Discharge medication delivery location and postpartum blood pressure control in patients with hypertensive disorders of pregnancy.

OBJECTIVE: This study examined whether use of bedside medication delivery (Meds to Beds, M2B) or on-campus pharmacy at discharge was associated with improved postpartum blood pressure (BP) control compared to outside pharmacy use in patients with hypertensive disorders of pregnancy (HDP). STUDY DESIGN: This was a secondary analysis of 357 patients with HDP enrolled in STAMPP-HTN (Systematic Treatment and Management of Postpartum Hypertension Program) who were discharged from delivery admission with antihypertensives between October 2018 and June 2020. Patients were grouped by discharge medication location: M2B/on-campus pharmacy (on-site) versus outside pharmacy (off-site). MAIN OUTCOME MEASURES: The primary outcome was BP values at the immediate postpartum visit. Secondary outcomes included six-week visit BP values, attendance at both visits, and readmission within six weeks. RESULTS: Median BP values were no different based on pharmacy location at immediate postpartum visit for both systolic ((135 [IQR 127, 139] on-site vs 137 [127, 145] off-site, p = 0.22) and diastolic (81 [74, 91] vs 83 [76, 92], p = 0.45) values. Similar findings were noted at six weeks. Patients who used an off-site pharmacy had higher attendance rates at the immediate postpartum visit but this difference was attenuated after adjusting for group differences (OR 0.67 [95 % CI 0.37-1.20], p = 0.18). Readmission rates were also not different between groups (12.2 % on-site vs 15.8 % off-site pharmacy, p = 0.43). CONCLUSION: In the context of a preexisting multicomponent HDP quality improvement program, on-campus pharmacy and bedside medication delivery use was not associated with additional improvement in postpartum BP control, follow-up rates, or readmission rates.

Sex differences in early and term placenta are conserved in adult tissues.

BACKGROUND: Pregnancy complications vary based on the fetus's genetic sex, which may, in part, be modulated by the placenta. Furthermore, developmental differences early in life can have lifelong health outcomes. Yet, sex differences in gene expression within the placenta at different timepoints throughout pregnancy and comparisons to adult tissues remains poorly characterized. METHODS: Here, we collect and characterize sex differences in gene expression in term placentas (≥ 36.6 weeks; 23 male XY and 27 female XX). These are compared with sex differences in previously collected first trimester placenta samples and 42 non-reproductive adult tissues from GTEx. RESULTS: We identify 268 and 53 sex-differentially expressed genes in the uncomplicated late first trimester and term placentas, respectively. Of the 53 sex-differentially expressed genes observed in the term placentas, 31 are also sex-differentially expressed genes in the late first trimester placentas. Furthermore, sex differences in gene expression in term placentas are highly correlated with sex differences in the late first trimester placentas. We found that sex-differential gene expression in the term placenta is significantly correlated with sex differences in gene expression in 42 non-reproductive adult tissues (correlation coefficient ranged from 0.892 to 0.957), with the highest correlation in brain tissues. Sex differences in gene expression were largely driven by gene expression on the sex chromosomes. We further show that some gametologous genes (genes with functional copies on X and Y) will have different inferred sex differences if the X-linked gene expression in females is compared to the sum of the X-linked and Y-linked gene expression in males. CONCLUSIONS: We find that sex differences in gene expression are conserved in late first trimester and term placentas and that these sex differences are conserved in adult tissues. We demonstrate that there are sex differences associated with innate immune response in late first trimester placentas but there is no significant difference in gene expression of innate immune genes between sexes in healthy full-term placentas. Finally, sex differences are predominantly driven by expression from sex-linked genes.

Erratum: X chromosome inactivation in the human placenta is patchy and distinct from adult tissues.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100121.].

X chromosome inactivation in the human placenta is patchy and distinct from adult tissues.

