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Decoding mechanisms of diabetic embryopathy suggests therapeutic targets
Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,1 making the risks of continuing the pregnancy quite high.
After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.2 Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.
Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.3
Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.
Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.4 Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.5
Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.
Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.
Unraveling the role of oxidative stress
Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.
A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.
Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.
Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).5
Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.6
When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.
Reduced autophagy and induction of cellular senescence
Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.
In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.4 Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.7Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.
All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.8
The role of epigenetics, future interventions
Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.
In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.
In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.9
Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.
Dr. Reece and Dr. Yang reported no relevant disclosures.
Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
*This story was updated on Nov. 3, 2022
References
1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.
2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).
3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.
4. Wang F et al. Nat. Commun. 2017;8:15182.
5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.
6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.
7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.
8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.
9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.
Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,1 making the risks of continuing the pregnancy quite high.
After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.2 Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.
Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.3
Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.
Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.4 Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.5
Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.
Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.
Unraveling the role of oxidative stress
Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.
A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.
Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.
Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).5
Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.6
When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.
Reduced autophagy and induction of cellular senescence
Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.
In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.4 Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.7Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.
All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.8
The role of epigenetics, future interventions
Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.
In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.
In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.9
Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.
Dr. Reece and Dr. Yang reported no relevant disclosures.
Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
*This story was updated on Nov. 3, 2022
References
1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.
2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).
3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.
4. Wang F et al. Nat. Commun. 2017;8:15182.
5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.
6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.
7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.
8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.
9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.
Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,1 making the risks of continuing the pregnancy quite high.
After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.2 Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.
Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.3
Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.
Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.4 Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.5
Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.
Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.
Unraveling the role of oxidative stress
Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.
A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.
Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.
Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).5
Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.6
When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.
Reduced autophagy and induction of cellular senescence
Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.
In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.4 Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.7Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.
All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.8
The role of epigenetics, future interventions
Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.
In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.
In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.9
Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.
Dr. Reece and Dr. Yang reported no relevant disclosures.
Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
*This story was updated on Nov. 3, 2022
References
1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.
2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).
3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.
4. Wang F et al. Nat. Commun. 2017;8:15182.
5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.
6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.
7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.
8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.
9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.
Discoveries in diabetic embryogenesis
Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.
However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.
Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.
In this issue of Ob.Gyn. News, the editor of Master Class in Obstetrics, E. Albert Reece MD, PhD, MBA, steps into the role of coauthor. He and his research colleague Peixin Yang, PhD, present exciting insights into the cellular mechanisms underlying structural birth defects in infants of diabetic mothers – especially cardiac and neural tube defects – and also provide a glimpse into some potentially effective maternal pharmacologic interventions. After appropriate human trials, these interventions could be effectively applied from the time of a positive pregnancy test with potentially dramatic results.
Dr. Reece and Dr. Yang, who lead the Center for the Study of Birth Defects at the University of Maryland School of Medicine, share their impressive accumulation of data from embryos of pregnant diabetic rodents. They demonstrate convincingly that, in first-trimester rodent embryos, maternal hyperglycemia induces excessive apoptosis, which in turn leads to structural defects in critical fetal organs. They further found that maternal hyperglycemia reduces embryonic autophagosomes – the developmentally essential organelles that remove abnormal or damaged cells during embryo formation.
These investigators also identified reactivators of these organelles which, when administered maternally in the first trimester, significantly reduced the incidence of neural tube defects. Thus, for optimal development of diabetes-affected embryos, first-trimester administration of reactivators of autophagy could offer a significant, life-changing intervention in the foreseeable future.
Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.
*This story was updated on Nov. 3, 2022.
Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.
However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.
Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.
In this issue of Ob.Gyn. News, the editor of Master Class in Obstetrics, E. Albert Reece MD, PhD, MBA, steps into the role of coauthor. He and his research colleague Peixin Yang, PhD, present exciting insights into the cellular mechanisms underlying structural birth defects in infants of diabetic mothers – especially cardiac and neural tube defects – and also provide a glimpse into some potentially effective maternal pharmacologic interventions. After appropriate human trials, these interventions could be effectively applied from the time of a positive pregnancy test with potentially dramatic results.
Dr. Reece and Dr. Yang, who lead the Center for the Study of Birth Defects at the University of Maryland School of Medicine, share their impressive accumulation of data from embryos of pregnant diabetic rodents. They demonstrate convincingly that, in first-trimester rodent embryos, maternal hyperglycemia induces excessive apoptosis, which in turn leads to structural defects in critical fetal organs. They further found that maternal hyperglycemia reduces embryonic autophagosomes – the developmentally essential organelles that remove abnormal or damaged cells during embryo formation.
These investigators also identified reactivators of these organelles which, when administered maternally in the first trimester, significantly reduced the incidence of neural tube defects. Thus, for optimal development of diabetes-affected embryos, first-trimester administration of reactivators of autophagy could offer a significant, life-changing intervention in the foreseeable future.
Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.
*This story was updated on Nov. 3, 2022.
Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.
However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.
Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.
In this issue of Ob.Gyn. News, the editor of Master Class in Obstetrics, E. Albert Reece MD, PhD, MBA, steps into the role of coauthor. He and his research colleague Peixin Yang, PhD, present exciting insights into the cellular mechanisms underlying structural birth defects in infants of diabetic mothers – especially cardiac and neural tube defects – and also provide a glimpse into some potentially effective maternal pharmacologic interventions. After appropriate human trials, these interventions could be effectively applied from the time of a positive pregnancy test with potentially dramatic results.
Dr. Reece and Dr. Yang, who lead the Center for the Study of Birth Defects at the University of Maryland School of Medicine, share their impressive accumulation of data from embryos of pregnant diabetic rodents. They demonstrate convincingly that, in first-trimester rodent embryos, maternal hyperglycemia induces excessive apoptosis, which in turn leads to structural defects in critical fetal organs. They further found that maternal hyperglycemia reduces embryonic autophagosomes – the developmentally essential organelles that remove abnormal or damaged cells during embryo formation.
These investigators also identified reactivators of these organelles which, when administered maternally in the first trimester, significantly reduced the incidence of neural tube defects. Thus, for optimal development of diabetes-affected embryos, first-trimester administration of reactivators of autophagy could offer a significant, life-changing intervention in the foreseeable future.
Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.
*This story was updated on Nov. 3, 2022.
Bugs, drugs, and the placenta
How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?
In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.1 In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.
Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.2 In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.3
Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.4 Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.5
The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.
Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.
References
1. World malaria report 2021. Geneva: World Health Organization; 2021.
2. Chua CLL et al. Front Immunol. 2021;12:621382.
3. McColl ER et al. Drug Metab Dispos. May 2022.
4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).
5. David AL et al. Ther Innov Regul Sci. 2022.
How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?
In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.1 In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.
Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.2 In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.3
Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.4 Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.5
The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.
Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.
References
1. World malaria report 2021. Geneva: World Health Organization; 2021.
2. Chua CLL et al. Front Immunol. 2021;12:621382.
3. McColl ER et al. Drug Metab Dispos. May 2022.
4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).
5. David AL et al. Ther Innov Regul Sci. 2022.
How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?
In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.1 In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.
Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.2 In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.3
Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.4 Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.5
The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.
Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.
References
1. World malaria report 2021. Geneva: World Health Organization; 2021.
2. Chua CLL et al. Front Immunol. 2021;12:621382.
3. McColl ER et al. Drug Metab Dispos. May 2022.
4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).
5. David AL et al. Ther Innov Regul Sci. 2022.
Maternal deaths show that ‘racism does exist among physicians’
Black mothers giving birth in hospitals are 53% more likely to die during childbirth than are Hispanic and White women, according to researchers who attributed the gap at least in part to bias among physicians and the health care system.
