This document summarizes a study examining the roles of erythropoietin (Epo) and soluble erythropoietin receptor (sEpoR) in maternal vascular adaptation to high altitude pregnancy. The study found that chronic hypoxia at high altitude augments the normal pregnancy-associated rise in Epo levels but does not affect sEpoR levels. Preeclampsia cases at high altitude had equivalent Epo levels as controls but higher sEpoR levels, which may impair Epo-stimulated angiogenesis and vascular function, contributing to increased preeclampsia risk at high altitude.
Poor and hyper responders: biomarkers management, strategies
This document discusses the use of biomarkers such as AMH, AFC, and genetic markers to predict ovarian response and tailor IVF stimulation strategies. Key points:
1. AMH and AFC are effective at predicting poor and hyper ovarian response but not live birth rates. They are useful for choosing protocols.
2. Genetic markers of FSH and LH receptors can help explain hypo-sensitivity to FSH in some patients.
3. An integrated approach combining hormonal, functional and genetic biomarkers is needed to select the optimal treatment protocol for each patient.
4. Individualized treatment based on biomarkers can reduce cancellations, OHSS
This document discusses Doppler studies in pregnancies complicated by maternal autoimmune diseases like systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). It notes that in SLE pregnancies, the risk of preeclampsia (PE) is about 25% and fetal growth restriction (FGR) occurs in about 20% of cases. Distinguishing SLE from PE can be difficult. In APS pregnancies, the risk of thrombosis, PE, and FGR are higher than normal. Doppler studies have shown that increased impedance in the umbilical and uterine arteries is associated with greater risk of PE and FGR in pregnancies complicated by SLE or APS.
This document summarizes key information about immunological diseases that can affect pregnancy, including antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), and idiopathic thrombocytopenic purpura (ITP). It discusses the pathogenesis, diagnosis, and management of these conditions. For APS, it describes how antiphospholipid antibodies can cause pregnancy complications like miscarriage and preeclampsia. Treatment involves low molecular weight heparin and aspirin. For ITP, it explains how antibodies destroy platelets, increasing bleeding risk, and treatment may involve corticosteroids and IVIG when platelet counts are low.
This document summarizes research on using traditional Chinese medicine (TCM) to treat female infertility caused by high follicle-stimulating hormone (FSH) levels. It discusses how high FSH affects fertility, potential causes, and TCM perspectives on the condition. The author analyzes TCM treatment principles and provides case studies to illustrate how combining herbal remedies and acupuncture following TCM diagnosis can effectively restore ovarian function and balance hormones to address the root causes of high FSH levels.
This document discusses fetal monitoring techniques during labor and delivery. It notes that electronic fetal monitoring (EFM) is associated with decreased mortality but increased cesarean rates compared to auscultation. The document then focuses on fetal ST analysis (STAN), which analyzes changes in the fetal ECG that indicate hypoxia. Studies in the UK and Sweden found that combining EFM with STAN reduced metabolic acidosis in umbilical cord blood gases and lowered operative delivery rates compared to EFM alone. STAN provides a more precise assessment of fetal condition during labor to guide management and avoid unnecessary interventions.
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive functioning. Exercise boosts blood flow, releases endorphins, and promotes changes in the brain which help regulate emotions and stress levels.
LOD: Participant Behaviors and Social EngagementPerformics
The document summarizes key findings from a study about people's daily use of media and their dependence on different devices. Some of the main findings presented include:
- People spend more time on their mobile (20% after 5 minutes, 52% after 1 hour) and desktop (11% after 5 minutes, 60% after 1 hour) compared to other devices like TV, newspaper, and tablet on their first daily use.
- Younger people aged 18-29 are more dependent on their mobile (78%) compared to older age groups for activities like checking email, social networks, news, and weather.
- If people forget their mobile phone, the top concerns are not being able to make/receive calls
Poor and hyper responders: biomarkers management, strategies
This document discusses the use of biomarkers such as AMH, AFC, and genetic markers to predict ovarian response and tailor IVF stimulation strategies. Key points:
1. AMH and AFC are effective at predicting poor and hyper ovarian response but not live birth rates. They are useful for choosing protocols.
2. Genetic markers of FSH and LH receptors can help explain hypo-sensitivity to FSH in some patients.
3. An integrated approach combining hormonal, functional and genetic biomarkers is needed to select the optimal treatment protocol for each patient.
4. Individualized treatment based on biomarkers can reduce cancellations, OHSS
This document discusses Doppler studies in pregnancies complicated by maternal autoimmune diseases like systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). It notes that in SLE pregnancies, the risk of preeclampsia (PE) is about 25% and fetal growth restriction (FGR) occurs in about 20% of cases. Distinguishing SLE from PE can be difficult. In APS pregnancies, the risk of thrombosis, PE, and FGR are higher than normal. Doppler studies have shown that increased impedance in the umbilical and uterine arteries is associated with greater risk of PE and FGR in pregnancies complicated by SLE or APS.
This document summarizes key information about immunological diseases that can affect pregnancy, including antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), and idiopathic thrombocytopenic purpura (ITP). It discusses the pathogenesis, diagnosis, and management of these conditions. For APS, it describes how antiphospholipid antibodies can cause pregnancy complications like miscarriage and preeclampsia. Treatment involves low molecular weight heparin and aspirin. For ITP, it explains how antibodies destroy platelets, increasing bleeding risk, and treatment may involve corticosteroids and IVIG when platelet counts are low.
This document summarizes research on using traditional Chinese medicine (TCM) to treat female infertility caused by high follicle-stimulating hormone (FSH) levels. It discusses how high FSH affects fertility, potential causes, and TCM perspectives on the condition. The author analyzes TCM treatment principles and provides case studies to illustrate how combining herbal remedies and acupuncture following TCM diagnosis can effectively restore ovarian function and balance hormones to address the root causes of high FSH levels.
This document discusses fetal monitoring techniques during labor and delivery. It notes that electronic fetal monitoring (EFM) is associated with decreased mortality but increased cesarean rates compared to auscultation. The document then focuses on fetal ST analysis (STAN), which analyzes changes in the fetal ECG that indicate hypoxia. Studies in the UK and Sweden found that combining EFM with STAN reduced metabolic acidosis in umbilical cord blood gases and lowered operative delivery rates compared to EFM alone. STAN provides a more precise assessment of fetal condition during labor to guide management and avoid unnecessary interventions.
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive functioning. Exercise boosts blood flow, releases endorphins, and promotes changes in the brain which help regulate emotions and stress levels.
LOD: Participant Behaviors and Social EngagementPerformics
The document summarizes key findings from a study about people's daily use of media and their dependence on different devices. Some of the main findings presented include:
- People spend more time on their mobile (20% after 5 minutes, 52% after 1 hour) and desktop (11% after 5 minutes, 60% after 1 hour) compared to other devices like TV, newspaper, and tablet on their first daily use.
- Younger people aged 18-29 are more dependent on their mobile (78%) compared to older age groups for activities like checking email, social networks, news, and weather.
- If people forget their mobile phone, the top concerns are not being able to make/receive calls
The document provides calculations to analyze lighting and acoustic conditions for two areas - the plants study area and limited edition section - of the Sentul Community Library. For lighting, it calculates daylight factor and artificial lighting requirements for both spaces based on Malaysian standards. It determines that the plants study area has good natural light but may experience glare, while the limited edition section lacks sufficient daylight. For acoustics, it measures external noise levels for the limited edition section during peak and non-peak hours.
Neil Armstrong, the first man to walk on the moon, was from the small town of Wapakoneta, Ohio. His passing at age 82 has deeply impacted the community, where he remains a point of local pride and connection. Many in Wapakoneta have strong childhood memories of Armstrong and his historic moonwalk. A ceremony to honor Armstrong saw 2,500 people gather, where they were asked to "wink at the moon" in his memory when seeing it at night. His legacy continues to inspire the town.
This document appears to be a timeline of events in the history of WPRB radio station. It lists various dates along with names of guests or events that occurred on those dates, including interviews with political and musical figures, broadcasts of sports and other programming, the station switching to FM broadcasting, upgrades to transmission equipment, and milestones in becoming established as a radio station. The timeline spans from December 14, 1955 to February 27, 2019 and tracks the development and growth of WPRB over 64 years.
The document outlines Ericsson's purpose to enable the networked society and details four quality standards to achieve this purpose. The quality standards are to guarantee safety and network integrity, listen to customers to meet and exceed expectations, honor commitments by delivering as promised the first time, and provide lean and agile operations by continuously examining processes.