In humans, one of the X chromosomes in genetic females is inactivated by a process called X chromosome inactivation (XCI). Variation in XCI across the placenta may contribute to observed sex differences and variability in pregnancy outcomes. However, XCI has predominantly been studied in human adult tissues. Here, we sequenced and analyzed DNA and RNA from two locations from 30 full-term pregnancies. Implementing an allele-specific approach to examine XCI, we report evidence that XCI in the human placenta is patchy, with large patches of either maternal or paternal X chromosomes inactivated. Further, using similar measurements, we show that this is in contrast to adult tissues, which generally exhibit mosaic X inactivation, where bulk samples exhibit both maternal and paternal X chromosome expression. Further, by comparing skewed samples in placenta and adult tissues, we identify genes that are uniquely inactivated or expressed in the placenta compared with adult tissues, highlighting the need for tissue-specific maps of XCI.

Does Antenatal Progesterone Administration Modify the Risk of Neonatal Intraventricular Hemorrhage?

OBJECTIVE: Progesterone administration has been associated with improved neurological outcomes following traumatic brain injury in adults. However, studies examining the effect of progesterone on the risk of neonatal intraventricular hemorrhage (IVH) are inconsistent. We sought to determine if maternal administration of intramuscular 17-α-hydroxyprogesterone caproate (17-OHPC) is associated with decreased rates of IVH in infants born before 32-weeks gestation. STUDY DESIGN: This is a retrospective study of liveborn singleton deliveries between 20- and 32-weeks gestation at two large academic medical centers from January 1, 2012 to August 30, 2020. Data were extracted from hospital electronic medical record data warehouses using standardized definitions and billing and diagnosis codes. We evaluated receipt of 17-OHPC in the antepartum period and diagnosis of IVH (grade I-IV, per Volpe classification) during the neonatal delivery hospitalization encounter. Bivariate and multivariate analyses were performed to examine the association between 17-OHPC and neonatal IVH adjusting for potential confounders. Odds ratio (ORs) and 95% confidence intervals (CIs) were presented. RESULTS: Among 749 neonates born between 20- and 32-week gestation, 140 (18.7%) of their mothers had received antenatal 17-OHPC and 148 (19.8%) were diagnosed with IVH after birth. No significant association was observed between maternal 17-OHPC and neonatal IVH in unadjusted (OR 1.14, 95% CI 0.72-1.78) or adjusted analyses (adjusted odds ratio 1.14, 95% CI 0.71-1.84). Independent of exposure to 17-OHPC, as expected, infants born <28-weeks gestation or those with very low birthweight (<1,500 g) were at an increased risk of IVH (OR 2.32, 95% CI 1.55-3.48 and OR 2.19, 95% CI 1.09-4.38, respectively). CONCLUSION: Antenatal maternal 17-OHPC administration was not associated with the risk of neonatal IVH. Further research may be warranted to determine whether timing, route of delivery, and duration of progesterone therapy impact rates of neonatal IVH. KEY POINTS: · This study aimed to compare the frequency of intraventricular hemorrhage in preterm neonates exposed to antenatal 17-α-hydroxyprogesterone caproate to those not exposed.. · In neonates born at <32-weeks gestation, maternal use of progesterone is not associated with the risk of intraventricular hemorrhage.. · In contrast to preclinical and adult data, this study suggests that progesterone exposure is not associated with the prevention of neonatal brain injury..

Perinatal outcomes in women with elevated blood pressure and stage 1 hypertension.

