Sarosh Rana, MD, MPH

Hirshberg A, Zhu Y, Smith-McLallen A, et al. Association of a remote blood pressure monitoring program with postpartum adverse outcomes. Obstet Gynecol. 2023;141:1163-1170. doi:10.1097/AOG.0000000000005197. 

EXPERT COMMENTARY

Courtney Bisson, MD, is a Maternal-Fetal Medicine Fellow, University of Chicago/NorthShore University HealthSystem, Chicago, Illinois.

Sarosh Rana, MD, MPH, is Professor of Obstetrics and Gynecology and Section Chief, Maternal-Fetal Medicine, University of Chicago.

Hypertensive disorders of pregnancy account for a significant amount of morbidity during pregnancy and postpartum. In the pregnant population, data have shown that the implementation of a standardized blood pressure education program, provision of a blood pressure cuff, and assistance with postpartum follow-up result in improved blood pressures and postpartum follow-up for up to 6 weeks. In the nonpregnant population, literature suggests that RBPM in patients with hypertension results in improved outcomes, although the long-term impact of RBPM in the postpartum population remains unclear.

Recently, Hirshberg and colleagues published the results of a retrospective cohort study that assessed the impact of RBPM with text message reminders for 10 days postpartum on a composite of adverse maternal outcomes, readmissions, and follow-up within 1 year postpartum.¹

PHOTO: MICROGEN/SHUTTERSTOCK

Details of the study

The retrospective cohort study was conducted during 2017–2021 based on insurance claims of patients with hypertensive disorders of pregnancy who were enrolled in a twice-daily text message–based RBPM program for 10 days postpartum.

Data from 1,700 patients enrolled in RBPM were compared with that of propensity score matched controls that included 2,297 women not enrolled in RBPM. Of these controls, 1,276 patients (cohort C) simultaneously received care at other institutions without RBPM, and 1,021 patients (cohort A) received care at the same institution prior to implementation of RBPM.

Results. Patients in the RBPM group were found to have a significantly lower rate of composite adverse maternal outcomes compared with their matched cohorts in the year after delivery. (Individual adverse outcomes included stroke, disseminated intravascular coagulation, eclampsia, pulmonary edema, renal injury or liver failure, HELLP [hemolysis, elevated liver enzymes, low platelet count] syndrome, myocardial infarction, and cardiomyopathy.) Rates were 2.9% versus 4.7% (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.40–0.98) in the RBPM group compared with cohort A; rates in the RBPM group compared with cohort C were 3.2% versus 4.5% (OR, 0.71; 95% CI, 0.47–1.07).

Although not statistically significant, rates of emergency department visits and readmissions also were lower in the RBPM patients. Those enrolled in the RBPM program were more likely to have follow-up with cardiologists or specialist visits within 6 months postpartum. Fewer emergency department visits and readmissions resulted in lower health care utilization costs.

Study strengths and limitations

This study’s strength lies in its design and implementation of standardized protocols that allowed assessment of clinically meaningful outcomes postpartum. Although the program for RBPM was for only 10 days postpartum, it showed effects beyond the timeframe of the direct care. No such prior data exist evaluating a program’s effectiveness in improving postpartum clinical outcomes and costs through 1 year postdelivery.

Study limitations include residual bias from unobserved confounders, analysis of only 1 payer type, lack of patient level data, and evaluation of disparity. ●

Hirshberg A, Zhu Y, Smith-McLallen A, et al. Association of a remote blood pressure monitoring program with postpartum adverse outcomes. Obstet Gynecol. 2023;141:1163-1170. doi:10.1097/AOG.0000000000005197. 

EXPERT COMMENTARY

Courtney Bisson, MD, is a Maternal-Fetal Medicine Fellow, University of Chicago/NorthShore University HealthSystem, Chicago, Illinois.

Sarosh Rana, MD, MPH, is Professor of Obstetrics and Gynecology and Section Chief, Maternal-Fetal Medicine, University of Chicago.

Hypertensive disorders of pregnancy account for a significant amount of morbidity during pregnancy and postpartum. In the pregnant population, data have shown that the implementation of a standardized blood pressure education program, provision of a blood pressure cuff, and assistance with postpartum follow-up result in improved blood pressures and postpartum follow-up for up to 6 weeks. In the nonpregnant population, literature suggests that RBPM in patients with hypertension results in improved outcomes, although the long-term impact of RBPM in the postpartum population remains unclear.

