Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing.

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. CONCLUSION: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy.

BACKGROUND: Among women with hypertensive disorders of pregnancy, biomarkers may stratify risk for developing preeclampsia with severe features (sPE). METHODS: Across 18 U.S. centers, we prospectively measured the ratio of serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) in pregnant women hospitalized between 23 and 35 weeks of gestation. The primary outcome was predicting sPE, and secondary outcomes included predicting adverse outcomes within 2 weeks. The prognostic performance of the sFlt-1:PlGF ratio was assessed by using a derivation/validation design. RESULTS: A total of 1014 pregnant women were evaluated; 299 were included in the derivation cohort and 715 in the validation cohort. In the derivation cohort, the median sFlt-1:PlGF ratio was 200 (interquartile range, 53 to 458) among women who developed sPE compared with 6 (interquartile range, 3 to 26) in those who did not (P<0.001). The discriminatory ratio of ≥40 was then tested in the validation cohort and yielded a 65% positive (95% confidence interval [CI], 59 to 71) and a 96% negative (95% CI, 93 to 98) predictive value for the primary outcome. The ratio performed better than standard clinical measures (area under the receiver-operating characteristic curve, 0.92 versus <0.75 for standard-of-care tests). Compared with women with a ratio <40, women with a ratio ≥40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2). CONCLUSIONS: In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1:PlGF provided stratification of the risk of progressing to sPE within the coming fortnight. (Funded by Cedars-Sinai Medical Center and Thermo Fisher Scientific; ClinicalTrials.gov NCT03815110.)

Haemophagocytic lymphohistiocytosis in pregnancy: a pertinent case during the COVID-19 pandemic.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, often fatal disease, and presents a diagnostic challenge in the pregnant patient. This challenge is particularly relevant during the current COVID-19 pandemic. We present a case of HLH in a pregnant woman presenting with fever predating the COVID-19 pandemic. A 33-year-old, gravida 2, para 1 at 27 weeks' gestation presented with fever, transaminitis, thrombocytopenia and elevated ferritin. After treatment according to the HLH-94 protocol, caesarean delivery and weeks of intensive care, the patient recovered fully. With prompt diagnosis and a multispecialty team at our tertiary care facility, she and her baby overcame a dire prognosis. HLH should be considered in pregnant patients presenting with a febrile illness. Particularly in cases of severe COVID-19, secondary HLH must be considered as an associated diagnosis.

Foley Plus Oxytocin Compared With Oxytocin for Induction After Membrane Rupture: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the use of a transcervical Foley catheter plus oxytocin infusion compared with oxytocin infusion alone for labor induction and cervical ripening in women 34 weeks of gestation or greater with prelabor rupture of membranes. METHODS: This is a randomized, multicenter trial of women with a live, singleton gestation at 34 weeks of gestation or greater with prelabor rupture of membranes, an unfavorable cervical examination (less than or equal to 2 cm dilated and less than or equal to 80% effaced), and no contraindication to labor. Participants were randomly allocated to a transcervical Foley catheter inflated to 30 cc with concurrent oxytocin infusion or oxytocin infusion alone. Oxytocin administration was standardized across sites. The primary study outcome was interval from induction to delivery. To detect a 2.5-hour difference in the interval from induction to delivery, we required outcome data on 194 women, assuming 80% power and a two-tailed α of 5%. Analysis was by intent to treat. RESULTS: We enrolled 201 women: 93 were allocated to Foley and 108 to oxytocin. Demographics were similar between the groups. Time to delivery was not significantly different between groups: in the Foley group, it was 13.9 hours (±6.9 SD) compared with 14.4 hours (±7.9 SD) in the oxytocin group (P=.69). There were more cases of clinical chorioamnionitis (8% compared with 0%, P<.01) in the Foley group compared with the oxytocin group. There were no differences for other infectious morbidities or any other variable studied. CONCLUSION: In patients with prelabor rupture of membranes, the use of a transcervical Foley catheter in addition to oxytocin does not shorten the time to delivery compared with oxytocin alone, but may increase the incidence of intraamniotic infection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01973036.