BACKGROUND: Hypertension was redefined in 2017 with lower diagnostic thresholds; elevated blood pressure is defined as systolic blood pressure of 120 to 129 mm Hg with diastolic blood pressure of <80 mm Hg and stage 1 hypertension as systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg. These guidelines did not include pregnant women. There is limited information on stage 1 hypertension and pregnancy outcomes. OBJECTIVE: This study aimed to determine whether elevated blood pressure and stage 1 hypertension as newly defined by the 2017 American College of Cardiology and the American Heart Association guidelines are associated with an increased risk of hypertensive disorders of pregnancy and other adverse maternal and neonatal outcomes. STUDY DESIGN: In this retrospective cohort study, 18,801 women with singletons from 2013 to 2019 were categorized as normotensive, prehypertensive (elevated blood pressure), stage 1 hypertensive, or chronic hypertensive. Women with ≥2 systolic blood pressures of 120 to 129 mm Hg before 20 weeks' gestation were classified into the elevated blood pressure group. Women with ≥2 systolic blood pressures of 130 to 139 mm Hg or ≥2 diastolic blood pressures of 80 to 89 mm Hg before 20 weeks' gestation were assigned to the stage 1 hypertension group. Women were classified as chronic hypertensives if they had any of the following: ≥2 systolic blood pressure of ≥140 mm Hg or ≥2 diastolic blood pressure of ≥90 mm Hg before 20 weeks' gestation, a history of chronic hypertension, or antihypertensive medication use before 20 weeks' gestation. Women with pregestational diabetes, lupus, or <2 blood pressures before 20 weeks' gestation were excluded. The association of stage 1 hypertension with the risk of developing hypertensive disorders of pregnancy was estimated using multivariate logistic regression controlling for maternal sociodemographic characteristics, gestational weight gain by prepregnancy body mass index, parity, and aspirin use. Secondary outcomes included subgroups of hypertensive disorders (gestational hypertension, preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count syndrome), gestational diabetes, placental abruption, intrauterine growth restriction, preterm birth, neonatal intensive care unit admission, stillbirth and neonatal death, and maternal intensive care unit admission. All outcomes were adjusted for potential confounders. RESULTS: Of the 18,801 women, 13,478 (71.7%) were normotensive, 2659 (14.1%) had elevated blood pressure, 1384 (7.4%) were stage 1 hypertensive, and 1280 (6.8%) were chronic hypertensive. A dose-response relationship was observed: the risk of hypertensive disorders of pregnancy increased from 4.2% in normotensive women to 6.7% (adjusted odds ratio, 1.50; 95% confidence interval, 1.26-1.79) in women with elevated blood pressure, to 10.9% (adjusted odds ratio, 2.54; 95% confidence interval, 2.09-3.08) in women with stage 1 hypertension, and 28.4% (adjusted odds ratio, 7.14; 95% confidence interval, 6.06-8.40) in women with chronic hypertension. Compared with normotensive women, women with stage 1 hypertension had an increased risk of neonatal intensive care unit admissions (15.8% vs 13.0%; adjusted odds ratio, 1.21; 95% confidence interval, 1.03-1.42), preterm birth at <37 weeks' gestation (7.2% vs 5.2%; adjusted odds ratio, 1.45; 95% confidence interval, 1.16-1.81), and gestational diabetes (14.8% vs 6.8%; adjusted odds ratio, 2.68; 95% confidence interval, 2.27-3.17). CONCLUSION: Our study demonstrates that elevated blood pressure and stage 1 hypertension, using the 2017 American College of Cardiology and the American Heart Association guideline definition, are associated with increased maternal and neonatal risk. This group of women warrants further investigation to determine whether pregnancy management can be altered to reduce maternal and neonatal morbidity.

Human Chorionic Gonadotropin modulates CXCL10 Expression through Histone Methylation in human decidua.

The process of implantation, trophoblast invasion and placentation demand continuous adaptation and modifications between the trophoblast (embryonic) and the decidua (maternal). Within the decidua, the maternal immune system undergoes continued changes, as the pregnancy progress, in terms of the cell population, phenotype and production of immune factors, cytokines and chemokines. Human chorionic gonadotropin (hCG) is one of the earliest hormones produced by the blastocyst and has potent immune modulatory effects, especially in relation to T cells. We hypothesized that trophoblast-derived hCG modulates the immune population present at the maternal fetal interface by modifying the cytokine profile produced by the stromal/decidual cells. Using in vitro models from decidual samples we demonstrate that hCG inhibits CXCL10 expression by inducing H3K27me3 histone methylation, which binds to Region 4 of the CXCL10 promoter, thereby suppressing its expression. hCG-induced histone methylation is mediated through EZH2, a functional member of the PRC2 complex. Regulation of CXCL10 expression has a major impact on the capacity of endometrial stromal cells to recruit CD8 cells. We demonstrate the existence of a cross talk between the placenta (hCG) and the decidua (CXCL10) in the control of immune cell recruitment. Alterations in this immune regulatory function, such as during infection, will have detrimental effects on the success of the pregnancy.

Herpesvirus-infected Hofbauer cells activate endothelial cells through an IL-1ß-dependent mechanism.

