Mitochondrial-targeted antioxidant attenuates preeclampsia-like phenotypes induced by syncytiotrophoblast-specific Gαq signaling.

Syncytiotrophoblast stress is theorized to drive development of preeclampsia, but its molecular causes and consequences remain largely undefined. Multiple hormones implicated in preeclampsia signal via the Gαq cascade, leading to the hypothesis that excess Gαq signaling within the syncytiotrophoblast may contribute. First, we present data supporting increased Gαq signaling and antioxidant responses within villous and syncytiotrophoblast samples of human preeclamptic placenta. Second, Gαq was activated in mouse placenta using Cre-lox and DREADD methodologies. Syncytiotrophoblast-restricted Gαq activation caused hypertension, kidney damage, proteinuria, elevated circulating proinflammatory factors, decreased placental vascularization, diminished spiral artery diameter, and augmented responses to mitochondrial-derived superoxide. Administration of the mitochondrial-targeted antioxidant Mitoquinone attenuated maternal proteinuria, lowered circulating inflammatory and anti-angiogenic mediators, and maintained placental vascularization. These data demonstrate a causal relationship between syncytiotrophoblast stress and the development of preeclampsia and identify elevated Gαq signaling and mitochondrial reactive oxygen species as a cause of this stress.

Video Education in Early Pregnancy and Parent Knowledge of Neonatal Resuscitation Options: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial investigates the proportion of correct answers on neonatal resuscitation options among parents after seeing a video on these options.

Smartphone-Based Video Antenatal Preterm Birth Education: The Preemie Prep for Parents Randomized Clinical Trial.

Importance: Preterm birth is a leading cause of infant mortality and child morbidity. Preterm birth is not always unexpected, yet standard prenatal care does not offer anticipatory education to parents at risk of delivering preterm, which leaves parents unprepared to make health care choices during the pregnancy that can improve survival and decrease morbidity in case of preterm birth. Objective: To evaluate the effect of the Preemie Prep for Parents (P3) program on maternal knowledge of preterm birth, preparation for decision-making, and anxiety. Design, Setting, and Participants: Recruitment for this randomized clinical trial conducted at a US academic medical center took place from February 3, 2020, to April 12, 2021. A total of 120 pregnant persons with a risk factor for preterm birth were enrolled between 16 and 21 weeks' gestational age and followed up through pregnancy completion. Intervention: Starting at 18 weeks' gestational age, P3 program participants received links delivered via text message to 51 gestational age-specific short animated videos. Control participants received links to patient education webpages from the American College of Obstetricians and Gynecologists. Main Outcomes and Measures: At 25 weeks' gestation, scores on the Parent Prematurity Knowledge Questionnaire (scored as percent correct), Preparation for Decision Making Scale (scored 0-100), and Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety computerized adaptive test. Analysis was based on an intention to treat. Results: A total of 120 pregnant participants (mean [SD] age, 32.5 [4.9] years) were included in the study; 60 participants were randomized to each group. Participants in the P3 group scored higher than those in the control group on knowledge of long-term outcomes at 25 weeks (88.5% vs 73.2%; estimated difference, 15.3 percentage points; 95% CI, 8.3-22.5 percentage points; P < .001). Participants in the P3 group reported being significantly more prepared than did participants in the control group for neonatal resuscitation decision-making at 25 weeks (Preparation for Decision Making Scale score, 76.0 vs 52.3; difference, 23.7; 95% CI, 14.1-33.2). There was no difference between the P3 group and the control group in anxiety at 25 weeks (mean [SE] PROMIS Anxiety scores, 53.8 [1.1] vs 54.0 [1.1]; difference, -0.1; 95% CI, -3.2 to 2.9). Conclusions and Relevance: In this randomized clinical trial, pregnant persons randomly assigned to the P3 program had more knowledge of core competencies and were more prepared to make decisions that affect maternal and infant health, without experiencing worse anxiety. Mobile antenatal preterm birth education may provide a unique benefit to parents with preterm birth risk factors. Trial Registration: ClinicalTrials.gov Identifier: NCT04093492.

