Maternal azithromycin therapy for Ureaplasma parvum intraamniotic infection improves fetal hemodynamics in a nonhuman primate model.

BACKGROUND: Ureaplasma parvum infection is a prevalent cause of intrauterine infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE: This study assessed the effect of intraamniotic Ureaplasma infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. STUDY DESIGN: Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. RESULTS: Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P<.05). Azithromycin treatment restored values to control levels. Amniotic fluid prostaglandin F2 alpha levels were significantly higher in animals with abnormal umbilical artery pulsatility index (>1.1) than in those with normal blood flow (P<.05; Spearman ρ=0.6, P<.05). In the intraamniotic inoculation with Ureaplasma parvum group, left ventricular cardiac output was significantly decreased (P<.001), and more animals had abnormal right-to-left ventricular cardiac output ratios (defined as >1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05). CONCLUSION: Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.

Exposure to systemic and intrauterine inflammation leads to decreased pup survival via different placental mechanisms.

PROBLEM: Exposure to systemic maternal inflammation (i.e., maternal sepsis, influenza, human immunodeficiency virus, or pyelonephritis) and intrauterine (IU) inflammation (i.e., chorioamnionitis or preterm labor) have been associated with adverse perinatal sequelae. Whether systemic and localized inflammation leading to adverse outcomes have similar placental mechanisms remain unclear. METHOD OF STUDY: We conducted a study by murine modeling systemic and localized IU inflammation with injections of either intraperitoneal (IP) or IU interleukin-1ß (IL-1ß) and compared fetoplacental hemodynamic changes, cytokine/chemokine expression, and fetal loss. RESULTS: IU IL-1ß exposure reduced offspring survival by 31.1% and IP IL-1ß exposure by 34.5% when compared with control pups. Despite this similar outcome in offspring survival, Doppler analysis revealed a stark difference: IU group displayed worsened fetoplacental hemodynamic changes while no differences were found between IP and control groups. While both IU and IP groups had increases in pro-inflammatory cytokines and chemokines, specific gene expression trends differed between the two groups, once again highlighting their mechanistic differences. CONCLUSION: While both IP and IU IL-1ß exposure similarly affected pup survival, only IU inflammation resulted in fetoplacental hemodynamic changes. We speculate that exposure to maternal systemic and IU inflammation plays a key role in fetal injury by utilizing different placental inflammatory pathways and mechanisms.

Obstetric management, tests, and technologies that impact childhood development.

Childhood brain development begins before birth, and obstetric management, tests, and technologies designed to diagnose and treat fetal conditions can have an impact on development. Preconception counseling for maternal diabetes and hypertension affect the risk of fetal congenital anomalies and growth restriction. Patients with risk factors for pre-existing maternal diabetes are offered early diabetic screening because earlier diagnosis and treatment can decrease the risk of fetal and neonatal complications. Screening for chromosomal abnormalities in the first or second trimester is offered to all females regardless of age. Cell-free fetal DNA screening can be used to test for fetal genetic abnormalities as early as 9 weeks of gestation with results available in 10 days. Ultrasound performed around 20 weeks' gestation can identify the 3% of fetuses that have a major congenital malformation. Fetal magnetic resonance imaging can be used to better assess fetal central nervous system abnormalities when neurosonography is inconclusive. Doppler ultrasound can be used to assess blood flow in the umbilical artery and fetal middle cerebral artery to aid in the management of the growth-restricted fetus. In summary, diagnosis and treatment of maternal and fetal conditions from the preconception period throughout pregnancy are important for optimizing fetal health and provide the best opportunity for optimal child development. WHAT THIS PAPER ADDS: Cell-free fetal DNA screening can identify fetal genetic abnormalities as early as 9 weeks' gestation. Ultrasound performed around 20 weeks' gestation can detect major fetal congenital malformations. Fetal magnetic resonance imaging can aid neurosonography in the assessment of fetal central nervous system abnormalities. Doppler ultrasound to assess fetal blood flow is used to successfully manage the growth-restricted fetus.