The United States is in the midst of a maternal healthcare crisis, said Robert White, MD, assistant professor of anesthesiology at Weill Cornell Medicine, New York, and lead author of the study. The maternal death rate among U.S. women in 2018, for instance, was 17.4 per 100,000 births, more than twice the figure in Canada (8.6 per 100,000 live births) and the United Kingdom (6.5 per 100,000 live births in 2016), according to the Commonwealth Fund.
“At baseline, our maternal mortality rates are higher than other comparable Western nations, and at the same time, there’s a huge spread in the maternal mortality ratio between White mothers and Black mothers, where Black mothers are experiencing maternal mortality about two or three times higher,” Dr. White told this news organization.
Previous research has shown racial disparities in rates of maternal mortality. But Dr. White said that his study controlled for income level, type of insurance, and other social factors that may have affected the health of the women.
“The research that I conducted is one of the largest of its kind, and the logistic regression model that we were able to run was able to control for a lot of these factors,” he said.
For the new study, presented at the 2022 annual meeting of the American Society of Anesthesiologists, Dr. White and his team analyzed data from 9.5 million deliveries across six states (California, Florida, Kentucky, Maryland, New York, and Washington) between 2007 and 2018. They found that 49,472 mothers (0.5%) either died in the hospital or experienced an injury during childbirth, which included damages to the brain, heart, eyes, or kidneys.
Overall, 0.8% of Black women experienced either a death or an injury, compared with 0.5% of Hispanic women and 0.4% of White women. The researchers concluded that Black women had a 53% increased chance of dying during childbirth in a hospital, even after adjusting for factors such as insurance type, hospital type, and income.
If income, insurance type, and other social factors aren’t driving this disparity in maternal mortality, what is? Dr. White said that the study didn’t uncover the underlying cause, but in his opinion, racial bias and systemic racism are likely contributing to the gap in deaths.
“I think the takeaway for physicians should be that we should humbly accept that prejudice, bias, and racism does exist among physicians,” Dr. White said.
Adi Davidov, MD, associate chair of obstetrics and gynecology at Staten Island (N.Y.) University Hospital, said that both anesthesiologists and ob.gyns. have been aware of these disparate health outcomes for years but have historically attributed the higher odds of injuries and death amongst Black women to health issues rather than racism.
“It is now quite evident that there is more to the story and that there is a degree of unconscious bias as well as systemic racism in health care that contributes to the disparities in outcomes,” said Dr. Davidov, who was not involved in the study.
Meanwhile, new data show that maternal mortality worsened during the COVID-19 pandemic, particularly for Black women. The rate of maternal death for Black women was 44 per 100,000 live births in 2019, 55.3 in 2020, and 68.9 in 2021, according to the U.S. Government Accountability Office. In contrast, White women had death rates of 17.9, 19.1, and 26.1, respectively.
“Bias or discrimination within the health care system can create communication challenges between providers and their patients, which may increase the risk of adverse outcomes,” the report stated.
What can be done
The most important thing physicians can do is to understand and acknowledge unconscious bias, Dr. Davidov told this news organization. “It is important to learn how to identify biases and make sure that it does not affect your medical decision making,” he said.
Dr. White suggested that physicians receive training in implicit bias and cultural competency and stay up to date on research regarding race and medicine as well as learning and using inclusive language.
He also urged physicians closely follow protocols for standard care for their discipline.
“Standardized care protocols have been shown to reduce variance between care of patients of different social structures and shown to decrease this disparity gap,” he said.
The study was supported by a Foundation for Anesthesia Education and Research Mentored Research Training Grant. Dr. White and Dr. Davidov report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Black mothers giving birth in hospitals are 53% more likely to die during childbirth than are Hispanic and White women, according to researchers who attributed the gap at least in part to bias among physicians and the health care system.
The United States is in the midst of a maternal healthcare crisis, said Robert White, MD, assistant professor of anesthesiology at Weill Cornell Medicine, New York, and lead author of the study. The maternal death rate among U.S. women in 2018, for instance, was 17.4 per 100,000 births, more than twice the figure in Canada (8.6 per 100,000 live births) and the United Kingdom (6.5 per 100,000 live births in 2016), according to the Commonwealth Fund.
“At baseline, our maternal mortality rates are higher than other comparable Western nations, and at the same time, there’s a huge spread in the maternal mortality ratio between White mothers and Black mothers, where Black mothers are experiencing maternal mortality about two or three times higher,” Dr. White told this news organization.
Previous research has shown racial disparities in rates of maternal mortality. But Dr. White said that his study controlled for income level, type of insurance, and other social factors that may have affected the health of the women.
“The research that I conducted is one of the largest of its kind, and the logistic regression model that we were able to run was able to control for a lot of these factors,” he said.
For the new study, presented at the 2022 annual meeting of the American Society of Anesthesiologists, Dr. White and his team analyzed data from 9.5 million deliveries across six states (California, Florida, Kentucky, Maryland, New York, and Washington) between 2007 and 2018. They found that 49,472 mothers (0.5%) either died in the hospital or experienced an injury during childbirth, which included damages to the brain, heart, eyes, or kidneys.
Overall, 0.8% of Black women experienced either a death or an injury, compared with 0.5% of Hispanic women and 0.4% of White women. The researchers concluded that Black women had a 53% increased chance of dying during childbirth in a hospital, even after adjusting for factors such as insurance type, hospital type, and income.
If income, insurance type, and other social factors aren’t driving this disparity in maternal mortality, what is? Dr. White said that the study didn’t uncover the underlying cause, but in his opinion, racial bias and systemic racism are likely contributing to the gap in deaths.
“I think the takeaway for physicians should be that we should humbly accept that prejudice, bias, and racism does exist among physicians,” Dr. White said.
Adi Davidov, MD, associate chair of obstetrics and gynecology at Staten Island (N.Y.) University Hospital, said that both anesthesiologists and ob.gyns. have been aware of these disparate health outcomes for years but have historically attributed the higher odds of injuries and death amongst Black women to health issues rather than racism.
“It is now quite evident that there is more to the story and that there is a degree of unconscious bias as well as systemic racism in health care that contributes to the disparities in outcomes,” said Dr. Davidov, who was not involved in the study.
Meanwhile, new data show that maternal mortality worsened during the COVID-19 pandemic, particularly for Black women. The rate of maternal death for Black women was 44 per 100,000 live births in 2019, 55.3 in 2020, and 68.9 in 2021, according to the U.S. Government Accountability Office. In contrast, White women had death rates of 17.9, 19.1, and 26.1, respectively.
“Bias or discrimination within the health care system can create communication challenges between providers and their patients, which may increase the risk of adverse outcomes,” the report stated.
What can be done
The most important thing physicians can do is to understand and acknowledge unconscious bias, Dr. Davidov told this news organization. “It is important to learn how to identify biases and make sure that it does not affect your medical decision making,” he said.
Dr. White suggested that physicians receive training in implicit bias and cultural competency and stay up to date on research regarding race and medicine as well as learning and using inclusive language.
He also urged physicians closely follow protocols for standard care for their discipline.
“Standardized care protocols have been shown to reduce variance between care of patients of different social structures and shown to decrease this disparity gap,” he said.
The study was supported by a Foundation for Anesthesia Education and Research Mentored Research Training Grant. Dr. White and Dr. Davidov report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Black mothers giving birth in hospitals are 53% more likely to die during childbirth than are Hispanic and White women, according to researchers who attributed the gap at least in part to bias among physicians and the health care system.