HLA antibodies in fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by antibodies against human platelet antigens (HPA). However, in many cases that meet clinical criteria for the condition, maternal sera do not have HPA antibodies. In studies examining whether human leukocyte antigen (HLA) antibodies cause FNAIT, the results are limited and inconclusive. This study sought to examine whether clinically suspected FNAIT cases with absent maternal HPA antibodies had different HLA antibody strength and specificity compared to controls. STUDY DESIGN AND METHODS: A retrospective case-control study assessed class I HLA antibody strength and specificity in cases submitted for testing to Versiti, Wisconsin. There were 813 cases that met initial screening criteria, but written consent could only be obtained for 50. After review of medical records and expert panel review, 31 cases with clinical criteria of FNAIT and maternal HLA but not HPA antibodies were included. Each case was matched for maternal age, gestational age at delivery, parity, and race/ethnicity to two controls from unaffected pregnancies that had maternal serum HLA antibodies. RESULTS: FNAIT cases were found to have both significantly higher HLA antibody strength, measured by mean fluorescence index (MFI), and broader HLA antibody specificity at antigen epitope level, compared to matched controls (p < .001). p-values remained significant after controlling for parity and gestational age at delivery. DISCUSSION: Additional studies are needed to further examine whether the strong HLA antibodies identified in HPA-antibody-negative cases directly cause neonatal thrombocytopenia and whether prenatal treatment may be warranted in select cases to prevent recurrence.

Multimedia tablet or paper handout to supplement counseling during preterm birth hospitalization: a randomized controlled trial.

BACKGROUND: Parents of premature infants engage in shared decision-making regarding the care of their infant. The process of prenatal counseling typically involves a verbal conversation with a neonatal provider during hospitalization. Support people may not be available, and the pregnant person's memory is impaired by medications, pain, and stress. The American Academy of Pediatrics, American College of Obstetricians and Gynecologists, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development have called for improvements to this process, including the development of educational aids. OBJECTIVE: This study aimed to investigate whether a multimedia tablet would be more effective than a paper handout in supplementing verbal clinician counseling during preterm birth hospitalization. STUDY DESIGN: This was a randomized controlled trial including English-speaking pregnant people aged ≥18 years and hospitalized at 22 to 33 weeks' gestation for preterm birth. Exclusion criteria were known fetal or chromosomal anomaly and delivery before study completion. Pregnant people received either a multimedia tablet or a paper handout before verbal clinician counseling. Preintervention assessment included demographics and State-Trait Anxiety Inventory, and postintervention assessment included the Parent Knowledge of Premature Birth Questionnaire and State-Trait Anxiety Inventory. Continuous variables were analyzed by t-test and categorical variables by Fisher exact test. RESULTS: A total of 122 pregnant people referred for counseling were screened; 76 were randomized, and 59 completed the study. Demographics were similar between groups, except that pregnant people in the handout group were older (mean 32 vs 29 years; P=.03). The multimedia tablet group (n=32) was less likely to report reviewing all the educational material than the paper handout group (n=27) (41% vs 72%; P=.037). Both groups correctly answered a similar number of knowledge items (P=.088). Postintervention state anxiety decreased in both groups (P<.0001), with no difference between groups. Computerized tracking showed that the multimedia group spent a median of 37 minutes reviewing the tablet. CONCLUSION: Contrary to our hypothesis, a paper handout and multimedia tablet were equally effective in the labor unit for supplementing verbal preterm birth counseling, and both decreased parental anxiety.

Peripartum management of deep venous thrombosis in the context of antithrombin deficiency and May-Thurner syndrome.

Literature regarding the management of thrombus refractory to first-line treatment in the setting of pregnancy is limited, and management is made even more complicated in the context of thrombophilia. This case reviews the management of a patient with antithrombin deficiency who developed a massive thrombus during pregnancy, which was complicated by May-Thurner syndrome, lack of improvement with heparin, and preterm labor. The patient received multidisciplinary care throughout the pregnancy. At 35 weeks, anticoagulation was paused as she underwent induction of labor and delivery followed by postpartum placement of inferior vena cava filter and restarting heparin. Successful management of our pregnant patient with thrombus refractory to heparin hinged on individualized treatment for medical optimization with anticoagulation and antithrombin concentrate prior to labor followed by immediate postpartum placement of inferior vena cava filter.

Vascular endothelial adiponectin signaling across the life span.