Quantification of DNA in Neonatal Dried Blood Spots by Adenine Tandem Mass Spectrometry.

Newborn screening programs have expanded to include molecular-based assays as first-tier tests and the success of these assays depends on the quality and yield of DNA extracted from neonatal dried blood spots (DBS). To meet high throughput and rapid turnaround time requirements, newborn screening laboratories adopted rapid DNA extraction methods that produce crude extracts. Quantification of DNA in neonatal DBS is not routinely performed due to technical challenges; however, this may enhance the performance of assays that are sensitive to amounts of input DNA. In this study, we developed a novel high throughput method to quantify total DNA in DBS. It is based on specific acid-catalyzed depurination of DNA followed by mass spectrometric quantification of adenine. The amount of adenine was used to calculate DNA quantity per 3.2 mm DBS. Reference intervals were established using archived, neonatal DBS (n = 501) and a median of 130.6 ng of DNA per DBS was obtained, which is in agreement with literature values. The intra- and interday variations were <15%. The limits of detection and quantification were 12.5 and 37.8 nmol/L adenine, respectively. We demonstrated that DNA from neonatal DBS can be successfully quantified in high throughput settings using instruments currently deployed in NBS laboratories.

Use of intracervical balloons and chorioamnionitis in term premature rupture of membranes.

OBJECTIVE: To determine whether ripening and induction in patients with term premature rupture of membranes (PROM) via intracervical balloon placement (ICB) increases the risk of chorioamnionitis when compared to women with term PROM ripened and induced with other methods. STUDY DESIGN: A retrospective cohort study of term singleton gestations undergoing ripening and induction after PROM between July 2009 and June 2012 was conducted. Exposure of interest was ICB placement. Primary outcome of interest was chorioamnionitis. Statistical analysis included bivariate and multivariate techniques. RESULTS: Of 124 term PROM patients, 42 were ripened by ICB with or without oxytocin (33.9%) and 82 were ripened and induced with oxytocin (66.1%). More women ripened with an ICB were nulliparous (n = 35, 83.3% ICB versus n = 44, 53.7% oxytocin, p = 0.001). Chorioamnionitis was slightly more common in women ripened with ICB and/or oxytocin versus oxytocin alone but difference did not reach statistical significance (p = 0.10). The rate of cesarean delivery, intrauterine pressure catheter (IUPC) use, and median lengths of membrane rupture and active labor were higher in the ICB group. After adjustment, chorioamnionitis was not correlated with ICB placement but with nulliparity [AOR 12.5 (1.36, 114.6), p = 0.03] and IUPC use [AOR 4.39 (1.04, 18.5), p = 0.04]. CONCLUSION: Nulliparity and IUPC, not ICB placement, were associated with chorioamnionitis.

Other mechanical methods for pre-induction cervical ripening.

Pre-induction cervical ripening is an important part of the labor induction process in women with an unfavorable cervix. This can be achieved either by pharmacologic or mechanical methods of cervical ripening. While the Foley catheter is the most commonly used mechanical method for labor induction, other mechanical methods are also available. This article reviews the safety profiles of osmotic dilators, extra-amniotic saline infusion, double-balloon catheters, and also compares their efficacy to that of other mechanical and pharmacologic cervical ripening methods. While mechanical methods have been shown to be safe and effective for cervical ripening, none of these alternatives has been shown to be superior to the Foley catheter.

hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling.