A 3-day training was held for participants on Farmer Managed Natural Regeneration (FMNR) at the Kiambogoko ADP destination. The training covered FMNR approaches and practices such as identifying regeneration sites, selecting tree stumps, and pruning unwanted stems. Farmers shared experiences of how FMNR has improved soil fertility and pasture, provided firewood and income, and saved time by reducing the need to travel long distances to collect firewood. Challenges included some community members' beliefs that agents are paid to do FMNR and fires/intrusions by neighbors, but overall FMNR has led to increased livestock, food security, and income generation through activities like beekeeping for participating farmers.
El documento describe el proceso de ingeniería de requisitos para el desarrollo de software. Explica que la ingeniería de requisitos incluye actividades como el análisis de requisitos, la definición de requisitos y la especificación de requisitos con el objetivo de definir formalmente las funciones y restricciones del sistema. También señala la importancia de validar los requisitos con los usuarios para asegurar que el sistema satisfaga realmente sus necesidades.
Dokumen tersebut membahas tentang kata ganti dan kata depan. Kata ganti digunakan untuk menggantikan kata benda sedangkan kata depan berfungsi menghubungkan kata dengan kata atau kalimat lain. Terdapat beberapa jenis kata ganti seperti kata ganti orang, milik, penunjuk, dan penghubung. Begitu pula dengan kata depan yang memiliki berbagai fungsi seperti menunjukkan arah, waktu, pelaku, dan hubun
Today the food production industry faces an ever-increasing challenge to feed more, both people and animals, with tightening antibiotic regulations and less land, labor, time and costs. This demand has placed a concentrated importance on livestock feed utilisation as a vital role to achieve future, sustainable global food security.
Dokumen tersebut menjelaskan tentang lima bagian utama geosfer, yaitu litosfer, atmosfer, biosfer, hidrosfer, dan antroposfer beserta contoh fenomena masing-masing.
Dokumen tersebut membahas tentang jenis-jenis imbuhan dalam bahasa Melayu, yaitu imbuhan awalan, akhiran, apitan, sisipan, dan pinjaman. Imbuhan berfungsi untuk melengkapi struktur kalimat secara tata bahasa. Contoh imbuhan dan kalimat yang menggunakannya juga dijelaskan.
1) O documento discute a importância da gestão de custos para as organizações e como os custos podem ser usados como uma ferramenta estratégica.
2) É explicado que os custos são divididos em custos contábeis e custos gerenciais e como a gestão de custos envolve mais do que apenas técnicas contábeis.
3) Os principais tipos de atividades nas organizações são discutidos (atividades fim x atividades meio) e como os gastos em cada uma delas são tratados (custos x desp
5th September 2016 - The Parables of the Hidden treasure and the pearl of gr...Thorn Group Pvt Ltd
The document summarizes Jesus' Parables of the Hidden Treasure and the Pearl of Great Price from the book of Matthew in the Bible. In these parables, Jesus teaches that the kingdom of heaven is of immeasurable value, like a treasure hidden in a field or a pearl of great worth. Both parables involve a man who sells all he possesses to obtain the treasure or pearl, representing how Christians must be willing to give up everything to possess salvation through Jesus Christ. While salvation cannot be bought, believers understand its great worth and value Christ above all things.
Com. Empresarial. Visão Geral do Conteúdo do Semestre.Dayane Dias
Este documento fornece informações sobre como calcular a média de um aluno e as regras para aprovação e reprovação. Também discute dicas para manter a estabilidade no emprego, incluindo manter boas relações, aprender novas habilidades e estar aberto a novas oportunidades.
Este documento analisa os efeitos da Lei de Responsabilidade Fiscal na gestão tributária de municípios da microrregião de Senhor do Bonfim. Apresenta os principais instrumentos de arrecadação tributária municipal e caracteriza os impostos municipais. Discute a origem e os instrumentos relacionados à Lei de Responsabilidade Fiscal, incluindo a dívida ativa municipal. Por fim, faz uma análise dos dados de arrecadação de impostos coletados em cinco municípios entre 2000 e 2009.
1) This study found that in a rat model of pulmonary hypertension (PH), female rats developed more pronounced thickening of small pulmonary arteries compared to male rats. However, only male rats showed infiltration of inflammatory cells in the small pulmonary arteries and associated fibrosis.
2) While peak right ventricular systolic pressure was similar between males and females, male rats had worse survival and more severe right ventricular fibrosis and dysfunction.
3) The results suggest that in PH, females experience greater pulmonary artery remodeling but better survival, while pulmonary and cardiac fibrosis in males leads to more severe right ventricular failure and lower survival rates.
This document discusses preeclampsia (PE), a serious pregnancy complication characterized by high blood pressure and protein in the urine. It summarizes several potential biochemical markers for predicting and diagnosing PE, including PAPP-A, PP13, sFlt-1/PlGF ratio, HbF/A1M, and cystatin C. New algorithms combining multiple factors can achieve prediction rates of 60-100% for early onset PE, but no single marker currently fulfills all the ideal characteristics of being pathogenically central, early-appearing, easy to measure, and highly sensitive and specific.
The document provides calculations to analyze lighting and acoustic conditions for two areas - the plants study area and limited edition section - of the Sentul Community Library. For lighting, it calculates daylight factor and artificial lighting requirements for both spaces based on Malaysian standards. It determines that the plants study area has good natural light but may experience glare, while the limited edition section lacks sufficient daylight. For acoustics, it measures external noise levels for the limited edition section during peak and non-peak hours.
Neil Armstrong, the first man to walk on the moon, was from the small town of Wapakoneta, Ohio. His passing at age 82 has deeply impacted the community, where he remains a point of local pride and connection. Many in Wapakoneta have strong childhood memories of Armstrong and his historic moonwalk. A ceremony to honor Armstrong saw 2,500 people gather, where they were asked to "wink at the moon" in his memory when seeing it at night. His legacy continues to inspire the town.
This document appears to be a timeline of events in the history of WPRB radio station. It lists various dates along with names of guests or events that occurred on those dates, including interviews with political and musical figures, broadcasts of sports and other programming, the station switching to FM broadcasting, upgrades to transmission equipment, and milestones in becoming established as a radio station. The timeline spans from December 14, 1955 to February 27, 2019 and tracks the development and growth of WPRB over 64 years.
The document outlines Ericsson's purpose to enable the networked society and details four quality standards to achieve this purpose. The quality standards are to guarantee safety and network integrity, listen to customers to meet and exceed expectations, honor commitments by delivering as promised the first time, and provide lean and agile operations by continuously examining processes.
A 3-day training was held for participants on Farmer Managed Natural Regeneration (FMNR) at the Kiambogoko ADP destination. The training covered FMNR approaches and practices such as identifying regeneration sites, selecting tree stumps, and pruning unwanted stems. Farmers shared experiences of how FMNR has improved soil fertility and pasture, provided firewood and income, and saved time by reducing the need to travel long distances to collect firewood. Challenges included some community members' beliefs that agents are paid to do FMNR and fires/intrusions by neighbors, but overall FMNR has led to increased livestock, food security, and income generation through activities like beekeeping for participating farmers.
El documento describe el proceso de ingeniería de requisitos para el desarrollo de software. Explica que la ingeniería de requisitos incluye actividades como el análisis de requisitos, la definición de requisitos y la especificación de requisitos con el objetivo de definir formalmente las funciones y restricciones del sistema. También señala la importancia de validar los requisitos con los usuarios para asegurar que el sistema satisfaga realmente sus necesidades.
Dokumen tersebut membahas tentang kata ganti dan kata depan. Kata ganti digunakan untuk menggantikan kata benda sedangkan kata depan berfungsi menghubungkan kata dengan kata atau kalimat lain. Terdapat beberapa jenis kata ganti seperti kata ganti orang, milik, penunjuk, dan penghubung. Begitu pula dengan kata depan yang memiliki berbagai fungsi seperti menunjukkan arah, waktu, pelaku, dan hubun
Today the food production industry faces an ever-increasing challenge to feed more, both people and animals, with tightening antibiotic regulations and less land, labor, time and costs. This demand has placed a concentrated importance on livestock feed utilisation as a vital role to achieve future, sustainable global food security.
Dokumen tersebut menjelaskan tentang lima bagian utama geosfer, yaitu litosfer, atmosfer, biosfer, hidrosfer, dan antroposfer beserta contoh fenomena masing-masing.
Dokumen tersebut membahas tentang jenis-jenis imbuhan dalam bahasa Melayu, yaitu imbuhan awalan, akhiran, apitan, sisipan, dan pinjaman. Imbuhan berfungsi untuk melengkapi struktur kalimat secara tata bahasa. Contoh imbuhan dan kalimat yang menggunakannya juga dijelaskan.
