern, healthy United States cohort is needed. OBJECTIVE: To define anemia in pregnancy in a United States population including a large county vs. private hospital population using uncomplicated patients. MATERIALS AND METHODS: Inclusion criteria were healthy women with the first prenatal visit before 20 weeks. Exclusion criteria included preterm birth, preeclampsia, hypertension, diabetes, short interval pregnancy (<18 months), multiple gestation, abruption, and fetal demise. All women had iron fortification (Ferrous sulfate 325 mg daily) recommended. The presentation to care and pre-delivery hematocrits were obtained, and the percentiles determined. A total of 2000 patients were included, 1000 from the public county hospital and 1000 from the private hospital. Each cohort had 250 patients in each 2011, 2013, 2015, and 2018. The cohorts were compared for differences in the fifth percentile for each antepartum epoch. Student's t-test and chi-squared statistical tests were used for analysis, p-value of ≤0.05 was considered significant. RESULTS: In the public and private populations, 777 and 785 women presented in the first trimester while 223 and 215 presented in the second. The women at the private hospital were more likely to be older, Caucasian race, nulliparous, and present earlier to care. The fifth percentile was compared between the women in the private and public hospitals and were clinically indistinguishable. When combining the cohorts, the fifth percentile for hemoglobin/hematocrit was 11 g/dL/32.8% in the first trimester, 10.3 g/dL/30.6% in the second trimester, and 10.0 g/dL/30.2% pre-delivery. CONCLUSIONS: Fifth percentile determinations were made from a combined cohort of normal, uncomplicated pregnancies to define anemia in pregnancy. Comparison of two different cohorts confirms that the same definition for anemia is appropriate regardless of demographics or patient mix.

Genetic basis of a spontaneous mutation's expressivity.

Genetic background often influences the phenotypic consequences of mutations, resulting in variable expressivity. How standing genetic variants collectively cause this phenomenon is not fully understood. Here, we comprehensively identify loci in a budding yeast cross that impact the growth of individuals carrying a spontaneous missense mutation in the nuclear-encoded mitochondrial ribosomal gene MRP20. Initial results suggested that a single large effect locus influences the mutation's expressivity, with 1 allele causing inviability in mutants. However, further experiments revealed this simplicity was an illusion. In fact, many additional loci shape the mutation's expressivity, collectively leading to a wide spectrum of mutational responses. These results exemplify how complex combinations of alleles can produce a diversity of qualitative and quantitative responses to the same mutation.

Pulmonary hypertension complicating pregnancy: cardiac remodeling and residual concerns.

OBJECTIVES: To assess pulmonary artery pressure and cardiac remodeling in pregnancy in women with pulmonary hypertension and compare these findings with studies done beyond three months postpartum. STUDY DESIGN: Pregnant women with pulmonary hypertension from 2006 to 2017 were studied. Pulmonary hypertension was diagnosed when the pulmonary artery pressure exceeded 30 mmHg as estimated by right ventricular systolic pressure (RVSP) on echocardiography or 20 mmHg measured directly by mean pulmonary artery pressure (PAPm) with right-heart catheterization (RHC). Disease severity was assigned using threshold cutoffs. Indices of cardiac remodeling were compared during pregnancy after 20 weeks' gestation and again beyond three months postpartum when available. Pulmonary artery pressures obtained by echocardiography versus right-heart catheterization were also compared. RESULTS: Forty-six pregnancies complicated by pulmonary hypertension in 41 women were identified. The study included 43 pregnancies that resulted in a livebirth. There were 20 women in whom studies were performed after 20 weeks' gestation and again at least 3 months postpartum or later. Pulmonary artery pressures determined during pregnancy versus beyond three months postpartum were not significantly different when measured by echocardiography (RVSP 53.5 ± 20.5 mmHg and 46.7 ± 20.4 mmHg, p = .26) in this limited cohort. In the 10 women in whom pulmonary artery pressures were measured with both echocardiography and right-heart catheterization, the former was found to significantly overestimate directly measured pulmonary artery pressure (63.3 ± 20.7 versus 37.7 ± 12.3 mmHg, p < .001). CONCLUSION: Pulmonary artery pressures did not appreciably change during pregnancy after 20 weeks' gestation compared with pressures measured again beyond three months postpartum. Women with pulmonary hypertension did not show evidence of remodeling of left ventricular mass or relative wall thickness when measured in pregnancy after 20 weeks' gestation compared with beyond three months postpartum in this limited cohort. These findings suggest that cardiac remodeling in women with pulmonary hypertension is different from that of normally pregnant women and confirms the need for careful long-term follow-up.

Postpartum Depression Risk following Prenatal Diagnosis of Major Fetal Structural Anomalies.