Recently, Hirshberg and colleagues published the results of a retrospective cohort study that assessed the impact of RBPM with text message reminders for 10 days postpartum on a composite of adverse maternal outcomes, readmissions, and follow-up within 1 year postpartum.¹

PHOTO: MICROGEN/SHUTTERSTOCK

Details of the study

The retrospective cohort study was conducted during 2017–2021 based on insurance claims of patients with hypertensive disorders of pregnancy who were enrolled in a twice-daily text message–based RBPM program for 10 days postpartum.

Data from 1,700 patients enrolled in RBPM were compared with that of propensity score matched controls that included 2,297 women not enrolled in RBPM. Of these controls, 1,276 patients (cohort C) simultaneously received care at other institutions without RBPM, and 1,021 patients (cohort A) received care at the same institution prior to implementation of RBPM.

Results. Patients in the RBPM group were found to have a significantly lower rate of composite adverse maternal outcomes compared with their matched cohorts in the year after delivery. (Individual adverse outcomes included stroke, disseminated intravascular coagulation, eclampsia, pulmonary edema, renal injury or liver failure, HELLP [hemolysis, elevated liver enzymes, low platelet count] syndrome, myocardial infarction, and cardiomyopathy.) Rates were 2.9% versus 4.7% (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.40–0.98) in the RBPM group compared with cohort A; rates in the RBPM group compared with cohort C were 3.2% versus 4.5% (OR, 0.71; 95% CI, 0.47–1.07).

Although not statistically significant, rates of emergency department visits and readmissions also were lower in the RBPM patients. Those enrolled in the RBPM program were more likely to have follow-up with cardiologists or specialist visits within 6 months postpartum. Fewer emergency department visits and readmissions resulted in lower health care utilization costs.

Study strengths and limitations

This study’s strength lies in its design and implementation of standardized protocols that allowed assessment of clinically meaningful outcomes postpartum. Although the program for RBPM was for only 10 days postpartum, it showed effects beyond the timeframe of the direct care. No such prior data exist evaluating a program’s effectiveness in improving postpartum clinical outcomes and costs through 1 year postdelivery.

Study limitations include residual bias from unobserved confounders, analysis of only 1 payer type, lack of patient level data, and evaluation of disparity. ●

Hirshberg A, Zhu Y, Smith-McLallen A, et al. Association of a remote blood pressure monitoring program with postpartum adverse outcomes. Obstet Gynecol. 2023;141:1163-1170. doi:10.1097/AOG.0000000000005197. 

EXPERT COMMENTARY

Courtney Bisson, MD, is a Maternal-Fetal Medicine Fellow, University of Chicago/NorthShore University HealthSystem, Chicago, Illinois.

Sarosh Rana, MD, MPH, is Professor of Obstetrics and Gynecology and Section Chief, Maternal-Fetal Medicine, University of Chicago.

Hypertensive disorders of pregnancy account for a significant amount of morbidity during pregnancy and postpartum. In the pregnant population, data have shown that the implementation of a standardized blood pressure education program, provision of a blood pressure cuff, and assistance with postpartum follow-up result in improved blood pressures and postpartum follow-up for up to 6 weeks. In the nonpregnant population, literature suggests that RBPM in patients with hypertension results in improved outcomes, although the long-term impact of RBPM in the postpartum population remains unclear.

Recently, Hirshberg and colleagues published the results of a retrospective cohort study that assessed the impact of RBPM with text message reminders for 10 days postpartum on a composite of adverse maternal outcomes, readmissions, and follow-up within 1 year postpartum.¹

PHOTO: MICROGEN/SHUTTERSTOCK

Details of the study

The retrospective cohort study was conducted during 2017–2021 based on insurance claims of patients with hypertensive disorders of pregnancy who were enrolled in a twice-daily text message–based RBPM program for 10 days postpartum.

Data from 1,700 patients enrolled in RBPM were compared with that of propensity score matched controls that included 2,297 women not enrolled in RBPM. Of these controls, 1,276 patients (cohort C) simultaneously received care at other institutions without RBPM, and 1,021 patients (cohort A) received care at the same institution prior to implementation of RBPM.

Results. Patients in the RBPM group were found to have a significantly lower rate of composite adverse maternal outcomes compared with their matched cohorts in the year after delivery. (Individual adverse outcomes included stroke, disseminated intravascular coagulation, eclampsia, pulmonary edema, renal injury or liver failure, HELLP [hemolysis, elevated liver enzymes, low platelet count] syndrome, myocardial infarction, and cardiomyopathy.) Rates were 2.9% versus 4.7% (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.40–0.98) in the RBPM group compared with cohort A; rates in the RBPM group compared with cohort C were 3.2% versus 4.5% (OR, 0.71; 95% CI, 0.47–1.07).