The United States is in the midst of a maternal healthcare crisis, said Robert White, MD, assistant professor of anesthesiology at Weill Cornell Medicine, New York, and lead author of the study. The maternal death rate among U.S. women in 2018, for instance, was 17.4 per 100,000 births, more than twice the figure in Canada (8.6 per 100,000 live births) and the United Kingdom (6.5 per 100,000 live births in 2016), according to the Commonwealth Fund.
“At baseline, our maternal mortality rates are higher than other comparable Western nations, and at the same time, there’s a huge spread in the maternal mortality ratio between White mothers and Black mothers, where Black mothers are experiencing maternal mortality about two or three times higher,” Dr. White told this news organization.
Previous research has shown racial disparities in rates of maternal mortality. But Dr. White said that his study controlled for income level, type of insurance, and other social factors that may have affected the health of the women.
“The research that I conducted is one of the largest of its kind, and the logistic regression model that we were able to run was able to control for a lot of these factors,” he said.
For the new study, presented at the 2022 annual meeting of the American Society of Anesthesiologists, Dr. White and his team analyzed data from 9.5 million deliveries across six states (California, Florida, Kentucky, Maryland, New York, and Washington) between 2007 and 2018. They found that 49,472 mothers (0.5%) either died in the hospital or experienced an injury during childbirth, which included damages to the brain, heart, eyes, or kidneys.
Overall, 0.8% of Black women experienced either a death or an injury, compared with 0.5% of Hispanic women and 0.4% of White women. The researchers concluded that Black women had a 53% increased chance of dying during childbirth in a hospital, even after adjusting for factors such as insurance type, hospital type, and income.
If income, insurance type, and other social factors aren’t driving this disparity in maternal mortality, what is? Dr. White said that the study didn’t uncover the underlying cause, but in his opinion, racial bias and systemic racism are likely contributing to the gap in deaths.
“I think the takeaway for physicians should be that we should humbly accept that prejudice, bias, and racism does exist among physicians,” Dr. White said.
Adi Davidov, MD, associate chair of obstetrics and gynecology at Staten Island (N.Y.) University Hospital, said that both anesthesiologists and ob.gyns. have been aware of these disparate health outcomes for years but have historically attributed the higher odds of injuries and death amongst Black women to health issues rather than racism.
“It is now quite evident that there is more to the story and that there is a degree of unconscious bias as well as systemic racism in health care that contributes to the disparities in outcomes,” said Dr. Davidov, who was not involved in the study.
Meanwhile, new data show that maternal mortality worsened during the COVID-19 pandemic, particularly for Black women. The rate of maternal death for Black women was 44 per 100,000 live births in 2019, 55.3 in 2020, and 68.9 in 2021, according to the U.S. Government Accountability Office. In contrast, White women had death rates of 17.9, 19.1, and 26.1, respectively.
“Bias or discrimination within the health care system can create communication challenges between providers and their patients, which may increase the risk of adverse outcomes,” the report stated.
What can be done
The most important thing physicians can do is to understand and acknowledge unconscious bias, Dr. Davidov told this news organization. “It is important to learn how to identify biases and make sure that it does not affect your medical decision making,” he said.
Dr. White suggested that physicians receive training in implicit bias and cultural competency and stay up to date on research regarding race and medicine as well as learning and using inclusive language.
He also urged physicians closely follow protocols for standard care for their discipline.
“Standardized care protocols have been shown to reduce variance between care of patients of different social structures and shown to decrease this disparity gap,” he said.
The study was supported by a Foundation for Anesthesia Education and Research Mentored Research Training Grant. Dr. White and Dr. Davidov report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Immediate skin-to-skin contact after cesarean section improves outcomes for parent, newborn
Birth parents are typically separated from their newborns following a cesarean section. However, a recent study published in the journal Nursing Open suggests immediate skin-to-skin contact may accelerate uterine contractions, reduce maternal blood loss, reduce newborn crying, improve patient satisfaction and comfort, and increase the rate of breastfeeding.
“[O]ur study contributes to scientific knowledge with key information to reduce maternal morbidity and mortality rates in mothers who have undergone scheduled cesarean sections,” José Miguel Pérez-Jiménez, MD, of the faculty of nursing, physiotherapy, and podiatry at Hospital Universitario Virgen Macarena, University of Sevilla, Spain, and colleagues wrote in their study. It promotes greater stability in the mothers by reducing the risk of postpartum hemorrhage, making it better to not separate mother and child in the first hours after this surgery, he said.
Dr. Pérez-Jiménez and colleagues evaluated 83 women who underwent a scheduled cesarean section in an unblinded, randomized controlled trial. The women were randomized to receive skin-to-skin contact in the operating room that continued in the postpartum unit, or the normal protocol after cesarean section that consisted of having the mother transferred to the postanesthesia recovery room while the newborn was sent to a maternity room with a parent or companion. Researchers assessed variables such as plasma hemoglobin, uterine contractions, breastfeeding, and postoperative pain, as well as subjective measures such as maternal satisfaction, comfort, previous cesarean section experience, and newborn crying.
Women who received usual care following cesarean section were more likely to have uterine contractions at the umbilical level compared with the skin-to-skin contact group (70% vs. 3%; P ≤ .0001), while the skin-to-skin group was more likely to have uterine contractions at the infraumbilical level (92.5% vs. 22.5%; P ≤ .0001). There was a statistically significant decrease in predischarge hemoglobin in the control group compared with the skin-to-skin group (10.522 vs. 11.075 g/dL; P ≤ .017); the level of hemoglobin reduction favored the skin-to-skin group (1.01 vs. 2.265 g/dL; P ≤ .0001). Women in the skin-to-skin group were more likely to report mild pain on a 10-point visual analog scale (VAS) after being transferred to the recovery room (1.48 vs. 6.23 points; P ≤ .0001) and being transferred to a maternity room or room in the postpartum unit (0.60 vs. 5.23 points; P ≤ .0001). Breastfeeding at birth was significantly higher among patients with immediate skin-to-skin contact compared with the control group (92.5% vs. 32.5%; P ≤ .0001), and continued at 1 month after birth (92.5% vs. 12.5%; P ≤ .0001). Newborns of mothers in the skin-to-skin group were significantly less likely to cry compared with newborns in the control group (90% vs. 55%; P ≤ .001).
When asked to rate their satisfaction on a 10-point Likert scale, women in the skin-to-skin contact group rated their experience significantly higher than did the control group (9.98 vs. 6.5; P ≤ .0001), and all women who had previously had a cesarean section in the skin-to-skin group (30%) rated their experience at 10 points compared with their previous cesarean section without skin-to-skin contact.
Implementing skin-to-skin contact after cesarean section
Betsy M. Collins, MD, MPH, assistant professor of obstetrics and gynecology at Emory University, Atlanta, said in an interview that while some of the findings were largely unsurprising and “confirmed a lot of the things that we already know about skin-to-skin [contact],” one major finding was the “stark difference” in the percentage of new birth parents who started breastfeeding after skin-to-skin contact and were still breastfeeding at 1 month postpartum compared with birth parents in the control group. She was not involved with the study and noted that the results complement recommendations from the World Health Organization on starting breastfeeding within the first hour after birth and continuing breastfeeding through the first 6 months of life.
“That was likely one of the greatest take-home points from the study ... that early skin-to-skin really promoted initiation of breastfeeding,” Dr. Collins said.
Two reasons why skin-to-skin contact after cesarean section isn’t regularly provided is that it can be difficult for personnel and safety reasons to have an extra nurse to continue monitoring the health of the newborn in the operating room, and there is a lack of culture supporting of skin-to-skin contact in the OR, Dr. Collins explained.