OBJECTIVES: Our primary objective was to evaluate how prenatal diagnosis of a major fetal structural anomaly and resulting pregnancy outcome affected postpartum depression risk, as assessed by the Edinburgh Postnatal Depression Scale (EPDS). Secondary objectives were to review the rate of mental health follow-up and subsequent diagnosis of postpartum depression in screen-positive women. STUDY DESIGN: Singleton pregnancies with prenatal diagnosis of one or more major fetal structural anomalies were ascertained from prospectively maintained databases that included perinatal outcomes and subsequent EPDS responses from January 2010 to May 2018. EPDS scores of 13 or higher were considered positive and prompted referral for mental health follow-up, which was verified by medical record review. Statistical analyses were performed using Student's t-test, χ2, and odds ratios (ORs) with p < 0.05 considered significant. RESULTS: A total of 1,306 women had a prenatal diagnosis of one or more major fetal structural anomalies, 896 (68%) also had a postpartum EPDS screening, and 82 (9.2%) screened positive. Positive EPDS screening was more common with anomalies of multiple organ systems (16.5 vs 7.8%, p = 0.002) and aneuploidy (17.1 vs 9.3%, p = 0.02). Pregnancies complicated by fetal death, neonatal death, and termination for anomaly were significantly more likely to screen positive than those with neonatal survival to discharge (OR, 3.1 [95% confidence interval [CI], 1.6-6.2], 3.0 [95% CI, 1.5-5.8], and 4.4 [95% CI, 2.1-8.9], respectively, p ≤ 0.002). Of the 35 (43%) screen-positive women who attended follow-up appointments with mental health providers, 18 (51%) were diagnosed with a depressive disorder, accounting overall for 22% of those with a positive EPDS screen. CONCLUSION: Among women with a prenatal diagnosis of a major fetal structural anomaly, those experiencing a perinatal loss or pregnancy termination have an increased risk of positive EPDS screen result compared with who have a neonate surviving to discharge. A depressive disorder was diagnosed postpartum in 22% of these women with a positive EPDS screen. Our findings highlight the mental health needs in this vulnerable population. KEY POINTS: · Adverse pregnancy outcome increased positive EPDS screen risk among women with prenatal anomalies.. · A depressive disorder was diagnosed postpartum in 22% of such women with a positive EPDS screen.. · Our findings highlight the mental health needs in this vulnerable population..

Genome of Spea multiplicata, a Rapidly Developing, Phenotypically Plastic, and Desert-Adapted Spadefoot Toad.

Frogs and toads (anurans) are widely used to study many biological processes. Yet, few anuran genomes have been sequenced, limiting research on these organisms. Here, we produce a draft genome for the Mexican spadefoot toad, Spea multiplicata, which is a member of an unsequenced anuran clade. Atypically for amphibians, spadefoots inhabit deserts. Consequently, they possess many unique adaptations, including rapid growth and development, prolonged dormancy, phenotypic (developmental) plasticity, and adaptive, interspecies hybridization. We assembled and annotated a 1.07 Gb Sp. multiplicata genome containing 19,639 genes. By comparing this sequence to other available anuran genomes, we found gene amplifications in the gene families of nodal, hyas3, and zp3 in spadefoots, and obtained evidence that anuran genome size differences are partially driven by variability in intergenic DNA content. We also used the genome to identify genes experiencing positive selection and to study gene expression levels in spadefoot hybrids relative to their pure-species parents. Completion of the Sp. multiplicata genome advances efforts to determine the genetic bases of spadefoots' unique adaptations and enhances comparative genomic research in anurans.

The complex underpinnings of genetic background effects.

Genetic interactions between mutations and standing polymorphisms can cause mutations to show distinct phenotypic effects in different individuals. To characterize the genetic architecture of these so-called background effects, we genotype 1411 wild-type and mutant yeast cross progeny and measure their growth in 10 environments. Using these data, we map 1086 interactions between segregating loci and 7 different gene knockouts. Each knockout exhibits between 73 and 543 interactions, with 89% of all interactions involving higher-order epistasis between a knockout and multiple loci. Identified loci interact with as few as one knockout and as many as all seven knockouts. In mutants, loci interacting with fewer and more knockouts tend to show enhanced and reduced phenotypic effects, respectively. Cross-environment analysis reveals that most interactions between the knockouts and segregating loci also involve the environment. These results illustrate the complicated interactions between mutations, standing polymorphisms, and the environment that cause background effects.

Modifiers of the Genotype-Phenotype Map: Hsp90 and Beyond.

Disruption of certain genes alters the heritable phenotypic variation among individuals. Research on the chaperone Hsp90 has played a central role in determining the genetic basis of this phenomenon, which may be important to evolution and disease. Key studies have shown that Hsp90 perturbation modifies the effects of many genetic variants throughout the genome. These modifications collectively transform the genotype-phenotype map, often resulting in a net increase or decrease in heritable phenotypic variation. Here, we summarize some of the foundational work on Hsp90 that led to these insights, discuss a framework for interpreting this research that is centered upon the standard genetics concept of epistasis, and propose major questions that future studies in this area should address.