MANEJO OBSTÉTRICO, PRUEBAS Y TECNOLOGÍAS QUE IMPACTAN EL DESARROLLO INFANTIL: El desarrollo infantil comienza antes del nacimiento, y el manejo obstétrico, las pruebas y las tecnologías diseñadas para diagnosticar y tratar las afecciones fetales pueden tener un impacto en el desarrollo. El asesoramiento previo a la concepción para la diabetes materna y la hipertensión puede modificar el riesgo de anomalías congénitas fetales y la restricción del crecimiento. A los pacientes con factores de riesgo para la diabetes materna preexistente se les ofrece la detección temprana de la diabetes debido a que un diagnóstico y tratamiento tempranos pueden disminuir el riesgo de complicaciones fetales y neonatales. El examen de detección de anomalías cromosómicas en el primer o segundo trimestre se ofrece a todas las mujeres, independientemente de su edad. La prueba de detección de ADN fetal sin células se puede usar para detectar anomalías genéticas fetales tan pronto como a las 9 semanas de gestación, con resultados disponibles en 10 días. La ecografía realizada alrededor de las 20 semanas de gestación puede identificar el 3% de los fetos que tienen una malformación congénita importante. La resonancia magnética fetal puede usarse para evaluar mejor las anomalías del sistema nervioso central fetal cuando la neurosonografía no es concluyente. La ecografía Doppler se puede usar para evaluar el flujo sanguíneo en la arteria umbilical y la arteria cerebral media fetal para ayudar en el manejo del feto con restricción de crecimiento. En resumen, el diagnóstico y el tratamiento de las afecciones maternas y fetales desde el período previo a la concepción, y durante todo el embarazo, son importantes para optimizar la salud fetal y ofrecen la mejor oportunidad para el desarrollo óptimo del niño.

MANEJO OBSTÉTRICO, TESTES E TECNOLOGIAS QUE IMPACTAM O DESENVOLVIMENTO INFANTIL.: O desenvolvimento infantil começa antes do nascimento, e o manejo obstétrico, testes e tecnologias projetados para diagnosticar e tratar condições fetais podem ter impacto no desenvolvimento. Aconselhamento pré-concepcional para diabetes materna e hipertensão afetam o risco de anomalias congênitas fetais e restrição do crescimento. Pacientes com fatores de risco para diabetes materna pré-existente recebem oferta de monitoramento precoce para diabetes porque o diagnóstico e tratamento precoces podem diminuir o risco de complicações fetais e neonatais. O monitoramento para anormalidades cromossômicas no primeiro ou segundo trimestre é oferecido para todas as mulheres independente da idade. A avaliação sem células do DNA fetal pode ser usada para testar anormalidades genéticas tão cedo como 9 semanas de gestação, com resultados disponíveis em 10 dias. O ultra-som realizado por volta de 20 semanas de gestação pode identificar os 3% de fetos que têm uma malformação congênita importante. Imagem por ressonância magnética fetal pode ser usada mara melhor avaliar anormalidades do sistema nervoso central quando a neurosonografia é inconcusiva. Ultra-som Doppler pode ser usado para avaliar o fluxo sanguíneo na artéria umbilical e artéria cerebral média fetal para ajudar no manejo de fetos com restrição de crescimento. Em resumo, o diagnóstico e tratamento de condições maternas e fetais no período pré-concepcional e durante toda a gestação são importantes para otimizar a saúde do feto e proporcionar a melhor oportunidade para o desenvolvimento infantil ótimo.

Risk Factors for Neonatal Hypoxic-Ischemic Encephalopathy in the Absence of Sentinel Events.