1) O documento discute a importância da gestão de custos para as organizações e como os custos podem ser usados como uma ferramenta estratégica.
2) É explicado que os custos são divididos em custos contábeis e custos gerenciais e como a gestão de custos envolve mais do que apenas técnicas contábeis.
3) Os principais tipos de atividades nas organizações são discutidos (atividades fim x atividades meio) e como os gastos em cada uma delas são tratados (custos x desp
5th September 2016 - The Parables of the Hidden treasure and the pearl of gr...Thorn Group Pvt Ltd
The document summarizes Jesus' Parables of the Hidden Treasure and the Pearl of Great Price from the book of Matthew in the Bible. In these parables, Jesus teaches that the kingdom of heaven is of immeasurable value, like a treasure hidden in a field or a pearl of great worth. Both parables involve a man who sells all he possesses to obtain the treasure or pearl, representing how Christians must be willing to give up everything to possess salvation through Jesus Christ. While salvation cannot be bought, believers understand its great worth and value Christ above all things.
Com. Empresarial. Visão Geral do Conteúdo do Semestre.Dayane Dias
Este documento fornece informações sobre como calcular a média de um aluno e as regras para aprovação e reprovação. Também discute dicas para manter a estabilidade no emprego, incluindo manter boas relações, aprender novas habilidades e estar aberto a novas oportunidades.
Este documento analisa os efeitos da Lei de Responsabilidade Fiscal na gestão tributária de municípios da microrregião de Senhor do Bonfim. Apresenta os principais instrumentos de arrecadação tributária municipal e caracteriza os impostos municipais. Discute a origem e os instrumentos relacionados à Lei de Responsabilidade Fiscal, incluindo a dívida ativa municipal. Por fim, faz uma análise dos dados de arrecadação de impostos coletados em cinco municípios entre 2000 e 2009.
1) This study found that in a rat model of pulmonary hypertension (PH), female rats developed more pronounced thickening of small pulmonary arteries compared to male rats. However, only male rats showed infiltration of inflammatory cells in the small pulmonary arteries and associated fibrosis.
2) While peak right ventricular systolic pressure was similar between males and females, male rats had worse survival and more severe right ventricular fibrosis and dysfunction.
3) The results suggest that in PH, females experience greater pulmonary artery remodeling but better survival, while pulmonary and cardiac fibrosis in males leads to more severe right ventricular failure and lower survival rates.
This document discusses preeclampsia (PE), a serious pregnancy complication characterized by high blood pressure and protein in the urine. It summarizes several potential biochemical markers for predicting and diagnosing PE, including PAPP-A, PP13, sFlt-1/PlGF ratio, HbF/A1M, and cystatin C. New algorithms combining multiple factors can achieve prediction rates of 60-100% for early onset PE, but no single marker currently fulfills all the ideal characteristics of being pathogenically central, early-appearing, easy to measure, and highly sensitive and specific.
This study analyzed 10,280 IVF cycles to determine if different ratios of administered luteinizing hormone (LH) to follicle-stimulating hormone (FSH) during ovarian stimulation impact the risk of clinically significant late follicular progesterone (P) elevations. The study found:
1) Stimulations using no administered LH had the highest risk of P elevation, while a ratio of 0.30-0.60 LH to FSH was associated with the lowest risk.
2) Ratios <0.30 or >0.60 LH to FSH were associated with increased risk of P elevation compared to a 0.30-0.60 ratio.
3) This relationship between LH
This study analyzed 10,280 IVF cycles to determine if different ratios of administered luteinizing hormone (LH) to follicle-stimulating hormone (FSH) during ovarian stimulation impact the risk of clinically significant late follicular progesterone (P) elevations. The study found:
1) Stimulations using no administered LH had the highest risk of P elevation, while a ratio of 0.30-0.60 LH to FSH had the lowest risk.
2) Ratios <0.30 or >0.60 LH to FSH were associated with an increased risk of P elevation compared to a 0.30-0.60 ratio.
3) This relationship between LH/F
This study analyzed 10,280 first in vitro fertilization (IVF) cycles to determine if different ratios of administered luteinizing hormone (LH) to follicle-stimulating hormone (FSH) during ovarian stimulation influence the risk of clinically significant late follicular increases in progesterone (P) levels. The study found that stimulations using no administered LH had the highest risk, while a ratio of 0.30-0.60 LH to FSH was associated with the lowest risk. Ratios below 0.30 or above 0.60 were associated with increased risk. This relationship held true when accounting for low, normal, and high ovarian response. Optimizing the LH to FSH ratio during gonadotrop
This study analyzed 10,280 first in vitro fertilization (IVF) cycles to determine if different ratios of administered luteinizing hormone (LH) to follicle-stimulating hormone (FSH) during ovarian stimulation influence the risk of clinically significant late follicular increases in progesterone (P) levels. The study found that stimulations using no administered LH had the highest risk, while a ratio of 0.30-0.60 LH to FSH was associated with the lowest risk. Ratios below 0.30 or above 0.60 were linked to increased risk. This relationship held true when accounting for ovarian response. The findings suggest optimizing the LH to FSH ratio during IVF stimulation may help mitigate premature
This study examined the relationship between maternal consumption of polyphenol-rich foods late in pregnancy and fetal ductus arteriosus flow dynamics. Doppler ultrasound was used to compare ductal velocities and right-to-left ventricular dimensions in 102 fetuses exposed to high maternal polyphenol intake versus 41 unexposed fetuses. Exposed fetuses had higher ductal velocities and right-to-left ventricular ratios, suggesting maternal polyphenol-rich food intake may influence fetal ductal dynamics by inhibiting prostaglandin synthesis, similarly to non-steroidal anti-inflammatory drugs. As polyphenol-rich foods are commonly consumed during pregnancy, their effects on the fetal ductus warrant further consideration.
This thesis examines the expression of the relaxin receptor RXFP1 in reproductive tissues from normotensive and preeclamptic women. The student demonstrates expression of Rxfp1 in human umbilical vein endothelial cells and in the placenta, with no significant change in expression levels between normotensive and preeclamptic women. However, the correlation between Rxfp1 and relaxin expression differed between the two groups. RXFP1 was also localized to cells in the Wharton's jelly of the umbilical cord, suggesting a potential new role for relaxin in extracellular matrix turnover and blood flow to the fetus. Bioinformatics analysis supported these findings regarding the importance of RXFP1 expression
This study examined the effects of maternal consumption of polyphenol-rich foods during late pregnancy on fetal ductus arteriosus blood flow dynamics. Doppler ultrasound was used to compare ductal blood flow velocities and right-to-left ventricular dimensions in 102 fetuses exposed to high maternal polyphenol intake versus 41 unexposed fetuses. Exposed fetuses had higher ductal velocities and right-to-left ventricular ratios, indicating potential inhibition of prostaglandin synthesis from polyphenols and effects on ductal constriction. The findings suggest maternal polyphenol-rich food intake during late pregnancy may impact fetal ductal dynamics and warrant changes to perinatal dietary guidance.
ANESTHETIC PHARMACOLOGY DURING PERINATAL PERIODRajesh Munigial
This document summarizes key aspects of perinatal pharmacology. It discusses the perinatal period and fetal circulation. It describes the three processes of transplacental drug transfer: distribution to the placenta, placental sequestration and metabolism, and transfer to the fetal and maternal circulations. The mechanisms of simple diffusion, facilitated diffusion, active transport, and pinocytosis are explained. Factors affecting transplacental drug transfer like lipid solubility, molecular weight, and protein binding are also summarized. The document concludes by reviewing the pharmacodynamics and pharmacokinetics of various drug classes as they relate to the perinatal period.