Although not statistically significant, rates of emergency department visits and readmissions also were lower in the RBPM patients. Those enrolled in the RBPM program were more likely to have follow-up with cardiologists or specialist visits within 6 months postpartum. Fewer emergency department visits and readmissions resulted in lower health care utilization costs.

Study strengths and limitations

This study’s strength lies in its design and implementation of standardized protocols that allowed assessment of clinically meaningful outcomes postpartum. Although the program for RBPM was for only 10 days postpartum, it showed effects beyond the timeframe of the direct care. No such prior data exist evaluating a program’s effectiveness in improving postpartum clinical outcomes and costs through 1 year postdelivery.

Study limitations include residual bias from unobserved confounders, analysis of only 1 payer type, lack of patient level data, and evaluation of disparity. ●

Chappell LC, Brocklehurst P, Green ME, et al; PHOENIX Study Group. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019;394:1181-1190.

EXPERT COMMENTARY

Preeclampsia is a common hypertensive disorder of pregnancy. Among women who develop the disease at late preterm gestation, the question remains, “What is the optimal timing for delivery?” The American College of Obstetricians and Gynecologists (ACOG) categorizes preeclampsia as “with and without severe features.”¹ Delivery is recommended for women with preeclampsia with severe features at or beyond 34 weeks’ gestation, and for women with preeclampsia without severe features at or beyond 37 weeks’ gestation.¹ For patients with fetal growth restriction and preeclampsia, ACOG also recommends delivery between 34 and 37 weeks’ gestation.

Details of the study

Chappell and colleagues conducted a randomized controlled trial among women with singleton or dichorionic diamniotic twin pregnancy between 34 and 36.6 weeks’ gestation. Women were assigned to either planned delivery within 48 hours of randomization or expectant management until 37 weeks or earlier with clinical deterioration.

Among the 901 women included in the study, 450 were allocated to planned delivery and 451 to expectant management.

Study outcomes. The co-primary short-term maternal outcome was a composite of maternal morbidity with the addition of recorded systolic blood pressure of at least 160 mm Hg postrandomization (on any occasion). The co-primary short-term perinatal outcome was a composite of neonatal deaths within 7 days of delivery and perinatal deaths or neonatal unit admissions.

Participant details. At baseline, the average gestational age at randomization was 35.6 weeks, with equal distribution through the 3 weeks (34 through 36 weeks). About 37% of the women had severe hypertension (≥ 160 mm Hg) in the previous 48 hours prior to randomization, and approximately 22% had fetal growth restriction. The authors did not categorize the women based on severe features of preeclampsia.

Results. The investigators found that the proportion of women with the maternal co-primary outcome was significantly lower in the planned delivery group compared with the expectant management group (65% vs 75%), and the proportion of infants with the perinatal co-primary outcome was significantly higher in the planned delivery group compared with the expectant management group (42% vs 34%). The fact that early delivery led to more neonatal unit admissions for the infant, principally for a listed indication of prematurity and without an excess of respiratory or other morbidity, intensity of care, or length of stay, is very reassuring.

Study strengths and limitations

This is the largest study of women in this group allocated, randomized, and multicenter investigation addressing a very important clinical question. The patient population was mostly white, with only 13% black women, and had an average body mass index of 29 kg/m² (which is low compared with many practices in the United States). The average difference between the 2 study groups was the additional prolongation of pregnancy from enrollment to delivery of only 3 days, which may not be clinically relevant. More than half of the women in the expectant management group had medically indicated delivery before 37 weeks’ gestation.

Continue to: A limitation of this study...

A limitation of this study is that all women with preeclampsia were considered the same—that is, no distinction was made between severe and nonsevere preeclampsia, and a significant proportion of women had severe hypertension at enrollment, which would make them ineligible for expectant management anyway.

The maternal composite outcome was driven mostly by severe hypertension and progression to severe preeclampsia (likely driven by severe hypertension). All other maternal outcomes were very rare or did not happen; however, the incidence of delivery indications for various preeclampsia-related complications was higher in the expectant management group.

The takeaway

In the absence of biomarkers for risk stratification and treatment of preeclampsia, delivering women who have a diagnosis of preeclampsia at or beyond 34 weeks’ gestation may be a viable option for preventing maternal complications.

Chappell LC, Brocklehurst P, Green ME, et al; PHOENIX Study Group. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019;394:1181-1190.

EXPERT COMMENTARY

Preeclampsia is a common hypertensive disorder of pregnancy. Among women who develop the disease at late preterm gestation, the question remains, “What is the optimal timing for delivery?” The American College of Obstetricians and Gynecologists (ACOG) categorizes preeclampsia as “with and without severe features.”¹ Delivery is recommended for women with preeclampsia with severe features at or beyond 34 weeks’ gestation, and for women with preeclampsia without severe features at or beyond 37 weeks’ gestation.¹ For patients with fetal growth restriction and preeclampsia, ACOG also recommends delivery between 34 and 37 weeks’ gestation.