INTRODUCTION: Placental viral infections are associated with fetal inflammation and adverse pregnancy outcomes. However, there have been limited studies on how placental macrophages in the villous and adjacent fetal umbilical endothelial cells respond to a viral insult. This study aimed to evaluate the communication between Hofbauer cells (HBCs) and human umbilical vein endothelial cells (HUVECs) during a viral infection. METHODS: HBCs were either uninfected or infected with the γ-herpesvirus, MHV-68, and the conditioned medium (CM) collected. HUVECs were exposed to HBC CM and the levels of the pro-neutrophilic response markers: IL-8; E-selectin; intercellular adhesion molecule 1 (ICAM-1); and vascular adhesion molecule 1 (VCAM-1) measured by ELISA and qPCR. The role of HBC-derived IL-1ß was investigated using an IL-1ß blocking antibody (Ab) or IL-1 receptor antagonist (IL-1Ra). RESULTS: MHV-68 infection of HBCs induced a significant increase in IL-1ß secretion. CM from infected HBCs induced HUVEC expression of IL-8, E-selectin, VCAM-1, ICAM-1 mRNA, and secretion of IL-8. The HUVEC response to the CM of MHV-infected HBCs was inhibited by a neutralizing IL-1ß Ab and by IL-1Ra. DISCUSSION: Virally-induced HBC IL-1ß activates HUVECs to generate a pro-neutrophilic response. This novel cell-cell communication pathway may play an important role in the genesis of fetal inflammation associated with placental viral infection.

Relevance of placental type I interferon beta regulation for pregnancy success.

Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens. Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications. Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the pregnancy via their antiviral and immune modulatory properties. In this study, we elucidate the mechanisms controlling the basal expression of IFNß and its negative feedback. Using in vitro and in vivo animal models, we found that TLR signaling maintains basal IFNß levels through the TLR4-MyD88-independent TBK/IRF3 signaling pathway. We describe the role of the TAM receptor Axl in the regulation of IFNß function in human and mouse trophoblast cells. The absence of TAM receptors in vivo is associated with fetal demise due to dysregulation of IFNß expression and its pro-apoptotic downstream effectors. Collectively, our data describe a feedback signaling pathway controlling the expression and function of IFNß in the trophoblast that is essential for an effective response during viral and microbial infections.

Early sonographic detection of a succenturiate placenta after IVF in a 42-year-old woman with multiple comorbidities.

We present a case of a 42-year-old woman with a pregnancy resulting from in vitro fertilisation and a medical history including two spontaneous abortions, hypercoagulable state and other comorbidities. At 13 4/7 weeks' gestation, during research ultrasonography, the patient was noted to have an anterior succenturiate placental lobe. Following an episode of vaginal bleeding at 21 6/7 weeks, she was diagnosed with a low-lying posterior placental lobe. Velamentous cord insertion, placenta previa and vasa previa were excluded at that time. After elective induction for advanced maternal age at 39 0/7 weeks, arrest of labour and chorioamnionitis resulted in a primary low transverse caesarean section and delivery of a healthy girl at 39 3/7 weeks. Gross examination of the placenta showed an irregular, singleton placenta with an attached succenturiate lobe and a marginally inserting umbilical cord. Both lobes were connected by two vessels.

Time course analysis of RNA quality in placenta preserved by RNAlater or flash freezing.

PROBLEM: Preservation of biospecimen quality is critical to accurately and reliably assessing genes and proteins. We evaluated the effect of preparation method and storage duration on RNA quality in placenta and decidua. METHOD OF STUDY: Aliquots of nine placentas and decidua were placed in RNAlater® (RL) or flash frozen (FF) within 30 minutes of delivery. RNA was extracted immediately (baseline) and from matched samples stored at -80°C for 1 and 8-10 months. RNA Integrity Number (RIN) and housekeeping gene expression were quantified. RESULTS: At both time points, RL placenta had RIN and housekeeping gene Ct values similar to baseline. However, FF placenta had significantly lower RIN and higher Ct values at 1 and 8-10 months. In RL and FF decidua, RIN was unchanged from baseline. CONCLUSION: We found RNAlater more effectively and consistently preserved placenta, compared to flash freezing. However, for decidua, which is less dense than placenta, both modes yielded comparable RNA integrity over time.

Viral infections during pregnancy.