recent evidence of unfractionated heparin and aspirin in recurrent miscarriage Ahmed Rafea
Recurrent miscarriage (RM) occurs in 1-2% of women and is emotionally traumatic. While the cause is often unknown, risk factors include anatomical, immune, and thrombotic issues. Low dose aspirin and unfractionated heparin are used to treat RM caused by antiphospholipid syndrome and inherited thrombophilia. Meta-analyses show that combining aspirin and heparin increases live birth rates for women with RM associated with antiphospholipid antibodies. For unexplained RM, aspirin and heparin combined may potentially increase live birth rates by reducing hypercoagulability, though evidence is mixed. Unfractionated heparin is advocated as an effective and low-cost treatment
Preeclampsia is a pregnancy complication characterized by high blood pressure and protein in the urine. It affects over 5-8% of pregnancies worldwide and is a leading cause of maternal and infant illness and death. The condition is caused by poor development of the placenta, which fails to properly remodel the mother's uterine arteries. This results in reduced blood flow to the placenta and release of factors that cause damage to other organs. Risk factors include first pregnancy, obesity, diabetes, and family history. Symptoms range from mild to severe, including headaches, visual issues, pain, and seizures in severe cases. Management involves monitoring and delivery of the baby if the condition worsens. Ongoing research is
A Case Report on Intrahepatic Cholestasis of Pregnancyijtsrd
This case study is about a primigravida mother period of gestation 29 weeks and 5 days diagnosed with intrahepatic cholestasis of pregnancy IHCP . She had been married since 1 year and it is her first pregnancy. The patient is having gestational diabetes mellitus and hypothyroidism. The patients was admitted to antenatal ward of St. Stephen’s Hospital , New Delhi, with chief complaints of itching in palms, soles and over umbilical area since 2 weeks. During the physical examination the rashes were seen on abdomen, legs and breast. Per abdomen examination and ultrasound revealed that vertex presentation of the fetus and FHR as 136 min and fetal weight as 1923 gram and presence of low lying placenta. Routine blood examination revealed that patient was also a case of gestational diabetes mellitus and hypothyroidism. After all the required investigation she was diagnosed with IHCP with gestational diabetes mellitus and hypothyroidism. IHCP is a pregnancy related liver disorder characterized by pruritus, most often in the late second or early trimester of pregnancy and raised serum bile acids. The maternal outcome after treatment is fair but fetal outcomes becomes adverse in most of the conditions. Ms. Rana Kamar | Dr. Rajwant Randhawa | Dr. Priyanaka Choudhary "A Case Report on Intrahepatic Cholestasis of Pregnancy" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-1 , December 2021, URL: https://www.ijtsrd.com/papers/ijtsrd49087.pdf Paper URL: https://www.ijtsrd.com/medicine/nursing/49087/a-case-report-on-intrahepatic-cholestasis-of-pregnancy/ms-rana-kamar
PRE-ECLAMPSIA ECLAMPSIA, BEST PRACTICES.pptxUmarAliyuSaadu
Pre-eclampsia and eclampsia are hypertensive disorders of pregnancy that can cause serious complications for both mother and baby if not properly managed. Pre-eclampsia is defined as new onset hypertension and proteinuria after 20 weeks of gestation, while eclampsia involves seizures in addition to the symptoms of pre-eclampsia. Delivery is the only cure for both conditions, and careful blood pressure management is important for preventing seizures in women with severe pre-eclampsia or eclampsia. Screening and preventive measures like low-dose aspirin can help identify at-risk women earlier and reduce the risk of the conditions.
Efectos fetales de la anestesia espinal maternaAnestesia Dolor
1. Spinal anesthesia is commonly used for cesarean sections due to advantages for the mother such as remaining awake for the birth and facilitating post-op pain relief. However, hypotension is a common side effect that can pose risks to both mother and baby if severe or prolonged.
2. The review found that no single method completely prevents hypotension during spinal anesthesia for c-section but the risk can be reduced through IV fluids, vasopressors like ephedrine or phenylephrine, and leg compression. Even minor hypotension may cause issues for the baby like transient carbon dioxide retention.
3. Fetal oxygenation is dependent on several factors like placental function, uterine and umbilical blood
IVIG may prolong pregnancies complicated by Rh alloimmunization before 18-20 weeks by delaying the onset of severe fetal anemia requiring intrauterine transfusion compared to previous untreated pregnancies. However, the evidence is conflicting and more research is still needed.
This document summarizes an article on persistent pulmonary hypertension of the newborn (PPHN). PPHN is a condition in which newborns fail to lower their pulmonary vascular resistance after birth, leading to hypoxemia. The article discusses normal fetal lung development and the transition to breathing at birth. It also covers the pathophysiology and treatment of PPHN, including use of inhaled nitric oxide and evaluation for underlying lung disorders if the newborn does not respond to initial therapy.
Lh in assisted reproduction by DR G A RAMARAJUG A RAMA Raju
Luteinizing hormone (LH) in synergy with follicle stimulating hormone (FSH) stimulates normal follicular growth and ovulation. FSH is frequently used in assisted reproductive technology (ART). Recent studies have facilitated better understanding on the complementary role of the LH to FSH in regulation of the follicle; however, role of LH in stimulation of follicle, optimal dosage of LH in stimulation and its importance in advanced aged patients has been a topic of discussion among medical fraternity. Though the administration of exogenous LH with FSH is obligatory for controlled ovarian stimulation in patients with hypogonadotropic hypogonadism, there is still a paucity of information of its usage in other patient population.A Brief introduction of Lh polymorphism in ovarian stimulation
This document discusses fetal circulation and placental transfer of drugs and anesthetic agents. It begins by describing the fetal circulation and transitional circulation at birth. It then discusses placental anatomy and the various mechanisms by which substances can transfer across the placenta, including diffusion, active transport, bulk flow, and pinocytosis. Several factors that can influence placental transfer are also outlined, including properties of the drug, fetal conditions, maternal conditions, and placental factors. Specific details are provided about the placental transfer and effects of various inhaled anesthetics, intravenous drugs, opioids, benzodiazepines, and local anesthetics.
1.
Erythropoietin and soluble erythropoietin receptor: a role for maternal
vascular adaptation to high altitude pregnancy
Gabriel H. Wolfson, Enrique Vargas, Vaughn A. Browne, Lorna G. Moore, Colleen G.
Julian
The Journal of Clinical Endocrinology & Metabolism
The Endocrine Society
Submitted: March 28, 2016
Accepted: November 01, 2016
First Online: November 03 , 2016
Early Release articles are PDF versions of manuscripts that have been peer reviewed and accepted
but not yet copyedited. The manuscripts are published online as soon as possible after acceptance
and before the copyedited, typeset articles are published. They are posted "as is" (i.e., as
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The Journal of Clinical Endocrinology & Metabolism; Copyright 2016 DOI: 10.1210/jc.2016-1767
Erythropoietin and soluble erythropoietin receptor: a role for maternal
vascular adaptation to high altitude pregnancy
Gabriel H. Wolfson 1
, Enrique Vargas 2
, Vaughn A. Browne 3
, Lorna G. Moore 4
, Colleen G.
Julian 1
1
Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
2
Bolivian Institute of High Altitude Biology, La Paz, Bolivia
3
Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
4
Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, USA
Received 28 March 2016. Accepted 01 November 2016.
Epo and sEpoR during pregnancy at high altitude
Corresponding Address: Colleen G. Julian, PhD, Department of Medicine, University
of Colorado Denver, 12700 E 19th
Avenue, Mailstop 8611, 3rd
Floor Research Complex
2, Aurora, CO 80045, Email: colleen.julian@ucdenver.edu, Phone: 303-724-644 | Fax:
303-724-1799
Supporting Grants: U.S. National Institutes of Health (NIH) Building Interdisciplinary
Research Careers Women's Health grant (5 K12 HD057022-07; CGJ) and NIH-HL079647
(LGM). No funding source was involved in the design, conduct, interpretation of data; in the
writing of the report; or in the decision to submit this article for publication.
Context: An imbalance of pro- and anti-angiogenic factors is thought to be central to the
widespread vascular dysfunction characteristic to preeclampsia (PreE). Erythropoietin (Epo), a
pleiotrophic cytokine known for its erythropoietic effects, has important angiogenic and
vasoactive properties, however its contribution to impaired maternal vascular responses in PreE
is unknown. Objective(s): Since chronic hypoxia raises the incidence of PreE we asked whether
the chronic hypoxia of high altitude (HA) increased maternal Epo and soluble Epo receptor
(sEpoR) levels, and whether such effects differed between PreE cases and normotensive controls
at HA. Design, Setting and Participants: Longitudinal studies were conducted in pregnant,
Andean HA (n=28; 3600 m) or sea level (SL, n=16; 300 m) residents. Cross-sectional studies
included 34 gestational-age matched Andean PreE cases (n=17) and controls (n=17) in La Paz-El
Alto, Bolivia (3600m – 4100m). Results: HA augmented the pregnancy-associated rise in Epo
relative to SL (P=0.002), despite a similar reduction of Hb concentration across pregnancy at
each altitude (7-9%, both P<0.001). HA PreE cases had equivalent circulating Epo levels
compared to normotensive controls, but greater sEpoR values (P<0.05) and reduced hemoglobin
(P=0.06, trend). Conclusion(s): Chronic hypoxia augments the pregnancy-associated rise in Epo
but has no effect on maternal sEpoR, an effect that may be important for successful vascular
adaptation to pregnancy at HA. In contrast, we speculate that elevated sEpoR observed in PreE
cases vs. controls at HA impedes Epo-stimulated angiogenesis, vasodilation and the maintenance
of endothelial function and may thereby be of pathophysiological relevance for increased
incidence of PreE at HA.