Cardiovascular disease risk increases with age regardless of sex. Some of this risk is attributable to alterations in natural hormones throughout the life span. The quintessential example of this being the dramatic increase in cardiovascular disease following the transition to menopause. Plasma levels of adiponectin, a "cardioprotective" adipokine released primarily by adipose tissue and regulated by hormones, also fluctuate throughout one's life. Plasma adiponectin levels increase with age in both men and women, with higher levels in both pre- and postmenopausal women compared with men. Younger cohorts seem to confer cardioprotective benefits from increased adiponectin levels yet elevated levels in the elderly and those with existing heart disease are associated with poor cardiovascular outcomes. Here, we review the most recent data regarding adiponectin signaling in the vasculature, highlight the differences observed between the sexes, and shed light on the apparent paradox regarding increased cardiovascular disease risk despite rising plasma adiponectin levels over time.

Vascular Dysfunction in Preeclampsia.

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.

Severe thrombocytopenia and microangiopathic hemolytic anemia in pregnancy: A guide for the consulting hematologist.

A hematologist receives a call from a maternal-fetal medicine (MFM) physician about a previously healthy patient who became ill at 25 weeks' gestation. Her mental status is deteriorating. There are signs of fetal distress. Platelet count and hemoglobin are falling. The MFM physician is considering the hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. For the hematologist, everything seems unfamiliar. Our goal is to provide hematologists with the fundamental knowledge required for understanding and managing these patients who become suddenly and seriously ill during pregnancy and in whom thrombocytopenia and microangiopathic hemolytic anemia are part of their presentation.

Maternal anemia and severe maternal morbidity in a US cohort.

BACKGROUND: Maternal anemia is a common pregnancy complication and often leads to a requirement for additional treatments and interventions. Identifying the frequency at which women with antenatally diagnosed anemia experience severe morbidity at the time of admission to the labor and delivery unit will guide future recommendations regarding screening and interventions for anemia during pregnancy. OBJECTIVE: The objective of this study was to evaluate the association between antenatally diagnosed anemia and severe maternal morbidity as defined by the Centers for Disease Control and Prevention in a large, contemporary, US cohort. Neonatal outcomes were also examined. STUDY DESIGN: This was a secondary analysis of the Consortium on Safe Labor database from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which collected data on 228,438 deliveries in 19 United States hospitals from 2002 to 2008. This analysis included women with viable, singleton gestations and excluded stillbirths and gestations with severe congenital anomalies. Women with a diagnosis of antenatal anemia were compared with those without. Identification of diagnoses of antenatal anemia was obtained via electronic medical record abstraction and International Classification of Diseases coding according to each hospital protocol within the Consortium on Safe Labor. The primary maternal outcome consisted of a composite of severe maternal morbidity as defined by the Centers for Disease Control and Prevention and included maternal death, eclampsia, thrombosis, transfusion, hysterectomy, and maternal intensive care unit admission. The primary neonatal outcome was a composite that included a 5-minute Apgar score of <7, hypoxic ischemic encephalopathy, respiratory distress syndrome, necrotizing enterocolitis, seizures, intracranial hemorrhage, periventricular or intraventricular hemorrhage, neonatal sepsis, neonatal intensive care unit admission, and neonatal death. Each outcome within the composites was assessed individually along with other additional secondary outcomes, including a composite of severe maternal morbidity not including transfusion morbidity. All statistical analyses were performed with Stata version 14.2 (StataCorp LLC, College Station, TX) using Student's t test, chi-square test, Fisher's exact test, and Wilcoxon rank-sum (Mann-Whitney U) test, as appropriate. A multivariable logistic regression was performed with potential confounding variables entered into the regression equation if they differed between groups at a significance level of P<.05. RESULTS: A total of 166,566 women met the inclusion criteria. From the original cohort, 56,734 women could not be included because of an unknown diagnosis of anemia. Of those included, 10,217 (6.1%) were diagnosed with anemia during the pregnancy. Women with anemia were more likely to be younger, non-Hispanic Black, single, multiparous, and have a higher prepregnancy body mass index than those without anemia. The frequency of the primary maternal composite outcome, the neonatal composite outcome, and other secondary outcomes including the severe maternal morbidity composite not including transfusion, maternal death, transfusion during labor and the postpartum period, hysterectomy, postpartum hemorrhage, infectious morbidity, cesarean delivery, and preterm delivery were more common in women with anemia (P<.05). After multivariable logistic regression analysis adjusting for confounders, higher rates of severe maternal morbidity remained persistently associated with anemia (adjusted odds ratio, 2.04; 95% confidence interval, 1.86-2.23) in addition to the association of anemia with the severe maternal morbidity composite not including transfusion, maternal death, thrombosis, transfusion, hysterectomy, intensive care unit admission, postpartum hemorrhage, hypertensive disorders of pregnancy, cesarean delivery, and infectious morbidity. The composite neonatal outcome also remained associated with anemia after adjusting for confounders (adjusted odds ratio, 1.14; 95% confidence interval, 1.06-1.23). CONCLUSION: Women with antepartum anemia experienced increased rates of severe maternal morbidity and other serious adverse outcomes. Diagnosis and treatment of anemia during the antepartum period may lead to the identification and treatment of women at higher risk for maternal morbidity and mortality.