“Just like anything else, if it’s built into your standard operating procedure, then you have everything set up in place to do that initial assessment of the infant and then get the baby skin-to-skin as quickly as possible,” she said. If it’s your standard operating procedure to not provide skin-to-skin contact, she said, then there is a little bit more inertia to overcome to start providing it as a standard procedure.
At her center, Dr. Collins said skin-to-skin contact is initiated as soon as possible after birth, even in the operating room. The steps to implementing that policy involved getting the anesthesiology department on board with supporting the policy in the OR and training the circulating nursing staff to ensure a that nurse is available to monitor the newborn.
“I think the most important thing to know is that it’s absolutely doable and that you just have to have a champion just like any other quality initiative,” she said. One of the best ways to do that is to have the patients themselves request it, she noted, compared with its being requested by a physician or nurse.
“I think some patients are disappointed when they have to undergo cesarean delivery or feel like they’re missing out if they can’t have a vaginal delivery,” Dr. Collins said. Immediate skin-to-skin contact is “very good for not only physiology, as we read about in this paper – all the things they said about the benefits of skin-to-skin [contact] are true – but it’s really good for mental health. That bonding begins right away.”
As a birth parent, being separated from your newborn for several hours after a cesarean section, on the other hand, can be “pretty devastating,” Dr. Collins said.
“I think this is something that, once it becomes a standard of care, it will be expected that most hospitals should be doing this,” she said.
The authors and Dr. Collins report no relevant conflicts of interest.
Birth parents are typically separated from their newborns following a cesarean section. However, a recent study published in the journal Nursing Open suggests immediate skin-to-skin contact may accelerate uterine contractions, reduce maternal blood loss, reduce newborn crying, improve patient satisfaction and comfort, and increase the rate of breastfeeding.
“[O]ur study contributes to scientific knowledge with key information to reduce maternal morbidity and mortality rates in mothers who have undergone scheduled cesarean sections,” José Miguel Pérez-Jiménez, MD, of the faculty of nursing, physiotherapy, and podiatry at Hospital Universitario Virgen Macarena, University of Sevilla, Spain, and colleagues wrote in their study. It promotes greater stability in the mothers by reducing the risk of postpartum hemorrhage, making it better to not separate mother and child in the first hours after this surgery, he said.
Dr. Pérez-Jiménez and colleagues evaluated 83 women who underwent a scheduled cesarean section in an unblinded, randomized controlled trial. The women were randomized to receive skin-to-skin contact in the operating room that continued in the postpartum unit, or the normal protocol after cesarean section that consisted of having the mother transferred to the postanesthesia recovery room while the newborn was sent to a maternity room with a parent or companion. Researchers assessed variables such as plasma hemoglobin, uterine contractions, breastfeeding, and postoperative pain, as well as subjective measures such as maternal satisfaction, comfort, previous cesarean section experience, and newborn crying.
Women who received usual care following cesarean section were more likely to have uterine contractions at the umbilical level compared with the skin-to-skin contact group (70% vs. 3%; P ≤ .0001), while the skin-to-skin group was more likely to have uterine contractions at the infraumbilical level (92.5% vs. 22.5%; P ≤ .0001). There was a statistically significant decrease in predischarge hemoglobin in the control group compared with the skin-to-skin group (10.522 vs. 11.075 g/dL; P ≤ .017); the level of hemoglobin reduction favored the skin-to-skin group (1.01 vs. 2.265 g/dL; P ≤ .0001). Women in the skin-to-skin group were more likely to report mild pain on a 10-point visual analog scale (VAS) after being transferred to the recovery room (1.48 vs. 6.23 points; P ≤ .0001) and being transferred to a maternity room or room in the postpartum unit (0.60 vs. 5.23 points; P ≤ .0001). Breastfeeding at birth was significantly higher among patients with immediate skin-to-skin contact compared with the control group (92.5% vs. 32.5%; P ≤ .0001), and continued at 1 month after birth (92.5% vs. 12.5%; P ≤ .0001). Newborns of mothers in the skin-to-skin group were significantly less likely to cry compared with newborns in the control group (90% vs. 55%; P ≤ .001).
When asked to rate their satisfaction on a 10-point Likert scale, women in the skin-to-skin contact group rated their experience significantly higher than did the control group (9.98 vs. 6.5; P ≤ .0001), and all women who had previously had a cesarean section in the skin-to-skin group (30%) rated their experience at 10 points compared with their previous cesarean section without skin-to-skin contact.
Implementing skin-to-skin contact after cesarean section
Betsy M. Collins, MD, MPH, assistant professor of obstetrics and gynecology at Emory University, Atlanta, said in an interview that while some of the findings were largely unsurprising and “confirmed a lot of the things that we already know about skin-to-skin [contact],” one major finding was the “stark difference” in the percentage of new birth parents who started breastfeeding after skin-to-skin contact and were still breastfeeding at 1 month postpartum compared with birth parents in the control group. She was not involved with the study and noted that the results complement recommendations from the World Health Organization on starting breastfeeding within the first hour after birth and continuing breastfeeding through the first 6 months of life.
“That was likely one of the greatest take-home points from the study ... that early skin-to-skin really promoted initiation of breastfeeding,” Dr. Collins said.
Two reasons why skin-to-skin contact after cesarean section isn’t regularly provided is that it can be difficult for personnel and safety reasons to have an extra nurse to continue monitoring the health of the newborn in the operating room, and there is a lack of culture supporting of skin-to-skin contact in the OR, Dr. Collins explained.
“Just like anything else, if it’s built into your standard operating procedure, then you have everything set up in place to do that initial assessment of the infant and then get the baby skin-to-skin as quickly as possible,” she said. If it’s your standard operating procedure to not provide skin-to-skin contact, she said, then there is a little bit more inertia to overcome to start providing it as a standard procedure.
At her center, Dr. Collins said skin-to-skin contact is initiated as soon as possible after birth, even in the operating room. The steps to implementing that policy involved getting the anesthesiology department on board with supporting the policy in the OR and training the circulating nursing staff to ensure a that nurse is available to monitor the newborn.
“I think the most important thing to know is that it’s absolutely doable and that you just have to have a champion just like any other quality initiative,” she said. One of the best ways to do that is to have the patients themselves request it, she noted, compared with its being requested by a physician or nurse.
“I think some patients are disappointed when they have to undergo cesarean delivery or feel like they’re missing out if they can’t have a vaginal delivery,” Dr. Collins said. Immediate skin-to-skin contact is “very good for not only physiology, as we read about in this paper – all the things they said about the benefits of skin-to-skin [contact] are true – but it’s really good for mental health. That bonding begins right away.”
As a birth parent, being separated from your newborn for several hours after a cesarean section, on the other hand, can be “pretty devastating,” Dr. Collins said.
“I think this is something that, once it becomes a standard of care, it will be expected that most hospitals should be doing this,” she said.
The authors and Dr. Collins report no relevant conflicts of interest.
Birth parents are typically separated from their newborns following a cesarean section. However, a recent study published in the journal Nursing Open suggests immediate skin-to-skin contact may accelerate uterine contractions, reduce maternal blood loss, reduce newborn crying, improve patient satisfaction and comfort, and increase the rate of breastfeeding.
“[O]ur study contributes to scientific knowledge with key information to reduce maternal morbidity and mortality rates in mothers who have undergone scheduled cesarean sections,” José Miguel Pérez-Jiménez, MD, of the faculty of nursing, physiotherapy, and podiatry at Hospital Universitario Virgen Macarena, University of Sevilla, Spain, and colleagues wrote in their study. It promotes greater stability in the mothers by reducing the risk of postpartum hemorrhage, making it better to not separate mother and child in the first hours after this surgery, he said.