PRECIS: Chronic hypoxia augments the pregnancy-associated rise in Epo but has no effect on sEpoR,
an effect that may be important for vascular adaptation to pregnancy.
Introduction
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The Journal of Clinical Endocrinology & Metabolism; Copyright 2016 DOI: 10.1210/jc.2016-1767
Preeclampsia (PreE) is a multisystem vascular disease that complicates roughly 8.5 million
pregnancies each year and accounts for 40% of fetal mortality and 18% of maternal deaths.1
PreE
and fetal growth restriction often coexist and account for nearly 30% of premature deliveries
with an estimated economic cost of $8.7 billion.2,3
Among the numerous factors known to
increase the risk of PreE are pre-existing vascular disease, primiparity, advanced maternal age
and hypoxia such as that experienced at high altitude (HA, ≥ 2500 m). HA residence raises the
incidence of PreE threefold, highlighting the clinical relevance of persistent maternal hypoxia for
hypertensive pregnancy disorders.4,5
Successful pregnancy is accompanied by pronounced, systemic arterial and venous
vasodilation, a 30% rise in cardiac output 6
and extensive remodeling of the maternal spiral
arteries that ultimately facilitate perfusion of the placental bed. In PreE a blunted maternal
vasodilatory response to pregnancy and incomplete remodeling of the decidual and myometrial
spiral arteries limits placental perfusion, thereby leading to hemodynamic and oxidative placental
stress.7,8
As a result, the PreE placenta is thought to release antiangiogenic and proinflammatory
factors into the maternal circulation and initiate the widespread maternal vascular endothelial
dysfunction hallmark to PreE.9-12
Placental expression of the antiangiogenic factor soluble fms-
like protein kinase 1 (sFlt1), for instance, is markedly greater in PreE, and paralleled by elevated
sFlt1 in the maternal circulation.9-12
Previous studies have focused on the roles of sFlt1, placental
growth factor and soluble endoglin in the angiogenic imbalance characteristic of PreE.9-12
We
consider the role of another angiogenic factor, erythropoietin (Epo) and its receptor (EpoR),
which are both regulated by hypoxia and thought to be essential for endothelial function and
vascular homeostasis.
Epo is the master regulator of hypoxia-induced erythropoiesis, yet it has several other
functions that promote successful placentation and vascular adaptation to pregnancy. Functional
Epo membrane bound receptors (mEpoR) are present not only on erythroid progenitors but also
vascular endothelial cells.13
Highlighting its pleiotrophic nature, Epo acts as a potent angiogenic
factor, promotes neovascularization, induces endothelial nitric oxide synthase (eNOS) activity
and enhances vascular repair in response to mechanical or ischemia-reperfusion injury.14-19
Further, Epo enhances trophoblast and decidual stromal cell proliferation and survival in early
human pregnancy.20
Alternative EpoR mRNA splicing produces a soluble form of EpoR (sEpoR) that is
present in human peripheral blood, and directly competes with mEpoR for unbound, circulating
Epo;21
in this way, sEpoR impairs Epo signaling and Epo-mediated erythropoiesis.22
We
hypothesized that HA would augment the pregnancy-induced rise in Epo and possibly reduce
sEpoR levels. Further, we expected that such changes were absent or compromised in PreE or, in
other words, that PreE women would have lower Epo and higher sEpoR levels than
normotensive controls at HA. To the best of our knowledge, this is the first study to (1) measure
sEpoR during pregnancy at any altitude, (2) compare changes in Epo and sEpoR levels during
pregnancy at sea level (SL) vs. HA, and (3) contrast Epo or sEpoR values between normotensive
and PreE pregnancy at HA.
Materials and Methods
Study Populations.
A longitudinal and cross-sectional cohort were included for study. Cohort I consisted of 48
Andean women residing at HA (n=28; 3600 – 4300 m) or SL (n=16; 300 m) who remained
normotensive throughout pregnancy. These women were participants in a larger investigation
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The Journal of Clinical Endocrinology & Metabolism; Copyright 2016 DOI: 10.1210/jc.2016-1767
designed to identify physiologic and genetic components of hypoxia-associated intrauterine
growth restriction.23,24
Subjects were studied longitudinally to determine whether HA altered the
magnitude and pattern of Epo and sEpoR across normotensive pregnancy. Subjects were referred
by their prenatal care provider. For inclusion, women were required to be receiving prenatal
care, having a singleton pregnancy, to be at no known risk for pregnancy complications (e.g.,
diabetes, preexisting hypertension, cardiovascular disease, history of gestational diabetes), and to
self-identify as being of Aymara or Quechua descent. Only women with serial samples for study
points of interest (20 and 36 weeks of pregnancy and 3-4 months post-partum) were included for
analysis. We excluded smokers and those with active infections. All women completed a health
and demographic questionnaire to determine her age, parity, duration of residence at current
altitude, and medical and reproductive history. All subjects also underwent an obstetrical exam.
During the physical exam, we measured bilateral upper extremity blood pressures (BP), height,
and weight. Urine samples were collected to screen for infection and proteinuria. Non-fasting
maternal venous blood samples were drawn between 09:00 and 11:00 am from an antecubital
vein into EDTA collection tubes using standard techniques; the plasma was then separated and
stored at -80o
C until analysis. HA studies were conducted at the Bolivian Institute of High
Altitude Biology (IBBA) and the Southern Clinic in La Paz-El Alto, Bolivia. SL studies were
performed at the Siraní Clinic in Santa Cruz de la Sierra, Bolivia.
Cohort II, the cross-sectional cohort, consisted of 34 pregnant Andean women who presented
for obstetrical care at five hospitals (Hospital de Los Andes, n=19; Bolivia-Holandés, n=5;
Materno-Infantil, n=9; Hospital de la Mujer, n=1) in La Paz-El Alto, Bolivia. Subjects included
normotensive controls (n=17) and PreE (n=17) cases matched by gestational age within two
weeks at the time of sampling (mean gestational age for sampling were 34.2 2.2 vs. 35.6 3.0
weeks for normotensive controls and PreE cases, respectively). PreE cases were recruited within
the first 24 hrs after diagnosis, blood samples obtained as described above after treatment with
alpha methyldopa and magnesium sulfate, which are standard of care in Bolivia. For ethical
reasons it wasn’t possible to delay treatment for research purposes therefore blood samples had
to be obtained post-treatment. Inclusion and exclusion criteria were the same as those described
for Cohort I. None of the normotensive controls developed PreE later in pregnancy.
All subjects gave written informed consent to study procedures that had been approved by
the Colorado Multiple Institutional Review Board and the Colégio Médico, its Bolivian
counterpart.
Definitions.
PreE women were normotensive before pregnancy but developed elevated systolic (>140
mmHg) and diastolic (>90 mmHg) pressures after 20 weeks. PreE was distinguished from
gestational hypertension by the presence of ≥1+ proteinuria at presentation and confirmed by
≥300 mg in a 24-h urine collection. In all cases, BP and proteinuria measurements obtained
before the initiation of treatment were used to classify subjects as PreE. Gestational week was
based on the date of last menstrual period and confirmed by fetal biometry at week 20 or clinical
assessment at delivery.
Assessment of Epo and sEpoR levels.
Plasma Epo and sEpoR were measured in duplicate using commercially available solid-phase
sandwich ELISA kits (R&D Systems, Inc. MN, USA) according to manufacturer specifications.
Detection ranges for the Epo and sEpoR ELISA kits are 2.5 – 200 mIU/ml and 62.50 - 4,000
pg/ml, respectively. Intra- and inter-assay variability for Epo ELISA kits are 2.8-5.2 % CV and
4.2-8.3 % CV, as indicated by R&D Systems. For sEpoR, the manufacturer does not report intra-
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The Journal of Clinical Endocrinology & Metabolism; Copyright 2016 DOI: 10.1210/jc.2016-1767
or inter-assay variability; we calculated an sEpoR intra-assay % CV of 6.9-12.9 and an inter-
assay % CV of 1.5-13.8. Samples with undetectable Epo or sEpoR levels were assigned the value
of the lower detection limit value (2.5 mIU/ml and 62.5 pg/ml, respectively).
Blood volume.