Information Order for Periviable Counseling: Does It Make a Difference?

OBJECTIVES: To examine whether the order of presenting survival vs disability information, with or without the description of infant neonatal intensive care unit (NICU) experiences would influence treatment choice during hypothetical periviable birth counseling. STUDY DESIGN: An internet sample of childbearing-aged women (n = 839) viewed a pictograph displaying the chances of survival and a pictograph on the chances of disability for a baby resuscitated during the periviable period. The sample was randomized to the order of pictographs and level of description of infant NICU experiences. Participants selected between intensive care or comfort care and reported their personal values. RESULTS: The order of the information influenced treatment choices (P = .02); participants were more likely to choose intensive care if they saw the survival pictograph first (70%) than the disability pictograph first (62%). Level of description of premature infant NICU experiences did not influence treatment choice (P = .92). Participants who valued sanctity of life, autonomy in making decisions, who were more religious, and had adequate health literacy were more likely to choose intensive care. Such participant characteristics had greater explanatory power than the experimental manipulations. CONCLUSIONS: Subtle differences in how information is presented may influence critical decisions. However, even among women with the same values, diversity in treatment choice remains.

BCR-ABL tyrosine kinase inhibitors promote pathological changes in dilator phenotype in the human microvasculature.

OBJECTIVE: Treatment with BCR-ABL tyrosine kinase inhibitors (TKIs) is the standard of care for patients with chronic myeloid leukemia, however evidence indicates these compounds may have cardiovascular side-effects. This study sought to determine if ex vivo exposure of human adipose arterioles to the BCR-ABL TKIs imatinib and nilotinib causes endothelial dysfunction. METHODS: Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10 µmol/L) or nilotinib (100 µmol/L). Arterioles were cannulated onto glass pipettes and flow mediated dilation (FMD) was assessed via video microscopy. To determine the mechanism of vasodilation, FMD was re-assessed in the presence of either the nitric oxide synthase inhibitor L-NAME (100 µmol/L) or the H2 O2 scavenger PEG-Catalase (500 U/mL). RESULTS: Neither imatinib nor nilotinib affected the magnitude of FMD (max dilation = 78±17% vehicle, 80 ± 24% nilotinib, 73 ± 13% imatinib). FMD was decreased by L-NAME in vehicle-treated arterioles (max dilation = 47±29%). Conversely, L-NAME had no effect on FMD in imatinib- or nilotinib-treated vessels (max dilation = 79±14% and 80 ± 24%, respectively), rather FMD was inhibited by PEG-Catalase (max dilation = 29±11% and 29 ± 14%, respectively). CONCLUSION: Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro-inflammatory H2 O2 .

Protecting Labor and Delivery Personnel from COVID-19 during the Second Stage of Labor.