Dr. Pérez-Jiménez and colleagues evaluated 83 women who underwent a scheduled cesarean section in an unblinded, randomized controlled trial. The women were randomized to receive skin-to-skin contact in the operating room that continued in the postpartum unit, or the normal protocol after cesarean section that consisted of having the mother transferred to the postanesthesia recovery room while the newborn was sent to a maternity room with a parent or companion. Researchers assessed variables such as plasma hemoglobin, uterine contractions, breastfeeding, and postoperative pain, as well as subjective measures such as maternal satisfaction, comfort, previous cesarean section experience, and newborn crying.
Women who received usual care following cesarean section were more likely to have uterine contractions at the umbilical level compared with the skin-to-skin contact group (70% vs. 3%; P ≤ .0001), while the skin-to-skin group was more likely to have uterine contractions at the infraumbilical level (92.5% vs. 22.5%; P ≤ .0001). There was a statistically significant decrease in predischarge hemoglobin in the control group compared with the skin-to-skin group (10.522 vs. 11.075 g/dL; P ≤ .017); the level of hemoglobin reduction favored the skin-to-skin group (1.01 vs. 2.265 g/dL; P ≤ .0001). Women in the skin-to-skin group were more likely to report mild pain on a 10-point visual analog scale (VAS) after being transferred to the recovery room (1.48 vs. 6.23 points; P ≤ .0001) and being transferred to a maternity room or room in the postpartum unit (0.60 vs. 5.23 points; P ≤ .0001). Breastfeeding at birth was significantly higher among patients with immediate skin-to-skin contact compared with the control group (92.5% vs. 32.5%; P ≤ .0001), and continued at 1 month after birth (92.5% vs. 12.5%; P ≤ .0001). Newborns of mothers in the skin-to-skin group were significantly less likely to cry compared with newborns in the control group (90% vs. 55%; P ≤ .001).
When asked to rate their satisfaction on a 10-point Likert scale, women in the skin-to-skin contact group rated their experience significantly higher than did the control group (9.98 vs. 6.5; P ≤ .0001), and all women who had previously had a cesarean section in the skin-to-skin group (30%) rated their experience at 10 points compared with their previous cesarean section without skin-to-skin contact.
Implementing skin-to-skin contact after cesarean section
Betsy M. Collins, MD, MPH, assistant professor of obstetrics and gynecology at Emory University, Atlanta, said in an interview that while some of the findings were largely unsurprising and “confirmed a lot of the things that we already know about skin-to-skin [contact],” one major finding was the “stark difference” in the percentage of new birth parents who started breastfeeding after skin-to-skin contact and were still breastfeeding at 1 month postpartum compared with birth parents in the control group. She was not involved with the study and noted that the results complement recommendations from the World Health Organization on starting breastfeeding within the first hour after birth and continuing breastfeeding through the first 6 months of life.
“That was likely one of the greatest take-home points from the study ... that early skin-to-skin really promoted initiation of breastfeeding,” Dr. Collins said.
Two reasons why skin-to-skin contact after cesarean section isn’t regularly provided is that it can be difficult for personnel and safety reasons to have an extra nurse to continue monitoring the health of the newborn in the operating room, and there is a lack of culture supporting of skin-to-skin contact in the OR, Dr. Collins explained.
“Just like anything else, if it’s built into your standard operating procedure, then you have everything set up in place to do that initial assessment of the infant and then get the baby skin-to-skin as quickly as possible,” she said. If it’s your standard operating procedure to not provide skin-to-skin contact, she said, then there is a little bit more inertia to overcome to start providing it as a standard procedure.
At her center, Dr. Collins said skin-to-skin contact is initiated as soon as possible after birth, even in the operating room. The steps to implementing that policy involved getting the anesthesiology department on board with supporting the policy in the OR and training the circulating nursing staff to ensure a that nurse is available to monitor the newborn.
“I think the most important thing to know is that it’s absolutely doable and that you just have to have a champion just like any other quality initiative,” she said. One of the best ways to do that is to have the patients themselves request it, she noted, compared with its being requested by a physician or nurse.
“I think some patients are disappointed when they have to undergo cesarean delivery or feel like they’re missing out if they can’t have a vaginal delivery,” Dr. Collins said. Immediate skin-to-skin contact is “very good for not only physiology, as we read about in this paper – all the things they said about the benefits of skin-to-skin [contact] are true – but it’s really good for mental health. That bonding begins right away.”
As a birth parent, being separated from your newborn for several hours after a cesarean section, on the other hand, can be “pretty devastating,” Dr. Collins said.
“I think this is something that, once it becomes a standard of care, it will be expected that most hospitals should be doing this,” she said.
The authors and Dr. Collins report no relevant conflicts of interest.
FROM NURSING OPEN
New electrodes made of sugar more effectively monitor mom’s health
A new type of electrode made from sugar could help doctors and researchers more effectively monitor contractions during preterm labor, a condition that precedes almost half of preterm births and is the leading cause of U.S. neonatal deaths.
The sensors, developed by engineers at the McKelvey School of Engineering at Washington University, St. Louis, could help us understand why some patients experience preterm labor, improve medical interventions, and save lives. In the experiment, the researchers built an array of the new electrodes and successfully tested it on a pregnant person in a lab.
The goal is a home-monitoring belt that is comfortable enough for patients to wear and accurate enough to be clinically useful. Built off a framework of sugar and conductive polymers, the thin electrodes have a sponge-like quality that allows them to hold more gel than standard electrodes, measure for 3 hours instead of 1, and resist artifacts created by patient movement. When tested on a pregnant woman, the new electrodes picked up clean signals even when the patient moved, said electrical engineer and article co-author Chuan Wang, PhD.
There is current technology that exists to monitor and map contractions during early labor, but the tests require hundreds of wire electrodes. Patients must sit still for half an hour while the electrodes are applied, then remain immobile for the test itself, which has a high sensitivity to movement.
“It’s very uncomfortable. In the clinical setting, the recording typically lasts for 15 minutes to half an hour. During that time, doctors want the patient to be still,” said Dr. Wang. “If the patient has to move, it’s going to introduce some artifacts, which is going to ruin the imaging process.”
Dr. Wang and colleagues wanted to develop an inexpensive new electrode that would be more comfortable for patients to wear for longer periods of time, yet sensitive enough to detect electrical signals in the body during preterm labor.
To do this, they used sugar structures to create a pliable electrode with a spongy structure. The new electrodes have micropores that hold conductive gel, increasing the amount of electrified surface area touching the skin.
“With the porous structure, we are effectively increasing the area by many, many times,” Dr. Wang said. “Because all those voids also contact the skin, increasing the contact area can boost the strength of the signal.”
With conventional electrodes, the gel dries quickly on the flat surface, causing signal quality to plummet. But the new electrodes can be used for “many hours” before drying out, according to Dr. Wang.
Additionally, the soft material of the new electrode acts “like a buffer” that absorbs motion and prevents the electrode from sliding around, according to Dr. Wang. That means patients can move while wearing the spongy electrodes without disturbing the recording of electrical signals in the body.
From sugar cube to spongy electrode
To create the new electrode, the researchers began by molding sugar into an electrode-shaped template. The template was then dipped into a liquid polymer, which oozed in between the grains of sugar. Next, the template underwent oven curing, emerging as a solid yet spongy structure. Hot water was then applied to dissolve the sugar.
The sugar structure is useful here because of the negative space around the grains, which is filled by the polymer – and then because of the negative space left when the sugar dissolves.
“When the sugar grains are removed, that’s where the pores are located,” Dr. Wang explained.