For the measurement of blood volume (BV), subjects breathed through a rebreathing circuit
initially containing 100% O2, from which CO2 was continuously removed and 100% O2
periodically added. A venous blood sample was withdrawn from an indwelling catheter after 5
min of quiet breathing. Carbon monoxide (CO, 100%, 60 ml ATP) was added to the rebreathing
circuit, and additional blood samples obtained after 10 and 15 min of rebreathing. The percent
CO-Hb rose from ∼2% to 6–8%, as measured in triplicate by OSM3 (Radiometer, Copenhagen,
Denmark). Total BV was calculated using the equation [CO added/ΔCO content] × [1/Hb] × 100
where CO is the volume of CO added to the rebreathing circuit, ΔCO content is the difference in
CO content between the baseline and the average of the 10- and 15-min values, and Hb is the
measured Hb concentration using the cyanmethemoglobin technique. RCM was calculated as
total BV multiplied by hematocrit (Hct) as determined by using the microcentrifuge technique
after correcting for trapped plasma using the constant 0.98,25
and the remainder considered
plasma volume (PV). Hb and Hct were measured in triplicate.
Statistical Analysis.
In the text, tables, and figures, data are expressed as means ± SD or percentages with 95%
confidence intervals after normality was affirmed using Kolmogorov and Smirnov tests. Pearson
correlation was used to identify the potential influence of gestational age at the time of sampling
and maternal characteristics (age, parity, weight) for our primary outcome variables (i.e., Epo
and sEpoR); none were significant in either cohort and were thus not included as covariates.
Repeated measures 2-way ANOVA with Sidak’s corrections for multiple comparisons were used
to compare continuous variables between altitudes across pregnancy. Paired t-tests were used to
compare continuous variables between gestational age matched normotensive controls and PreE
cases. Proportions were compared using Fisher's exact test. Pearson correlation and linear
regression were used to determine the relationship between Epo and indicators of pregnancy-
induced hemodilution. All analyses were conducted using SPSS 24.0 (IBM Corp, Armonk, NY)
and considered significant when P < 0.05. Sample sizes and statistical tests are noted for each
table and figure, as appropriate.
Results
Maternal, newborn and delivery characteristics (Table 1).
Cohort I:
Women studied longitudinally at SL and HA were similar in age (26.4 1.2 vs. 27.2 1.3 years)
and lived at their current altitude of residence for the vast majority of their life (20.5 7.6 and
21.7 9.1 years, respectively). HA women were of greater parity (1.6 0.8 vs. 2.9 1.9 live
births, p<0.05) and shorter stature than their SL counterparts (p<0.001, Table 1). Compared to
LA, HA women gained less weight from 20 to 36 weeks of pregnancy (p<0.05), and weighed
less at 36 weeks and postpartum (p <0.01, each).
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The Journal of Clinical Endocrinology & Metabolism; Copyright 2016 DOI: 10.1210/jc.2016-1767
Infants born to SL and HA women were equivalent with respect to gestational age at
birth, ponderal index, Apgar scores (1 or 5 minutes), sex as well as the proportion born IUGR
(18.8% and 8.7%, respectively) or premature (12.5% and 8.0%, respectively; all p=NS). Eighty
percent (80%) of SL infants were delivered by cesarean section versus 18% of HA infants
(p<0.05, Table 1). Compared to LA, birth weight (p=0.09), length (p=0.08) and head
circumference (p<0.01) were or tended to be reduced in HA newborns.
Cohort II:
In the cross-sectional cohort, normotensive and PreE women were of similar age 25.8 2.8 and
28.0 7.0 years), parity (0.7 0.7 and 0.9 1.2 live births) and height (150 4 and 151 9 cm),
and had lived at high altitude for a similar duration (24.8 3.7 and 23.1 9.1, all p=NS). PreE
weighed more than NORM at the time of gestational age-matched sampling (p<0.01, Table 1).
Compared to normotensive cases, PreE infants tended to be born at a younger gestational age
(38.8 1.0 vs 37.5 2.4, p<0.10), and were of lower birth weight and birth length (p<0.05,
both), but with similar head circumference and ponderal index (Table 1). An equivalent
proportion of NORM and PreE infants were female, IUGR or premature (all p=NS, Table 1).
Apgar scores were lower in infants born to PreE women compared to those born to normotensive
controls at 5 minutes (p<0.01), despite similar values at 1 minute. More than half (59%) of PreE
were delivered by cesarean section compared to only 12% of normotensives (p<0.05, Table 1).
Effect of altitude on maternal Epo and sEpoR across pregnancy.
Epo increased with pregnancy at each altitude (Fig. 1A). Epo was equivalent between altitudes in
the non-pregnant state, but values were greater among HA women during pregnancy (2.6 and
2.4-fold greater for 20 and 36 weeks, respectively, with a significant interaction between
pregnancy and altitude, p=0.001). Specifically, Epo rose more sharply and to a greater extent at
HA than SL (Fig. 1A). sEpoR values were consistent across pregnancy at SL and HA and did
not differ between altitudes at any point (Fig. 1B).
As expected, Hb and Hct were greater at HA than SL at all times (Fig. 1C & D). Notably,
however, the magnitude by which pregnancy lowered Hb and Hct was equivalent between
altitudes (7 - 9 % drop by 36 weeks) despite vastly different Epo profiles. Given this observation
we subsequently tested whether HA modified the relationship between Epo and Hb or Hct. At
HA Epo was negatively associated with Hb and Hct at all times but at SL, Epo was independent
of Hb and Hct at 36 weeks and post-partum, and tended to be positively associated with Hb and
Hct at 20 weeks (Fig. 2A-C). As a result, the relationship between Epo and Hct differed between
altitudes, with an inverse relationship being present at HA at all time points but either absent
(nonpregnant and week 36, Fig 2A & C) or opposite in direction (week 20, Fig 2B) at SL. In
contrast, sEpoR was unrelated to Hb or Hct at either altitude with the exception of the non-
pregnant state at HA (Hb: r = -0.33, P=0.04, Hct: r = -0.38, P=0.02)
Relationship of BV and Epo during HA pregnancy.
Compared to the non-pregnant state, total BV, expressed either as an absolute value or per kg,
rose across normotensive pregnancy due to a 28% expansion of total PV by 36 weeks and a
lesser, but statistically significant, 17% increase in total RCM across the same time frame (Fig.
3A-C). Epo was not associated with PV or RCM in the non-pregnant state but, as expected, was
positively associated with PV (mL/kg) during pregnancy (20 weeks: r = 0.33, P=0.04; 36 weeks:
r = 0.35, P=0.04) and inversely related to RCM (mL/kg) at 36 weeks (r = - 0.39, P=0.02).
Effect of PreE on maternal Epo and sEpoR.
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Compared to normotensive controls PreE women had higher sEpoR values (322.7 401.8 vs.
72.2 40.1, respectively; P=0.02) (Fig. 4A). In contrast, Epo values were similar between PreE
and controls, and Hb tended to be lower (P=NS and P=0.06, respectively) (Fig. 4B and C).
Discussion
Our findings demonstrate that environmental hypoxia increases the pregnancy-associated rise in
Epo, despite a similar reduction in Hb across pregnancy at each altitude. Maternal sEpoR levels,
on the other hand, were unaffected by HA during normotensive pregnancy or in the non-
pregnant, postpartum state. Compared to normotensive women at HA PreE cases had similar Epo
but higher sEpoR, which may reduce Epo bioavailability and thereby impair Epo-mediated
responses necessary for vascular adaptation to pregnancy. In vitro studies indicating that
recombinant sEpoR inhibits Epo mediated Stat-5 phosphorylation in BaF/EpoR cells support this
possibility.22
Extensive hematological and ventilatory adaptations during pregnancy serve to maintain
maternal CaO2 and, in turn, support maternal and fetal metabolism.6
Such adaptations include a
pronounced expansion of PV and a smaller, yet significant, increase in RCM that is paralleled by
rising maternal Epo. This pregnancy-associated rise in Epo reflects augmented production rather
than reduced clearance.26
Consistent with existing literature, our data indicate that maternal Epo
increases approximately twofold across normotensive, SL pregnancy.27
Notably, however,
among normotensive, HA women Epo was twofold greater compared to SL at 20 and 36 weeks
despite being similar in the non-pregnant, postpartum state. Our findings agree with those of a
cross-sectional study indicating higher maternal Epo at HA relative to SL at the time of
delivery28
and, to the best of our knowledge, are the first prospective comparison of Epo across
pregnancy between HA and SL.
The source of the elevated basal maternal Epo levels during uncomplicated HA vs. SL
pregnancy is unknown, but is likely placental in origin. First, Epo produced by fetal tissues,
primarily hepatocytes, does not cross the placental barrier 29
and therefore cannot be responsible
for rising maternal Epo levels during gestation. Second, because renal blood flow and
oxygenation rise during uncomplicated pregnancy and is preserved during acute exposure to mild
or moderate hypoxia,30-32
it is unlikely that hypoxia-induced renal Epo production accounts for
the elevated Epo levels we observed at HA. Third, as previously reported maternal Hb is
consistently greater during HA pregnancy relative to SL,33
but dropped similarly at each altitude
across gestation; this suggests that plasma volume expansion was also similar between altitudes.