Viral infections during pregnancy have long been considered benign conditions with a few notable exceptions, such as herpes virus. The recent Ebola outbreak and other viral epidemics and pandemics show how pregnant women suffer worse outcomes (such as preterm labor and adverse fetal outcomes) than the general population and non-pregnant women. New knowledge about the ways the maternal-fetal interface and placenta interact with the maternal immune system may explain these findings. Once thought to be 'immunosuppressed', the pregnant woman actually undergoes an immunological transformation, where the immune system is necessary to promote and support the pregnancy and growing fetus. When this protection is breached, as in a viral infection, this security is weakened and infection with other microorganisms can then propagate and lead to outcomes, such as preterm labor. In this manuscript, we review the major viral infections relevant to pregnancy and offer potential mechanisms for the associated adverse pregnancy outcomes.

Understanding the complexity of the immune system during pregnancy.

Progress in our understanding of the role of the maternal immune system during healthy pregnancy will help us better understand the role of the immune system in adverse pregnancy outcomes. In this review, we discuss our present understanding of the 'immunity of pregnancy' in the context of the response to cervical and placental infections and how these responses affect both the mother and the fetus. We discuss novel and challenging concepts that help explain the immunological aspects of pregnancy and how the mother and fetus respond to infection.

Human chorionic gonadotropin enhances trophoblast-epithelial interaction in an in vitro model of human implantation.

Embryo implantation, which is an absolute requirement for reproduction, starts with blastocyst apposition to the uterine endometrium, followed by attachment to the endometrial surface epithelium. Recent clinical studies reported an increase in implantation and pregnancy rates among women receiving intrauterine human chorionic gonadotropin (hCG) prior to embryo transfer suggesting that, at least in some cases, female infertility is a result of inadequate secretion of hCG. In this study, we characterized the effect of hCG on trophoblast-epithelial interaction by further developing our recently described in vitro model of implantation. Here, we confirmed hCG increased attachment of trophoblast to epithelial cells, using a single-cell trophoblast-epithelial coculture system in addition to a blastocyst-like spheroid-epithelial coculture system. Furthermore, we discovered that the source and concentration was pivotal; the first preparation of hCG affected 2 molecules related to implantation, MUC16 and osteopontin, while the second preparation required additional cytokines to mimic the effects. Using this system, we can develop a comprehensive knowledge of the cellular and gene targets of hCG and other factors involved in embryo apposition and implantation and potentially increase the number of therapeutic targets for subfertile patients.

Robotic versus abdominal hysterectomy for very large uteri.

BACKGROUND AND OBJECTIVES: We sought to examine the outcomes of patients with myomatous uteri weighing >1000 g who underwent hysterectomy by one of two modalities, either with a robotic system or by laparotomy. METHODS: All patients who underwent robotic hysterectomy for uteri weighing >1000 g at our institution between May 2007 and January 2011 were identified, and a retrospective chart review was performed. These patients were matched to a laparotomy control group by body mass index and uterine weight, and the postoperative outcomes in both groups were analyzed and compared. RESULTS: Sixty patients with uteri weighing >1000 g underwent hysterectomy, 30 with the robotic system and 30 by laparotomy. The median body mass index was 31.8 kg/m(2) (range, 18.5-56.3 kg/m(2)) and the median uterine weight was 1259 g (range, >1000 -3543 g) in the robotic group versus 30.2 kg/m(2) (range, 18 - 48 kg/m(2)) and 1509 g (range, 1000 -3570 g), respectively, in the laparotomy group (P = .31). The median operating time was 255 minutes (range, 180 -372 minutes) in the robotic group versus 150 minutes (range, 100 -285 minutes) in the laparotomy group (P < .001). There were no conversions to laparotomy. In both groups the operative time was not increased with increasing specimen weight. The median blood loss was 150 mL in the robotic group versus 425 mL in the laparotomy group. Of 30 patients in the robotic group, 23 (76.6%) were discharged from the hospital on postoperative day 1. The median hospital stay for the robotic group was 1 day, and for the laparotomy group, it was 2.5 days (P < .01). CONCLUSION: Robotic surgeries for very large myomatous uteri are feasible and have minimal morbidity even in morbidly obese patients. The robotic surgery requires a longer operative time but results in a shorter hospital stay and decreased intraoperative blood loss.

Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy.

A role for microbial invasion leading to inflammation in the amniotic cavity and subsequent pre-term delivery has been well established. For years, the role of viral infections in pregnancy has been minimized and thought of as harmless, with a few exceptions. Recent evidence now encourages us to expand our thinking and realize that viral infections during pregnancy may influence pregnancy more that we thought.

Decidual stromal cells as regulators of T-cell access to the maternal-fetal interface.

A recent study in the journal Science offers insights into the mechanism behind feto-maternal tolerance, as evidenced by changes in the immuno-logical environment of the uterus and decidua. They also provide a rich area of research for the understanding of the regulation of the immune system in other complicated medical conditions, including cancer and pregnancies affected by infection or autoimmunity.

Placental origins of angiogenic dysfunction in mirror syndrome.

UNLABELLED: BACKGROUNDL: Mirror syndrome is characterized by preeclampsia-like syndrome in pregnancies complicated by fetal hydrops. We describe a case of mirror syndrome associated with angiogenic dysfunction in maternal plasma and the placenta. CASE: A pregnant patient with known fetal hydrops presented at 22 weeks gestation with features of severe preeclampsia. Measurements of plasma anti- and proangiogenic factors were consistent with a profound antiangiogenic state. Immunohistochemistry of the placenta for antiangiogenic proteins showed a pattern similar to that seen in patients with severe preeclampsia. CONCLUSION: Angiogenic imbalance may also be responsible for the preeclampsia-like condition seen in mirror syndrome.

Placental expression of angiogenic factors in Trisomy 13.

OBJECTIVE: Increased levels of soluble fms-like tyrosine kinase (sFlt-1) in Trisomy 13 pregnancies are thought to be mediated by the placenta. This study aimed to compare sFlt-1 expression in Trisomy 13 (n = 7) placentas with that in control placentas (Trisomy 21, n = 11, and euploid, n = 6). STUDY DESIGN: This was a retrospective case-control study analyzing paraffin-embedded placental blocks that were stained with hematoxylin and eosin and antibodies to sFlt-1. Their staining intensity was compared using a semiquantitative technique. The Kruskal-Wallis test and Wilcox rank sum test were used for statistical analysis. RESULTS: The median staining was significantly higher in Trisomy 13 compared with control specimens (P = .008) (for Trisomy 13 vs Trisomy 21, P = .003, and Trisomy 13 vs euploid, P = .004). CONCLUSION: Our study demonstrates that Trisomy 13 placentas express more sFlt-1 than control placentas. These results strengthen the hypothesis that the increased incidence of preeclampsia in Trisomy 13 pregnancies is secondary to placental up-regulation of sFlt-1.

Abnormal placentation, angiogenic factors, and the pathogenesis of preeclampsia.

Preeclampsia is a common complication of pregnancy with potentially devastating consequences to both the mother and the baby.It is the leading cause of maternal deaths in developing countries. In developed countries it is the major cause of iatrogenic premature delivery and contributes significantly to increasing health care cost associated with prematurity. There is currently no known treatment for preeclampsia; ultimate treatment involves delivery of the placenta. Although there are several risk factors (such as multiple gestation or chronic hypertension), most patients present with no obvious risk factors. The molecular pathogenesis of preeclampsia is just now being elucidated. It has been proposed that abnormal placentation and an imbalance in angiogenic factors lead to the clinical findings and complications seen in preeclampsia. Preeclampsia is characterized by high levels of circulating antiangiogenic factors such as soluble fms-like tyrosine kinase-1 and soluble endoglin, which induce maternal endothelial dysfunction. These soluble factors are altered not only at the time of clinical disease but also several weeks before the onset of clinical signs and symptoms. Many methods of prediction and surveillance have been proposed to identify women who will develop preeclampsia, but studies have been inconclusive. With the recent discovery of the role of angiogenic factors in preeclampsia, novel methods of prediction and diagnosis are being developed to aid obstetricians and midwives in clinical practice. This article discusses the role of angiogenic factors in the pathogenesis, prediction, diagnosis, and possible treatment of preeclampsia.