The novel coronavirus disease 2019 (COVID-19) is spreading fast and is affecting the clinical workers at much higher risk than the general population. Little is known about COVID-19 effect on pregnant women; however, the emerging evidence suggests they may be at high risk of asymptomatic disease. In light of projected shortage of personal protective equipment (PPE), there is an aggressive attempt at conservation. In obstetrics, the guidelines on PPE use are controversial and differ among hospitals, globally, as well as nationally. The centers for disease control and prevention (CDC) recommend using N95 respirators, which are respirators that offer a higher level of protection instead of a facemask for when performing or present for an aerosol-generating procedures (AGP). However, the second stage of labor is not considered an AGP. The second stage of labor can last up to 4 hours. During that time, labor and delivery personnel is in close contact to patients, who are exerting extreme effort during and frequently blow out their breath, cough, shout, and vomit, all of which put the health care team at risk, considering that COVID-19 transmission occurs through aerosol generated by coughing and sneezing. The CDC and the American College of Obstetricians and Gynecologists (ACOG) do not provide clarification on the use of N95 during the second stage. We recommend that labor and delivery personnel have the utmost caution and be granted the protection they need to protect themselves and other patients. This includes providing labor and delivery personnel full PPE including N95 for the second stage of labor. This is critical to ensure the adequate protection for health care workers and to prevent spread to other health care workers and patients. KEY POINTS: · Second stage of labor exposes providers to aerosol.. · COVID-19 risk during second stage of labor is high.. · N95 should be used during second stage of labor..

The Impact of Fetal Anomalies on Contemporary Labor Patterns.

OBJECTIVE: To compare labor patterns in pregnancies affected by fetal anomalies to low-risk singletons. STUDY DESIGN: Labor data from the Consortium on Safe Labor, a multicenter retrospective study from 19 U.S. hospitals, including 98,674 low-risk singletons compared with 6,343 pregnancies with fetal anomalies were analyzed. Repeated-measures analysis constructed mean labor curves by parity, gestational age, and presence of fetal anomaly in women who reached full dilation. Interval-censored regression analysis adjusted for covariables was used to determine the median traverse times for labor progression. RESULTS: Labor curves for all groups indicated slower labor progress for patients with fetal anomalies. The most significant trends in median traverse times were observed in the preterm nulliparous and term multiparous groups. The median traverse times from 4 cm to complete dilation in the preterm nulliparous control versus anomaly groups were 5.0 and 5.4 hours (p < 0.0001). CONCLUSION: Labor proceeds at a slower rate in pregnancies affected by anomalies.

Platelet Counts during Pregnancy.

BACKGROUND: Platelet counts of less than 150,000 per cubic millimeter during uncomplicated pregnancies are described as gestational thrombocytopenia if no alternative cause is identified. Platelet counts may be even lower in women with pregnancy-related complications. However, the occurrence and severity of thrombocytopenia throughout pregnancy are not defined. METHODS: We evaluated platelet counts throughout pregnancy in women who delivered at Oklahoma University Medical Center between 2011 and 2014. These platelet counts were compared with those of nonpregnant women who were included in the National Health and Nutrition Examination Survey from 1999 through 2012. RESULTS: Among the 15,723 deliveries that occurred during the study period, 7351 women had sufficient data for our analyses. Of these women, 4568 had uncomplicated pregnancies, 2586 had pregnancy-related complications, and 197 had preexisting disorders associated with thrombocytopenia. Among the women who had uncomplicated pregnancies, the mean platelet count in the first trimester (mean gestation, 8.7 weeks) was 251,000 per cubic millimeter, which was lower than the mean platelet count in the 8885 nonpregnant women (273,000 per cubic millimeter) (P<0.001). At the time of delivery, 9.9% of the women with uncomplicated pregnancies had a platelet count below 150,000 per cubic millimeter. During the course of the uncomplicated pregnancies and deliveries, only 45 women (1.0%) had a platelet count below 100,000 per cubic millimeter. Among the 12 women with uncomplicated pregnancies who had a platelet count below 80,000 per cubic millimeter, only 5 (0.1%, among whom the range of platelet counts was 62,000 to 78,000 per cubic millimeter; median, 65,000) were identified by medical record review as having no alternative cause for the thrombocytopenia. Platelet counts of less than 150,000 per cubic millimeter at the time of delivery were more common among women who had pregnancy-related complications than among women who had uncomplicated pregnancies (11.9% vs. 9.9%, P=0.01). Throughout their pregnancies and deliveries, 59 women (2.3%) with pregnancy-related complications had a platelet count below 100,000 per cubic millimeter, and 31 (1.2%) had a platelet count below 80,000 per cubic millimeter. CONCLUSIONS: Mean platelet counts decreased during pregnancy in all the women, beginning in the first trimester. In women who have a platelet count of less than 100,000 per cubic millimeter, a cause other than pregnancy or its complications should be considered. (Funded by the National Heart, Lung, and Blood Institute.).