Thus, excessive hemodilutional anemia does not appear to trigger the elevated Epo production at
HA vs. SL during pregnancy. Finally, placental Epo production is highly sensitive to maternal
oxygenation, as indicated by the effect of maternal hypoxia to raise the estimated umbilical Epo
secretion rate of 27,900 mU/min in an in vivo ovine model.34
We speculate that the non-hematopoetic actions of Epo, including enhanced eNOS
activation and endothelium-dependent vasodilation, stimulation of angiogenesis, and induction
of placental growth factor,14,15,17-19,35
support the preservation of placental and maternal vascular
adaptations that are essential for successful pregnancy under conditions of chronic hypoxia.
Using this logic, we would expect elevated sEpoR, such as those we observed in PreE vs.
normotensive controls at HA, to impair Epo-mediated vascular responses. On the other hand
excessive placental Epo may be maladaptive by, for example, preventing the extensive vascular
cell apoptosis and extracellular matrix decomposition that is essential for complete remodeling of
the spiral arteries 20
. In line with this possibility, some reports indicate that maternal Epo is
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elevated in cases of abnormal placentation or PreE,36,37
a putatively compensatory response to
impaired placental and renal perfusion. In support of a causal relationship, however, the
therapeutic use of recombinant human Epo (rhEpo) for renal anemia during pregnancy evokes
systemic arterial hypertension.38
Moreover, rhEpo treatment induced vasoconstriction of isolated
human placental vessels studied in vitro, suggesting that Epo participates in the vasoregulation of
the placental vascular bed in ways that are likely of pathophysiological importance for PreE.39
Therefore, we cannot exclude the possibility that the enhanced pregnancy-associated rise in Epo
observed at HA contributes to the modest impairment of vascular adaptation characteristic to
uncomplicated HA pregnancy or the increased incidence of PreE or IUGR.24
However, we found
that Epo values were equivalent in PreE and normotensive pregnancy, an observation that is
similar to other reports (e.g., 40
) and does not suggest elevated Epo levels are linked to PreE.
Existing literature strongly indicates a positive association between maternal Hb,
contracted plasma volume and pregnancy-induced hypertension at low altitude.41,42
Our finding
that Hb was marginally lower in PreE compared to normotensive controls suggests that maternal
Hb values within the range reported to be associated with minimal risk of stillbirth, prematurity
or small-for-gestational-age birth at HA (11 to 13.6 g/dL) also do not influence the risk of
PreE.33
One explanation for the modestly lower Hb levels we observed in PreE may be that the
excessive inflammation in PreE dampens erythroid progenitor responsiveness to Epo and thereby
impairs Epo-mediated erythropoiesis,43
as appears to be the case for anemia associated with other
inflammatory conditions such as chronic kidney disease.44,45
Such effects may be the due to the
capacity of endogenous cytokines (e.g., interferon gamma, interleukin 6 [IL6]) and T-cell
activation to diminish erythroid progenitor responsiveness to Epo, or to regulate sEpoR
production. Khankin, et al. demonstrated a link between inflammation and Epo resistance,
reporting increased sEpoR levels in human erythroleukemia cells stimulated with IL6 and tumor
necrosis factor alpha compared to untreated cells.22
Thus, the elevated sEpoR we observed in
PreE may be stimulated by inflammatory cytokines. In support of this possibility, we have
previously shown that HA women with PreE have higher IL6 and IL8 compared to normotensive
controls.46
Moreover, elevated Epo levels in PreE have been shown to be unassociated with
circulating erythroblasts, further suggesting that responsiveness to Epo is impaired in PreE.37
Finally, the elevated sEpoR levels we observed in PreE may impair Epo-mediated erythropoiesis
and thereby reduce maternal Hb levels.22
Our findings suggest that Epo and sEpoR play important roles in maternal vascular
responses to pregnancy at high altitude. We speculate that the enhanced pregnancy-induced rise
in Epo at HA serves to maintain uteroplacental blood flow during hypoxic pregnancy. We further
propose that enhanced sEpoR levels may be of pathophysiological relevance for the onset of
PreE, and the elevated PreE incidence at high altitude by impeding Epo-stimulated angiogenesis,
vasodilation and the maintenance of endothelial function. Further work, utilizing more sensitive
methods to detect circulating sEpoR levels and experimental animal studies, including rhEpo or
Epo antagonist treatment, are needed to understand the effect of sEpoR for Epo bioavailability
during pregnancy and its impact on pregnancy outcome. Such studies may improve methods for
the early detection of vascular disorders during pregnancy or reveal novel therapeutic avenues
for PreE.
Acknowledgement(s).
The authors acknowledge all of the women who participated in this project. Their appreciation is
also extended to physicians and technical staff at the IBBA and Clinica Siraní for their assistance
with the conduct of this project.
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Disclosure Statement: The authors report no conflict of interest.
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1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in
preeclampsia. J Clin Invest. 2003;111(5):649-658.
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promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res.
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one. 2010;5(2):e9246.
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Erythropoietin does not cross the placenta into the fetus. Pathobiology. 1993;61(3-4):211-215.
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35. Gonsalves CS, Li C, Mpollo MS, et al. Erythropoietin-mediated expression of placenta
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36. Goldstein JD, Garry DJ, Maulik D. Obstetric conditions and erythropoietin levels. Am J
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37. Troeger C, Holzgreve W, Ladewig A, Zhong XY, Hahn S. Examination of maternal
plasma erythropoietin and activin A concentrations with regard to circulatory erythroblast levels
in normal and preeclamptic pregnancies. Fetal Diagn Ther. 2006;21(1):156-160.
38. Kashiwagi M, Breymann C, Huch R, Huch A. Hypertension in a pregnancy with renal
anemia after recombinant human erythropoietin (rhEPO) therapy. Arch Gynecol Obstet.
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39. Resch BE, Gaspar R, Sonkodi S, Falkay G. Vasoactive effects of erythropoietin on
human placental blood vessels in vitro. Am J Obstet Gynecol. 2003;188(4):993-996.
40. Hershkovitz R, Ohel I, Sheizaf B, et al. Erythropoietin concentration among patients with
and without preeclampsia. Arch Gynecol Obstet. 2005;273(3):140-143.
41. Knottnerus JA, Delgado LR, Knipschild PG, Essed GG, Smits F. Haematologic
parameters and pregnancy outcome. A prospective cohort study in the third trimester. J Clin
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42. Murphy JF, O'Riordan J, Newcombe RG, Coles EC, Pearson JF. Relation of haemoglobin
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44. Priyadarshi A, Shapiro JI. Erythropoietin resistance in the treatment of the anemia of
chronic renal failure. Semin Dial. 2006;19(4):273-278.
45. Stenvinkel P, Barany P. Anaemia, rHuEPO resistance, and cardiovascular disease in end-
stage renal failure; links to inflammation and oxidative stress. Nephrol Dial Transplant. 2002;17
Suppl 5:32-37.
46. Davila RD, Julian CG, Browne VA, et al. Role of cytokines in altitude-associated
preeclampsia. Pregnancy Hypertens. 2012;2(1):65-70.
Figure 1. Maternal Epo, sEpoR and indices of hemodilution during pregnancy at HA and
SL. Repeated measures 2-way ANOVA with Sidak’s corrections for multiple comparisons were
used to contrast Epo, sEpoR, hemoglobin (Hb) and hematocrit (Hct) levels across pregnancy
between Andean women residing at HA (n=28) versus SL (n=16). Complete Epo, sEpoR, Hb
and Hct data were available for each subject at every study point. Pregnancy increased
circulating Epo levels at HA but not at SL with the result that Epo was greater at 20 and 36
weeks compared to sea-level values (A). sEpoR did not change across pregnancy at either
altitude and values were equivalent between altitudes at each point of study (B). Despite
substantially higher Epo levels during pregnancy at HA, the magnitude of pregnancy-associated
fall in hemoglobin (Hb) and hematocrit (Hct) were similar at each altitude (C & D). As expected
Hb and Hct values were greater at HA than SL at all times. Superscripts a, b,
and c
indicate
significant differences relative to the non-pregnant state, 20 weeks or 36 weeks, respectively.
Significant differences between altitudes are noted by ** (P<0.01) or *** (P<0.001). Data are
shown as the mean ± SD.