The increased cap-independent translation of anti-apoptotic proteins is involved in the development of drug resistance in lung cancer but signalling events regulating this are poorly understood. Fibroblast growth factor 2 (FGF-2) signalling-induced S6 kinase 2 (S6K2) activation is necessary, but the downstream mediator(s) coupling this kinase to the translational response is unknown. Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. In the cytoplasm, phosphoS4/6-hnRNPA1 dissociates from these mRNAs de-repressing their IRES-mediated translation. This correlates with the phosphorylation-dependent association of hnRNPA1 with 14-3-3 leading to hnRNPA1 sumoylation on K183 and its re-import into the nucleus. A non-phosphorylatible, S4/6A mutant prevented these processes, hindering the pro-survival activity of FGF-2/S6K2 signalling. Interestingly, immunohistochemical staining of lung and breast cancer tissue samples demonstrated that increased S6K2 expression correlates with decreased cytoplasmic hnRNPA1 and increased BCL-XL expression. In short, phosphorylation on novel N-term sites of hnRNPA1 promotes translation of anti-apoptotic proteins and is indispensable for the pro-survival effects of FGF-2.

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.

Nucleotide composition of cellular internal ribosome entry sites defines dependence on NF45 and predicts a posttranscriptional mitotic regulon.

The vast majority of cellular mRNAs initiate their translations through a well-defined mechanism of ribosome recruitment that occurs at the 5'-terminal 7-methylguanosine cap with the help of several canonical protein factors. A subset of cellular and viral mRNAs contain regulatory motifs in their 5' untranslated regions (UTRs), termed internal ribosome entry sites (IRES), that sidestep this canonical mode of initiation. On cellular mRNAs, this mechanism requires IRES trans-acting protein factors (ITAFs) that facilitate ribosome recruitment downstream of the cap. While several ITAFs and their target mRNAs have been empirically identified, the in silico prediction of targets has proved difficult. Here, we report that a high AU content (>60%) of the IRES-containing 5' UTRs serves as an excellent predictor of dependence on NF45, a recently identified ITAF. Moreover, we provide evidence that cells deficient in NF45 ITAF activity exhibit reduced IRES-mediated translation of X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 (cIAP1) mRNAs that, in turn, leads to dysregulated expression of their respective targets, survivin and cyclin E. This specific defect in IRES translation explains in part the cytokinesis impairment and senescence-like phenotype observed in HeLa cells expressing NF45 RNA interference (RNAi). This study uncovers a novel role for NF45 in regulating ploidy and highlights the importance of IRES-mediated translation in cellular homeostasis.

HuR controls mitochondrial morphology through the regulation of BclxL translation.

BclxL is a key prosurvival factor that in addition to controlling mitochondrial membrane permeability regulates mitochondrial network dynamics. The expression of BclxL is regulated at the level of translation, splicing and selective translation. In this study, we show that the RNA-binding protein HuR, which is known to orchestrate an anti-apoptotic cellular program, functions as a translational repressor of BclxL. We show that HuR binds directly to the 5'UTR of BclxL, and represses BclxL translation through the inhibition of its internal ribosome entry site (IRES). Reduction of HuR levels leads to the derepression of BclxL translation and subsequent rearrangement of the mitochondrial network. Our results place BclxL into the HuR-regulated operon and provide further insight into the regulation of cellular stress response by HuR.

Risk factors for wound complications in morbidly obese women undergoing primary cesarean delivery.

OBJECTIVE: To determine factors influencing separation and infectious type wound complications (WCs) in morbidly obese women undergoing primary cesarean delivery (CD). METHODS: Retrospective cohort study evaluating infectious and separation WC in morbidly obese (body mass index [BMI] > 35 kg/m(2)) women undergoing primary CD between January 1994 and December 2008. Chi-square, Fisher's exact and Student's t tests used to assess associated factors; backward logistic regression to determine unadjusted and adjusted odds ratios. RESULTS: Of 623 women, low transverse skin incisions were performed in 588 (94.4%), vertical in 35 (7%). Overall WC rate was 13.5%, which varied by incision type (vertical 45.7% vs. 11.6% transverse; p < 0.01), but not BMI class. Incision type and unscheduled CD were associated with infection risk, while incision type, BMI, race and drain use were associated with wound separation. CONCLUSION: In morbidly obese women both infectious and separation type WC are more common in vertical than low transverse incisions; therefore transverse should be preferred.