The sponge surface was then converted from hydrophobic to hydrophilic, thanks to an oxygen plasma treatment. Next, the sponge was blanketed in a layer of conductive polymer – a liquid that Dr. Wang likens to black ink – transforming it into an electrode. (Without the oxygen plasma step, the sponge wouldn’t have absorbed the conductive material.) After another oven-curing session, the device was affixed with wires and ready to be used.
The researchers are continuing to refine the concept and hope to develop a wireless wearable device with many spongy electrodes that record signals simultaneously – and that patients can use at home.
In addition to monitoring maternal and fetal health during labor, the researchers say the belt-like device could be used for other types of imaging and diagnosis.
“Depending on the scenario, different signals can be recorded,” Dr. Wang said. “It could be an EMG for a pregnant woman, or an ECG for an athlete or a patient with chronic cardiovascular disease that needs monitoring.”
This work was funded by the Bill & Melinda Gates Foundation (INV-005417, INV-035476). The authors acknowledge the Washington University in St. Louis Institute of Materials Science and Engineering for the use of instruments and staff assistance.
A version of this article first appeared on Medscape.com.
A new type of electrode made from sugar could help doctors and researchers more effectively monitor contractions during preterm labor, a condition that precedes almost half of preterm births and is the leading cause of U.S. neonatal deaths.
The sensors, developed by engineers at the McKelvey School of Engineering at Washington University, St. Louis, could help us understand why some patients experience preterm labor, improve medical interventions, and save lives. In the experiment, the researchers built an array of the new electrodes and successfully tested it on a pregnant person in a lab.
The goal is a home-monitoring belt that is comfortable enough for patients to wear and accurate enough to be clinically useful. Built off a framework of sugar and conductive polymers, the thin electrodes have a sponge-like quality that allows them to hold more gel than standard electrodes, measure for 3 hours instead of 1, and resist artifacts created by patient movement. When tested on a pregnant woman, the new electrodes picked up clean signals even when the patient moved, said electrical engineer and article co-author Chuan Wang, PhD.
There is current technology that exists to monitor and map contractions during early labor, but the tests require hundreds of wire electrodes. Patients must sit still for half an hour while the electrodes are applied, then remain immobile for the test itself, which has a high sensitivity to movement.
“It’s very uncomfortable. In the clinical setting, the recording typically lasts for 15 minutes to half an hour. During that time, doctors want the patient to be still,” said Dr. Wang. “If the patient has to move, it’s going to introduce some artifacts, which is going to ruin the imaging process.”
Dr. Wang and colleagues wanted to develop an inexpensive new electrode that would be more comfortable for patients to wear for longer periods of time, yet sensitive enough to detect electrical signals in the body during preterm labor.
To do this, they used sugar structures to create a pliable electrode with a spongy structure. The new electrodes have micropores that hold conductive gel, increasing the amount of electrified surface area touching the skin.
“With the porous structure, we are effectively increasing the area by many, many times,” Dr. Wang said. “Because all those voids also contact the skin, increasing the contact area can boost the strength of the signal.”
With conventional electrodes, the gel dries quickly on the flat surface, causing signal quality to plummet. But the new electrodes can be used for “many hours” before drying out, according to Dr. Wang.
Additionally, the soft material of the new electrode acts “like a buffer” that absorbs motion and prevents the electrode from sliding around, according to Dr. Wang. That means patients can move while wearing the spongy electrodes without disturbing the recording of electrical signals in the body.
From sugar cube to spongy electrode
To create the new electrode, the researchers began by molding sugar into an electrode-shaped template. The template was then dipped into a liquid polymer, which oozed in between the grains of sugar. Next, the template underwent oven curing, emerging as a solid yet spongy structure. Hot water was then applied to dissolve the sugar.
The sugar structure is useful here because of the negative space around the grains, which is filled by the polymer – and then because of the negative space left when the sugar dissolves.
“When the sugar grains are removed, that’s where the pores are located,” Dr. Wang explained.
The sponge surface was then converted from hydrophobic to hydrophilic, thanks to an oxygen plasma treatment. Next, the sponge was blanketed in a layer of conductive polymer – a liquid that Dr. Wang likens to black ink – transforming it into an electrode. (Without the oxygen plasma step, the sponge wouldn’t have absorbed the conductive material.) After another oven-curing session, the device was affixed with wires and ready to be used.
The researchers are continuing to refine the concept and hope to develop a wireless wearable device with many spongy electrodes that record signals simultaneously – and that patients can use at home.
In addition to monitoring maternal and fetal health during labor, the researchers say the belt-like device could be used for other types of imaging and diagnosis.
“Depending on the scenario, different signals can be recorded,” Dr. Wang said. “It could be an EMG for a pregnant woman, or an ECG for an athlete or a patient with chronic cardiovascular disease that needs monitoring.”
This work was funded by the Bill & Melinda Gates Foundation (INV-005417, INV-035476). The authors acknowledge the Washington University in St. Louis Institute of Materials Science and Engineering for the use of instruments and staff assistance.
A version of this article first appeared on Medscape.com.
A new type of electrode made from sugar could help doctors and researchers more effectively monitor contractions during preterm labor, a condition that precedes almost half of preterm births and is the leading cause of U.S. neonatal deaths.
The sensors, developed by engineers at the McKelvey School of Engineering at Washington University, St. Louis, could help us understand why some patients experience preterm labor, improve medical interventions, and save lives. In the experiment, the researchers built an array of the new electrodes and successfully tested it on a pregnant person in a lab.
The goal is a home-monitoring belt that is comfortable enough for patients to wear and accurate enough to be clinically useful. Built off a framework of sugar and conductive polymers, the thin electrodes have a sponge-like quality that allows them to hold more gel than standard electrodes, measure for 3 hours instead of 1, and resist artifacts created by patient movement. When tested on a pregnant woman, the new electrodes picked up clean signals even when the patient moved, said electrical engineer and article co-author Chuan Wang, PhD.
There is current technology that exists to monitor and map contractions during early labor, but the tests require hundreds of wire electrodes. Patients must sit still for half an hour while the electrodes are applied, then remain immobile for the test itself, which has a high sensitivity to movement.
“It’s very uncomfortable. In the clinical setting, the recording typically lasts for 15 minutes to half an hour. During that time, doctors want the patient to be still,” said Dr. Wang. “If the patient has to move, it’s going to introduce some artifacts, which is going to ruin the imaging process.”
Dr. Wang and colleagues wanted to develop an inexpensive new electrode that would be more comfortable for patients to wear for longer periods of time, yet sensitive enough to detect electrical signals in the body during preterm labor.
To do this, they used sugar structures to create a pliable electrode with a spongy structure. The new electrodes have micropores that hold conductive gel, increasing the amount of electrified surface area touching the skin.
“With the porous structure, we are effectively increasing the area by many, many times,” Dr. Wang said. “Because all those voids also contact the skin, increasing the contact area can boost the strength of the signal.”
With conventional electrodes, the gel dries quickly on the flat surface, causing signal quality to plummet. But the new electrodes can be used for “many hours” before drying out, according to Dr. Wang.
Additionally, the soft material of the new electrode acts “like a buffer” that absorbs motion and prevents the electrode from sliding around, according to Dr. Wang. That means patients can move while wearing the spongy electrodes without disturbing the recording of electrical signals in the body.
From sugar cube to spongy electrode
To create the new electrode, the researchers began by molding sugar into an electrode-shaped template. The template was then dipped into a liquid polymer, which oozed in between the grains of sugar. Next, the template underwent oven curing, emerging as a solid yet spongy structure. Hot water was then applied to dissolve the sugar.