Figure 2. Relationship between Epo and Hct at HA vs. SL in the non-pregnant state and
during pregnancy. Linear regression models were used to test whether the relationship (slope)
between Epo and Hct differed between Andean women residing at HA vs. SL in the non-
pregnant, postpartum period, or during pregnancy (20 or 36 weeks). Complete Epo and Hct data
were available for HA (n=28) and SL (n=16) women at all study points. Regression lines and
individual data points for HA (HA: solid line, solid squares) and (SL: dashed line, open circles)
are shown. At SL Epo and Hct are unrelated in the non-pregnant state; in contrast, non-pregnant
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Epo and Hct values are inversely associated at HA (A). At 20 weeks the relationship between
Epo and Hct are significantly different between the two altitudes, as indicated by the HA-SL
slope contrast (P=0.04; B). Specifically, 20 wk Epo and Hct values are inversely related at HA
and positively associated at SL. At 36 weeks the relationship between Epo and Hct is similar to
that of the non-pregnant state, with an inverse association apparent at HA and no association at
SL (C).
Figure 3. Red cell mass, plasma and blood volume across HA pregnancy. Repeated measures
ANOVA was used to test the effect of pregnancy on hematological parameters in HA Andean
women (n=28, for all study points). Total red cell mass (RCM) increased ~17% by 36 weeks of
pregnancy (P<0.0001), however when expressed as a function of maternal weight RCM was
consistent across time (A). Plasma volume (PV, mL and mL/kg) expanded consistently across
pregnancy, with values being ~28% and ~20% higher at 36 weeks vs. the non-pregnant state,
respectively (B; both P<0.0001). As a result, blood volume (BV, mL and mL/kg) and increased
progressively with pregnancy, rising ~24% and ~ 20% by 36 weeks, respectively (C; both
P<0.001). Notably, maximal expansion of RCM, PV and BV expressed as mL/kg was achieved
by 20 weeks. Superscripts indicate a significant difference relative to a
non-pregnant, b
20 wk or c
36 wk values. Data are shown as the mean ± SD.
Figure 4. Epo and sEpoR levels in preeclamptic (PreE) vs. normotensive pregnancies at
HA. Paired t-tests were used to contrast Epo, sEpoR and Hb values in PreE vs. normotensive
pregnancy in Andean HA residents with Bonferroni multiple testing correction. PreE cases (open
squares) and normotensive controls (solid circles) were gestational-age matched (n=17, each
group). Maternal Epo levels were equivalent between normotensive controls and PreE cases (A,
control: 26.4 17.2 vs. PreE: 32.1 23.7 mIU/mL). In contrast, compared to controls PreE
women had greater sEpoR values (B, control: 72.2 40.1 vs. PreE: 322.7 401.8 pg/mL;
P=0.02), a statistically significant difference after Bonferroni correction.
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12
Table 1. Maternal, Newborn and Delivery Characteristics
Maternal Characteristics Longitudinal Normotensive, SL vs. HA Cross-sectional HA, Control vs. PreE
Variable Sea level High altitude P-value Control PreE P-value
Age, yrs 26.4 ± 1.2 (16) 27.2 ± 1.3 (28) NS 25.8 ± 2.8 (17) 28.0 ± 7.0 (17) NS
Parity, # 1.6 ± 0.8 (16) 2.9 ± 1.9 (28) <0.05 0.7 ± 0.7 (17) 0.9 ± 1.2 (17) NS
Current altitude, yrs 20.5 ± 7.6 (16) 21.7 ± 9.1 (28) ---- 25.2 ± 3.3 (17) 23.1 ± 9.2 (17) NS
Height, cm 158 ± 2 (16) 150 ± 1 (28) <0.001 150 ± 4 (17) 151 ± 9 (17) NS
Weight gain, 20-36 wks, kg 8.2 ± 3.9 (15) 6.0 ± 3.1 (28) <0.05 ---- ---- ----
Weight, 36 wks, kg 65.8 ± 7.4 (16) 76.9 ± 13.3 (28) <0.01 63.7 ± 7.2 (17) 72.7 ± 10.5 (17) <0.01
Weight, post-partum, kg 68.8 ± 12.7 (16) 59.3 ± 9.0 (28) <0.01 ---- ---- ----
BMI, post-partum, kg 27.4 ± 3.7 (16) 26.3 ± 3.7 (28) NS ---- ---- ----
Delivery and Newborn Information
Variable Sea level High altitude P-value Control PreE P-value
Gestational age, wks 39.5 ± 2.2, (15) 39.4 ± 1.4 (25) NS 38.8 ± 1.0 (17) 37.5 ± 2.4 (17) trend
Birth weight, gm 3425 ± 573, (16) 3194 ± 364 (25) =0.10 3104 ± 384 (17) 2641 ± 641 (17) <0.05
Head circumference, cm 35.4 ± 1.0 (16) 34.2 ± 1.0 (21) <0.01 33.8 ± 1.1 (16) 33.7 ± 1.8 (16) NS
Birth length, cm 49.9 ± 2.4 (16) 48.7 ± 1.9 (24) =0.08 49.7 ± 1.4 (15) 47.9 ± 2.1 (15) <0.05
Ponderal index, kg/m3
27.5 ± 3.0 (16) 27.6 ± 2.7 (24) NS 25.0 ± 2.6 (15) 24.2 ± 2.7 (15) NS
Infant sex, % female 50 (26, 75) (16) 57 (39, 77) (26) NS 30 (6,56) (13) 30 (6,56) (13) NS
SGA, % yes 18.8 (0,37.9) (16) 8.7 (0, 20.2) (23) NS 29 (7,51) (17) 35 (12,58) (17) NS
Preterm, % yes 12.5 (0, 28.7) (16) 8 (0, 18.6) (25) NS 0 (0,0) (17) 0 (0,0) (17) NS
Apgar 1 min 7.9 ± 0.3 (16) 7.9 ± 0.8 (21) NS 7.7 ± 0.5 (15) 7.3 ± 1.4 (15) NS
Apgar 5 min 8.9 ± 0.7 (16) 9.0 ± 0.8 (21) NS 9.6 ± 0.5 (15) 9.1 ± 0.7 (15) <0.01
Cesarean delivery, % 80 (59.8, 100.2) (15) 17.9 (3.6, 32.0) (28) <0.05 12 (0,27) (17) 59 (36, 82) (17) <0.01
Abbreviations: body mass index (BMI), small for gestational age (SGA); continuous variables are shown as the
mean ± SD, categorical variables are shown as proportions with 95% CI; subject numbers are shown in italics for
each variable.
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ENP 20 36
8
10
12
14
16
18
Pregnancy week
Hemoglobin,g/dL
SL
HA
NP 20 36
25
30
35
40
45
50
Pregnancy week
Hematocrit,%
HA
SL
NP 20 36
0
10
20
30
Pregnancy week
Epo,mIU/mL
SL
HA
NP 20 36
0
100
200
300
400
Pregnancy week
sEpoR,pg/mL
HA
SL
pregnancy <0.0001
altitude = 0.002
preg x altitude =0.001
pregnancy <0.0001
altitude <0.0001
preg x altitude NS
pregnancy <0.0001
altitude <0.0001
preg x altitude NS
pregnancy NS
altitude NS
preg x altitude NS
Figure 1
A. B.
C. D.
a
a
a
a
a
a
a
a
a
***
**
a a
a
***
******
***
***
***
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30 35 40 45 50 55
0
10
20
30
40
Hct, %
Epo,mIU/mL
Epo HA slope - 0.9, p=0.05
Epo SL slope - 0.2, p=0.27
HA vs. SL slope, p=0.26
25 30 35 40 45 50
0
20
40
60
80
Hct, %
Epo,mIU/mL
Epo HA slope - 2.4, p=0.06
Epo SL slope + 0.6, p=0.06
HA vs. SL slope, p=0.04
25 30 35 40 45 50 55
0
20
40
60
80
100
Hct, %
Epo,mIU/mL
Epo HA slope - 2.0, p=0.01
Epo SL slope - 0.4, p=0.18
HA vs. SL slope, p=0.17
A. Non-pregnant
B. 20 wks
C. 36 wks
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NP 20 wks 36 wks
0
1000
2000
3000
0
20
40
60
Pregnancy week
RCM,mL
RCM,mL/kg
c c
a, b
RCM, mL/kg
RCM, mL
NP 20 wks 36 wks
0
1000
2000
3000
4000
0
20
40
60
80
Pregnancy week
PV,mL
PV, mL
PV, mL/kg
b, c
a, c
a, b
a a
b, c
PV,mL/kg
NP 20 wks 36 wks
0
2000
4000
6000
8000
0
50
100
150
Pregnancy week
BV,mL
BV, mL
BV, mL/kg
b, c
a, c
a, b
b, c
a a
BV,mL/kg
B.
C.
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