Details of the study

Chappell and colleagues conducted a randomized controlled trial among women with singleton or dichorionic diamniotic twin pregnancy between 34 and 36.6 weeks’ gestation. Women were assigned to either planned delivery within 48 hours of randomization or expectant management until 37 weeks or earlier with clinical deterioration.

Among the 901 women included in the study, 450 were allocated to planned delivery and 451 to expectant management.

Study outcomes. The co-primary short-term maternal outcome was a composite of maternal morbidity with the addition of recorded systolic blood pressure of at least 160 mm Hg postrandomization (on any occasion). The co-primary short-term perinatal outcome was a composite of neonatal deaths within 7 days of delivery and perinatal deaths or neonatal unit admissions.

Participant details. At baseline, the average gestational age at randomization was 35.6 weeks, with equal distribution through the 3 weeks (34 through 36 weeks). About 37% of the women had severe hypertension (≥ 160 mm Hg) in the previous 48 hours prior to randomization, and approximately 22% had fetal growth restriction. The authors did not categorize the women based on severe features of preeclampsia.

Results. The investigators found that the proportion of women with the maternal co-primary outcome was significantly lower in the planned delivery group compared with the expectant management group (65% vs 75%), and the proportion of infants with the perinatal co-primary outcome was significantly higher in the planned delivery group compared with the expectant management group (42% vs 34%). The fact that early delivery led to more neonatal unit admissions for the infant, principally for a listed indication of prematurity and without an excess of respiratory or other morbidity, intensity of care, or length of stay, is very reassuring.

Study strengths and limitations

This is the largest study of women in this group allocated, randomized, and multicenter investigation addressing a very important clinical question. The patient population was mostly white, with only 13% black women, and had an average body mass index of 29 kg/m² (which is low compared with many practices in the United States). The average difference between the 2 study groups was the additional prolongation of pregnancy from enrollment to delivery of only 3 days, which may not be clinically relevant. More than half of the women in the expectant management group had medically indicated delivery before 37 weeks’ gestation.

Continue to: A limitation of this study...

A limitation of this study is that all women with preeclampsia were considered the same—that is, no distinction was made between severe and nonsevere preeclampsia, and a significant proportion of women had severe hypertension at enrollment, which would make them ineligible for expectant management anyway.

The maternal composite outcome was driven mostly by severe hypertension and progression to severe preeclampsia (likely driven by severe hypertension). All other maternal outcomes were very rare or did not happen; however, the incidence of delivery indications for various preeclampsia-related complications was higher in the expectant management group.

The takeaway

In the absence of biomarkers for risk stratification and treatment of preeclampsia, delivering women who have a diagnosis of preeclampsia at or beyond 34 weeks’ gestation may be a viable option for preventing maternal complications.

Chappell LC, Brocklehurst P, Green ME, et al; PHOENIX Study Group. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019;394:1181-1190.

EXPERT COMMENTARY

Preeclampsia is a common hypertensive disorder of pregnancy. Among women who develop the disease at late preterm gestation, the question remains, “What is the optimal timing for delivery?” The American College of Obstetricians and Gynecologists (ACOG) categorizes preeclampsia as “with and without severe features.”¹ Delivery is recommended for women with preeclampsia with severe features at or beyond 34 weeks’ gestation, and for women with preeclampsia without severe features at or beyond 37 weeks’ gestation.¹ For patients with fetal growth restriction and preeclampsia, ACOG also recommends delivery between 34 and 37 weeks’ gestation.

Details of the study

Chappell and colleagues conducted a randomized controlled trial among women with singleton or dichorionic diamniotic twin pregnancy between 34 and 36.6 weeks’ gestation. Women were assigned to either planned delivery within 48 hours of randomization or expectant management until 37 weeks or earlier with clinical deterioration.

Among the 901 women included in the study, 450 were allocated to planned delivery and 451 to expectant management.

Study outcomes. The co-primary short-term maternal outcome was a composite of maternal morbidity with the addition of recorded systolic blood pressure of at least 160 mm Hg postrandomization (on any occasion). The co-primary short-term perinatal outcome was a composite of neonatal deaths within 7 days of delivery and perinatal deaths or neonatal unit admissions.

Participant details. At baseline, the average gestational age at randomization was 35.6 weeks, with equal distribution through the 3 weeks (34 through 36 weeks). About 37% of the women had severe hypertension (≥ 160 mm Hg) in the previous 48 hours prior to randomization, and approximately 22% had fetal growth restriction. The authors did not categorize the women based on severe features of preeclampsia.