The sugar structure is useful here because of the negative space around the grains, which is filled by the polymer – and then because of the negative space left when the sugar dissolves.
“When the sugar grains are removed, that’s where the pores are located,” Dr. Wang explained.
The sponge surface was then converted from hydrophobic to hydrophilic, thanks to an oxygen plasma treatment. Next, the sponge was blanketed in a layer of conductive polymer – a liquid that Dr. Wang likens to black ink – transforming it into an electrode. (Without the oxygen plasma step, the sponge wouldn’t have absorbed the conductive material.) After another oven-curing session, the device was affixed with wires and ready to be used.
The researchers are continuing to refine the concept and hope to develop a wireless wearable device with many spongy electrodes that record signals simultaneously – and that patients can use at home.
In addition to monitoring maternal and fetal health during labor, the researchers say the belt-like device could be used for other types of imaging and diagnosis.
“Depending on the scenario, different signals can be recorded,” Dr. Wang said. “It could be an EMG for a pregnant woman, or an ECG for an athlete or a patient with chronic cardiovascular disease that needs monitoring.”
This work was funded by the Bill & Melinda Gates Foundation (INV-005417, INV-035476). The authors acknowledge the Washington University in St. Louis Institute of Materials Science and Engineering for the use of instruments and staff assistance.
A version of this article first appeared on Medscape.com.
Burden of pregnancy-related conditions and severe cardiovascular outcomes: What is the link?
Key clinical point: Pregnancy-related cardiometabolic condition of any type was associated with almost a 3-fold higher risk for severe cardiovascular outcomes in the perinatal and postnatal periods, with preeclampsia being associated with a 7-fold higher risk for severe cardiovascular outcomes.
Major finding: Risk for severe cardiovascular outcomes was higher in women with vs without pregnancy-related cardiometabolic conditions (adjusted odds ratio [aOR] 3.1; 95% CI 2.7-3.5), with the risk being most prominent for severe preeclampsia (aOR 7.0; 95% CI 5.7-8.6).
Study details: This was a post hoc analysis of the deidentified administrative data of 74,510 women who had at least one delivery during the observation period.
Disclosures: This study did not declare any specific source of funding. The authors did not declare any conflicts of interest.
Source: Marschner S et al. Pregnancy-related cardiovascular conditions and outcomes in a United States Medicaid population. Heart. 2022;108(19):1524-1529 (Sep 12). Doi: 10.1136/heartjnl-2021-320684
Key clinical point: Pregnancy-related cardiometabolic condition of any type was associated with almost a 3-fold higher risk for severe cardiovascular outcomes in the perinatal and postnatal periods, with preeclampsia being associated with a 7-fold higher risk for severe cardiovascular outcomes.
Major finding: Risk for severe cardiovascular outcomes was higher in women with vs without pregnancy-related cardiometabolic conditions (adjusted odds ratio [aOR] 3.1; 95% CI 2.7-3.5), with the risk being most prominent for severe preeclampsia (aOR 7.0; 95% CI 5.7-8.6).
Study details: This was a post hoc analysis of the deidentified administrative data of 74,510 women who had at least one delivery during the observation period.
Disclosures: This study did not declare any specific source of funding. The authors did not declare any conflicts of interest.
Source: Marschner S et al. Pregnancy-related cardiovascular conditions and outcomes in a United States Medicaid population. Heart. 2022;108(19):1524-1529 (Sep 12). Doi: 10.1136/heartjnl-2021-320684
Key clinical point: Pregnancy-related cardiometabolic condition of any type was associated with almost a 3-fold higher risk for severe cardiovascular outcomes in the perinatal and postnatal periods, with preeclampsia being associated with a 7-fold higher risk for severe cardiovascular outcomes.
Major finding: Risk for severe cardiovascular outcomes was higher in women with vs without pregnancy-related cardiometabolic conditions (adjusted odds ratio [aOR] 3.1; 95% CI 2.7-3.5), with the risk being most prominent for severe preeclampsia (aOR 7.0; 95% CI 5.7-8.6).
Study details: This was a post hoc analysis of the deidentified administrative data of 74,510 women who had at least one delivery during the observation period.
Disclosures: This study did not declare any specific source of funding. The authors did not declare any conflicts of interest.
Source: Marschner S et al. Pregnancy-related cardiovascular conditions and outcomes in a United States Medicaid population. Heart. 2022;108(19):1524-1529 (Sep 12). Doi: 10.1136/heartjnl-2021-320684
Maternal serum sST2 and NT-proBNP levels associated with preeclampsia occurrence in twin pregnancies
Key clinical point: A significant and independent association was observed between the serum soluble suppression of tumorigenicity 2 (sST2) and N-terminal probrain natriuretic peptide (NT-proBNP) levels during the second or early-third trimester and the onset of preeclampsia in women with twin pregnancies.
Major finding: Twin pregnancies with vs without preeclampsia were associated with significantly higher maternal serum levels of sST2 and NT-proBNP in the second and early-third trimesters (both P < .001), with a serum sST2 level of ≥30.7 ng/mL (odds ratio [OR] 8.13; P < .001) and NT-proBNP level of ≥282.2 pg/mL (OR 7.20; P < .001) being independently associated with the occurrence of preeclampsia in twin pregnancies.
Study details: Findings are from a longitudinal nested case-control study that included women with dichorionic twin pregnancies from a prospective cohort and compared women with (n = 78) and without (n = 78) preeclampsia.
Disclosures: This study was funded by the National Natural Science Foundation of China. The authors declared no conflicts of interest.
Source: Xiang Q et al. The correlation between maternal serum sST2, IL-33 and NT-proBNP concentrations and occurrence of pre-eclampsia in twin pregnancies: A longitudinal study. J Clin Hypertens (Greenwich). 2022 (Sep 23). Doi: 10.1111/jch.14579
Key clinical point: A significant and independent association was observed between the serum soluble suppression of tumorigenicity 2 (sST2) and N-terminal probrain natriuretic peptide (NT-proBNP) levels during the second or early-third trimester and the onset of preeclampsia in women with twin pregnancies.
Major finding: Twin pregnancies with vs without preeclampsia were associated with significantly higher maternal serum levels of sST2 and NT-proBNP in the second and early-third trimesters (both P < .001), with a serum sST2 level of ≥30.7 ng/mL (odds ratio [OR] 8.13; P < .001) and NT-proBNP level of ≥282.2 pg/mL (OR 7.20; P < .001) being independently associated with the occurrence of preeclampsia in twin pregnancies.
Study details: Findings are from a longitudinal nested case-control study that included women with dichorionic twin pregnancies from a prospective cohort and compared women with (n = 78) and without (n = 78) preeclampsia.
Disclosures: This study was funded by the National Natural Science Foundation of China. The authors declared no conflicts of interest.
Source: Xiang Q et al. The correlation between maternal serum sST2, IL-33 and NT-proBNP concentrations and occurrence of pre-eclampsia in twin pregnancies: A longitudinal study. J Clin Hypertens (Greenwich). 2022 (Sep 23). Doi: 10.1111/jch.14579
Key clinical point: A significant and independent association was observed between the serum soluble suppression of tumorigenicity 2 (sST2) and N-terminal probrain natriuretic peptide (NT-proBNP) levels during the second or early-third trimester and the onset of preeclampsia in women with twin pregnancies.
Major finding: Twin pregnancies with vs without preeclampsia were associated with significantly higher maternal serum levels of sST2 and NT-proBNP in the second and early-third trimesters (both P < .001), with a serum sST2 level of ≥30.7 ng/mL (odds ratio [OR] 8.13; P < .001) and NT-proBNP level of ≥282.2 pg/mL (OR 7.20; P < .001) being independently associated with the occurrence of preeclampsia in twin pregnancies.