Is the accuracy of prior preterm birth history biased by delivery characteristics?

To assess the sensitivity of birth certificates to preterm birth history and determine whether omissions are randomly or systemically biased. Subjects who experienced a preterm birth followed by a subsequent pregnancy were identified in a regional database. The variable "previous preterm birth" was abstracted from birth certificates of the subsequent pregnancy. Clinical characteristics were compared between subjects who were correctly versus incorrectly coded. 713 subjects were identified, of whom 65.5% were correctly coded in their subsequent pregnancy. Compared to correctly coded patients, patients who were not correctly identified tended to have late and non-recurrent preterm births or deliveries that were secondary to maternal or fetal indications. A recurrence of preterm birth in the subsequent pregnancy was also associated with correct coding. The overall sensitivity of birth certificates to preterm birth history is suboptimal. Omissions are not random, and are associated with obstetrical characteristics from both the current and prior deliveries. As a consequence, resulting associations may be flawed.

Effect of second-trimester and third-trimester rate of gestational weight gain on maternal and neonatal outcomes.

OBJECTIVE: To estimate the effect of second- and third-trimester rate of gestational weight gain on pregnancy outcomes using the revised Institute of Medicine guidelines. METHODS: This is a retrospective cohort study of singleton live births in upstate New York between January 2004 and December 2008. Women were grouped by prepregnancy body mass index (BMI) and rates of second- and third-trimester gestational weight gain were calculated. Women were then classified as having less than, within, or greater than recommended rates of gain. Maternal and neonatal outcomes were assessed based on rate of weight gain within each BMI class. RESULTS: Of 73,977 women meeting inclusion criteria, 4% were underweight, 48% normal weight, 24% overweight, and 24% obese: 13% class I, 6% class II, and 5% class III, respectively. After controlling for potential confounding variables, less than recommended rates of second- and third-trimester weight gain were associated with increased odds of small-for-gestational-age neonates in all BMI groups except obese classes II and III. Greater than recommended rates of weight gain were associated with increased odds of large-for-gestational-age neonates in all BMI groups and increased odds of cesarean delivery in all BMI groups with the exception of underweight and obese class III women. CONCLUSION: Suboptimal second- and third-trimester rates of gestational weight gain in the most obese women, even with net weight loss, do not increase the odds of small-for-gestational-age neonates. Excessive rates of gestational weight gain increase the odds of large-for-gestational-age neonates regardless of BMI. LEVEL OF EVIDENCE: II.

Mode of delivery and outcomes in very low-birth-weight infants in the vertex presentation.

We sought to determine the relationship between mode of delivery and neonatal outcomes in infants <1500 g in a vertex presentation. This was a retrospective cohort study of singleton, vertex-presenting infants weighing <1500 g in a level III neonatal intensive care unit between July 1993 and July 2006. Infants were divided into vaginal or cesarean delivery, and outcomes were compared with univariable and multivariable analysis. Of the 937 infants that met inclusion criteria, 402 (42.9%) underwent cesarean delivery. After controlling for potential confounding variables, there was no increased odds of death (odds ratio [OR] = 1.6: 95% confidence interval [CI] 0.8 to 3.0), severe intraventricular hemorrhage (IVH; OR = 1.2: 95% CI 0.7 to 1.2), necrotizing enterocolitis (OR = 0.82: 95% CI 0.35 to 1.9), or sepsis (OR = 0.79: 95% CI 0.44 to 13) in the vaginally delivered group compared with the cesarean group. In a post hoc analysis, this study had 80% power to detect an absolute difference in death or severe IVH of 6% between study groups, with an α of 0.05. In our population of very low-birth-weight infants, there was no association between mode of delivery and neonatal outcomes.