OBJECTIVE: Hypoxic-ischemic encephalopathy (HIE) may be associated with intrapartum sentinel events or may be unexplained. We sought to identify risk factors for unexplained HIE cases and compare their morbidity and mortality to cases associated with sentinel events. STUDY DESIGN: Retrospective cohort study of all neonates admitted with suspected HIE treated with whole-body hypothermia from January 2007 through July 2017. Cases of unexplained HIE were compared with those with a sentinel event. RESULTS: A total of 223 neonates met the inclusion criteria, of which 86 (38.6%) experienced a sentinel event and 137 (61.4%) did not. Placental histopathology was performed for 28/31 (90.3%) and 48/53 (90.6%) inborn neonates with and without sentinel events, respectively. Placentas from unexplained HIE cases more often exhibited histologic chorioamnionitis (43.8% vs. 17.9%, p = 0.02) and funisitis (25% vs. 3.6%, p = 0.02). Neonatal morbidity and mortality were similar. On multivariable regression, nulliparity (odds ratio [OR], 4.11, 95% confidence interval [CI]: 1.24-13.62) and histologic funisitis (OR, 20.33, 95% CI: 1.11-373.4) remained significant. CONCLUSION: Other than nulliparity and infection which could be identified on umbilical cord examination following delivery but not on clinical assessment prior to delivery, there are no other identifiable risk factors for HIE in the absence of a sentinel event, and morbidity and mortality are similar between groups.

Increased placental T cell trafficking results in adverse neurobehavioral outcomes in offspring exposed to sub-chronic maternal inflammation.

Interleukin-1 beta (IL-1ß) is a cytokine mediator of perinatal brain injury. The effect of sub-chronic systemic IL-1ß exposure in perinatal and offspring outcomes is unclear. The aim of this study was to examine the effects of maternal IL-1ß exposure on pregnancy and offspring outcomes. At E15, CD1 dams were allocated to receive intraperitoneal injection of phosphate buffered saline or mouse recombinant IL-1ß (1 mcg) for four consecutive days. We analyzed pup survivaland neurobehavioral status. At E18, placental H&E staining and fetal brain Nissl staining was performed. Placental gene expression was analyzed by qPCR and T cell infiltration was analyzed by flow cytometry. Effects of inflammation on feto-placental blood flow were analyzed by Doppler ultrasonography. IL-1ß decreased pup survival (P < .0001) and adversely affected offspring performance on neurodevelopmental tests (P < .05). Placentas of exposed dams exhibited significant thinning of maternal and fetal sides, and fetal brain exhibited cortical thinning. Placental qPCR analysis revealed significant upregulation of NFκB2 (P = .0021) and CXCL11 (P = .0401). While maternal IL-1ß exposure did not affect feto-placental blood flow, placental flow cytometry showed an increase in placental infiltration of CD4+ T cells at 24 h post-injection (hpi, P < .0001) and CD8+ T cells at 72 hpi (P = .0217). Maternal sub-chronic, systemic inflammation with IL-1ß decreased pup survival and played a key role in perinatal brain injury. The mechanisms behind these outcomes may involve immune system activation and alterations in placental T cell trafficking.

Perinatal Brain Injury: Mechanisms, Prevention, and Outcomes.

Perinatal brain injury may lead to long-term morbidity and neurodevelopmental impairment. Improvements in perinatal care have resulted in the survival of more infants with perinatal brain injury. The effects of hypoxia-ischemia, inflammation, and infection during critical periods of development can lead to a common pathway of perinatal brain injury marked by neuronal excitotoxicity, cellular apoptosis, and microglial activation. Various interventions can prevent or improve the outcomes of different types of perinatal brain injury. The objective of this article is to review the mechanisms of perinatal brain injury, approaches to prevention, and outcomes among children with perinatal brain injury.

Progesterone improves perinatal neuromotor outcomes in a mouse model of intrauterine inflammation via immunomodulation of the placenta.