Study details: Findings are from a longitudinal nested case-control study that included women with dichorionic twin pregnancies from a prospective cohort and compared women with (n = 78) and without (n = 78) preeclampsia.
Disclosures: This study was funded by the National Natural Science Foundation of China. The authors declared no conflicts of interest.
Source: Xiang Q et al. The correlation between maternal serum sST2, IL-33 and NT-proBNP concentrations and occurrence of pre-eclampsia in twin pregnancies: A longitudinal study. J Clin Hypertens (Greenwich). 2022 (Sep 23). Doi: 10.1111/jch.14579
No neonatal hypothyroidism risk in newborns from mothers investigated for suspected PE using CTPA
Key clinical point: Exposure to computed tomography pulmonary angiography (CTPA) in pregnant women with clinically suspected pulmonary embolism (PE) did not lead to neonatal hypothyroidism among newborns.
Major finding: In newborns from pregnant women with suspected PE who underwent CTPA, all reported Guthrie levels were below 15 U/mL, with no newborns with neonatal hypothyroidism (0.0%, 95% CI 0.0%-2.5%).
Study details: The data come from a prospective management outcome study that evaluated 149 pregnant women (including 14 with twin pregnancies) with suspected PE who underwent CTPA.
Disclosures: This study was supported by grants from the Swiss National Foundation for scientific research, Groupe d'Etude de la Thrombose de Bretagne Occidentale, and International Society on Thrombosis and Haemostasis Presidential Grant. The authors declared no conflicts of interest.
Source: Righini M et al for the CT-PE-Pregnancy group. Risk of neonatal hypothyroidism in newborns from mothers exposed to CTPA during pregnancy: Ancillary data from a prospective outcome study. J Thromb Haemost. 2022 (Aug 11). Doi: 10.1111/jth.15843
Key clinical point: Exposure to computed tomography pulmonary angiography (CTPA) in pregnant women with clinically suspected pulmonary embolism (PE) did not lead to neonatal hypothyroidism among newborns.
Major finding: In newborns from pregnant women with suspected PE who underwent CTPA, all reported Guthrie levels were below 15 U/mL, with no newborns with neonatal hypothyroidism (0.0%, 95% CI 0.0%-2.5%).
Study details: The data come from a prospective management outcome study that evaluated 149 pregnant women (including 14 with twin pregnancies) with suspected PE who underwent CTPA.
Disclosures: This study was supported by grants from the Swiss National Foundation for scientific research, Groupe d'Etude de la Thrombose de Bretagne Occidentale, and International Society on Thrombosis and Haemostasis Presidential Grant. The authors declared no conflicts of interest.
Source: Righini M et al for the CT-PE-Pregnancy group. Risk of neonatal hypothyroidism in newborns from mothers exposed to CTPA during pregnancy: Ancillary data from a prospective outcome study. J Thromb Haemost. 2022 (Aug 11). Doi: 10.1111/jth.15843
Key clinical point: Exposure to computed tomography pulmonary angiography (CTPA) in pregnant women with clinically suspected pulmonary embolism (PE) did not lead to neonatal hypothyroidism among newborns.
Major finding: In newborns from pregnant women with suspected PE who underwent CTPA, all reported Guthrie levels were below 15 U/mL, with no newborns with neonatal hypothyroidism (0.0%, 95% CI 0.0%-2.5%).
Study details: The data come from a prospective management outcome study that evaluated 149 pregnant women (including 14 with twin pregnancies) with suspected PE who underwent CTPA.
Disclosures: This study was supported by grants from the Swiss National Foundation for scientific research, Groupe d'Etude de la Thrombose de Bretagne Occidentale, and International Society on Thrombosis and Haemostasis Presidential Grant. The authors declared no conflicts of interest.
Source: Righini M et al for the CT-PE-Pregnancy group. Risk of neonatal hypothyroidism in newborns from mothers exposed to CTPA during pregnancy: Ancillary data from a prospective outcome study. J Thromb Haemost. 2022 (Aug 11). Doi: 10.1111/jth.15843
Postpartum hemorrhage: Most common maternal morbidity after MTOP at ≥20 weeks’ gestation
Key clinical point: Majority of women undergoing medical termination of pregnancy (MTOP) for fetal anomaly at ≥20 weeks’ gestation had successful unassisted deliveries, but a quarter had common or severe morbidities, with the most common morbidities being postpartum hemorrhage and manual removal of retained placental tissue.
Major finding: Overall, 99.0% of women undergoing MTOP for fetal anomaly at ≥20 weeks' gestation had spontaneous vaginal deliveries and 25.5% had a common or severe morbidity, with the most common maternal morbidities being manual removal of retained placental tissue (16.0%) and postpartum hemorrhage (11.1%). Severe maternal morbidity occurred in 1.3% of cases and included amniotic fluid embolism. No maternal deaths were reported.
Study details: Findings are from a 10-year retrospective cohort study including 407 women with singleton pregnancies undergoing MTOP for fetal structure or chromosomal anomaly at ≥20 weeks' gestation.
Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.
Source: Stewart B et al. Medical termination of pregnancy for fetal anomaly at or beyond 20 weeks' gestation-What are the maternal risks? Prenat Diagn. 2022 (Sep 25). Doi: 10.1002/pd.6241
Key clinical point: Majority of women undergoing medical termination of pregnancy (MTOP) for fetal anomaly at ≥20 weeks’ gestation had successful unassisted deliveries, but a quarter had common or severe morbidities, with the most common morbidities being postpartum hemorrhage and manual removal of retained placental tissue.
Major finding: Overall, 99.0% of women undergoing MTOP for fetal anomaly at ≥20 weeks' gestation had spontaneous vaginal deliveries and 25.5% had a common or severe morbidity, with the most common maternal morbidities being manual removal of retained placental tissue (16.0%) and postpartum hemorrhage (11.1%). Severe maternal morbidity occurred in 1.3% of cases and included amniotic fluid embolism. No maternal deaths were reported.
Study details: Findings are from a 10-year retrospective cohort study including 407 women with singleton pregnancies undergoing MTOP for fetal structure or chromosomal anomaly at ≥20 weeks' gestation.
Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.
Source: Stewart B et al. Medical termination of pregnancy for fetal anomaly at or beyond 20 weeks' gestation-What are the maternal risks? Prenat Diagn. 2022 (Sep 25). Doi: 10.1002/pd.6241
Key clinical point: Majority of women undergoing medical termination of pregnancy (MTOP) for fetal anomaly at ≥20 weeks’ gestation had successful unassisted deliveries, but a quarter had common or severe morbidities, with the most common morbidities being postpartum hemorrhage and manual removal of retained placental tissue.
Major finding: Overall, 99.0% of women undergoing MTOP for fetal anomaly at ≥20 weeks' gestation had spontaneous vaginal deliveries and 25.5% had a common or severe morbidity, with the most common maternal morbidities being manual removal of retained placental tissue (16.0%) and postpartum hemorrhage (11.1%). Severe maternal morbidity occurred in 1.3% of cases and included amniotic fluid embolism. No maternal deaths were reported.
Study details: Findings are from a 10-year retrospective cohort study including 407 women with singleton pregnancies undergoing MTOP for fetal structure or chromosomal anomaly at ≥20 weeks' gestation.
Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.
Source: Stewart B et al. Medical termination of pregnancy for fetal anomaly at or beyond 20 weeks' gestation-What are the maternal risks? Prenat Diagn. 2022 (Sep 25). Doi: 10.1002/pd.6241