To assess the fetal neuroprotective potential of progesterone using a well-validated mouse model of lipopolysaccharide (LPS)-induced intrauterine inflammation (IUI). Embryonic day 17 pregnant mouse dams (n = 69) were randomly allocated to receive 17-hydroxyprogesterone caproate (17-OHPC), micronized progesterone (MP), or vehicle 1 hour prior to intrauterine injection of phosphate-buffered saline (PBS) or LPS. After 6 hours, mice were killed for the collection of placentas and fetal brains, or pregnancy continued for the evaluation of preterm birth (PTB) and offspring neuromotor function. Placentas and fetal brains were analyzed by mini-mRNA array for 96 immune markers with individual confirmatory qPCR. Progesterone pre-treatment before LPS-induced IUI improved neuromotor tests in offspring at PND5 compared to no pre-treatment (P < .05). In placentas, 17-OHPC, but not MP, significantly reduced CXCL9 (P < .05) with a trend toward a lower level of CXCL10. In fetal brains, 17-OHPC significantly reduced CXCL9 compared to no pre-treatment (P < .05) and IL-1ß compared to pre-treatment with MP (P < .01). Progesterone pre-treatment prior to LPS-induced IUI improved offspring neuromotor outcomes. 17-OHPC, but not MP, resulted in greater immunomodulation of T cell-mediated immunity in placenta and fetal brain, suggesting a possible mechanism for the observed neuroprotective effects.

Zika virus: Future reproductive concerns.

The pandemic spread of Zika virus (ZIKV), a member of the flavivirus genus of the Flaviviridae family, has become a major public health concern. Reproductive specialists are particularly concerned over the spread of ZIKV as it is now known to have both sexual and transplacental routes of transmission resulting in fetal congenital abnormalities. Other members of the Flaviviridae family, hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV) (which primarily affects cattle), are well known to reproductive specialists as both sexually transmitted illnesses that are capable of vertical transmission. Congenital infection with BVDV also has a predilection for neuro-teratogenicity as has been seen with ZIKV. HCV and BVDV are also known to be capable of persistent infection in offspring. Could this be the case with ZIKV? Examining what we know about HCV and BVDV, in addition to what we have already learned about ZIKV, may answer some of the questions that remain about ZIKV. Herein, we review the current literature as it pertains to ZIKV vertical transmission and neuro-teratogenicity and compare it to what is known about HCV and BVDV.

Disparities in obstetrical outcomes in ART pregnancies compared with natural conceptions.

Health disparities are observed in all fields of medicine and reproductive health is not immune to this phenomenon. The incidence of women using infertility treatments to conceive is increasing. Women undergoing assisted reproduction appear to be at increased risk of adverse outcomes, and minority women tend to be at even greater risk. This article examines several adverse obstetrical outcomes including preterm birth, congenital malformations, and preeclampsia among women receiving infertility treatments compared with those who conceive spontaneously. It will further examine societal costs associated with these procedures.

Maternal coagulopathy after umbilical cord occlusion for twin reversed arterial perfusion sequence.

BACKGROUND: Twin reversed arterial perfusion sequence is a rare complication of monochorionic twin gestations for which therapy involves the disruption of vascular anastomoses between the pump twin and acardiac twin and death of the acardius. CASE: A 37-year-old woman, gravida 11 para 2, with a monochorionic twin pregnancy complicated by twin reversed arterial perfusion sequence who underwent umbilical cord occlusion at 24 weeks of gestation was admitted in preterm labor at 33 weeks of gestation. Maternal disseminated intravascular coagulation (DIC) was diagnosed and her labor was induced. She received multiple blood products to correct her coagulopathy and had an uncomplicated vaginal delivery of the viable pump twin. CONCLUSION: Maternal DIC may complicate fetal death after umbilical cord occlusion.

Survey of robotic surgery training in obstetrics and gynecology residency.

To examine the status of resident training in robotic surgery in obstetrics and gynecology programs in the United States, an online survey was emailed to residency program directors of 247 accredited programs identified through the Accreditation Council for Graduate Medical Education website. Eighty-three of 247 program directors responded, representing a 34% response rate. Robotic surgical systems for gynecologic procedures were used at 65 (78%) institutions. Robotic surgery training was part of residency curriculum at 48 (58%) residency programs. Half of respondents were undecided on training effectiveness. Most program directors believed the role of robotic surgery would increase and play a more integral role in gynecologic surgery. Robotic surgery was widely reported in residency training hospitals with limited availability of effective resident training. Robotic surgery training in obstetrics and gynecology residency needs further assessment and may benefit from a structured curriculum.