Results. The investigators found that the proportion of women with the maternal co-primary outcome was significantly lower in the planned delivery group compared with the expectant management group (65% vs 75%), and the proportion of infants with the perinatal co-primary outcome was significantly higher in the planned delivery group compared with the expectant management group (42% vs 34%). The fact that early delivery led to more neonatal unit admissions for the infant, principally for a listed indication of prematurity and without an excess of respiratory or other morbidity, intensity of care, or length of stay, is very reassuring.

Study strengths and limitations

This is the largest study of women in this group allocated, randomized, and multicenter investigation addressing a very important clinical question. The patient population was mostly white, with only 13% black women, and had an average body mass index of 29 kg/m² (which is low compared with many practices in the United States). The average difference between the 2 study groups was the additional prolongation of pregnancy from enrollment to delivery of only 3 days, which may not be clinically relevant. More than half of the women in the expectant management group had medically indicated delivery before 37 weeks’ gestation.

Continue to: A limitation of this study...

A limitation of this study is that all women with preeclampsia were considered the same—that is, no distinction was made between severe and nonsevere preeclampsia, and a significant proportion of women had severe hypertension at enrollment, which would make them ineligible for expectant management anyway.

The maternal composite outcome was driven mostly by severe hypertension and progression to severe preeclampsia (likely driven by severe hypertension). All other maternal outcomes were very rare or did not happen; however, the incidence of delivery indications for various preeclampsia-related complications was higher in the expectant management group.

The takeaway

In the absence of biomarkers for risk stratification and treatment of preeclampsia, delivering women who have a diagnosis of preeclampsia at or beyond 34 weeks’ gestation may be a viable option for preventing maternal complications.

EXPERT COMMENTARY

Preeclampsia is a disorder of impaired placentation. ELABELA (ELA) encodes an endogenous ligand for the apelin receptor and is detected in preimplantation human blastocysts and in 2 organs in adults: the placenta and kidney. Recently, an international team of researchers described their study findings on ELA and its role in placental vascular development and preeclampsia in mice.

Details of the study

To delineate the contribution of ELA to mammalian development, Ho and colleagues generated Ela knockout mice. The investigators showed that during development, the ELA protein is first detected in the early placenta and becomes abundant later in placenta formation. They also demonstrated that ELA is a pregnancy hormone that circulates in the blood of pregnant, but not nonpregnant, mice.

Placental structure. The Ela knockout mice had placentas that demonstrated thin labyrinths, with poor vascularization, increased apoptosis, and reduced proliferation. Further, RNA analysis of ELA-lacking placentas revealed a gene expression profile indicative of hypoxia, including the upregulation of certain genes involved in blood vessel building. Placental vessels showed overall stunted architecture characterized by little or no extension and branching of angiogenic sprouts and impaired formation of the adequate labyrinth network required for proper perfusion in the placenta.

Given these gene expression findings and the fact that placental and vascular abnormalities have long been suspected to underlie preeclampsia, the investigators sought to determine if ELA-lacking mice exhibit preeclampsia. Evidence indicated they do.

Indicators of preeclampsia. Pregnant ELA-lacking mice had significantly higher levels of proteinuria and significantly higher blood pressure than either pregnant wild-type mice or nonpregnant ELA-lacking mice. Further, at the end of pregnancy, histology and transmission electron microscopy of kidney glomerular sections from ELA-lacking pregnant mice revealed signs of endotheliosis, a unique renal pathology that is also observed in women with preeclampsia. Pups of ELA-lacking mothers tended to weigh less than those of wild-type mothers, a situation that may be similar to the fetal intrauterine growth restriction commonly seen in women with preeclampsia.

Angiogenic factors. The authors then looked at levels of angiogenic proteins implicated in the pathogenesis of preeclampsia to determine if ELA is upstream. They found that ELA-lacking mice placentas had increased levels of sFlt1, Vegfa, and Plgf mRNA; these transcriptional changes, however, did not translate into significantly elevated plasma levels of the respective proteins. Thus, these findings indicate that ELA acts independently of, and possibly earlier than, angiogenic factors in the pathogenesis of preeclampsia.

Experimental treatment. The authors further showed that infusing recombinant ELA protein could alleviate symptoms of preeclampsia in mice. Injection of ELA protein in ELA-lacking mice led to reduction of blood pressure, reversal of glomerular endotheliosis, and rescue of fetal growth restriction.

Study strengths and weaknesses

This animal study contributes compelling molecular evidence of ELA’s role in mammalian placental development and angiogenesis, revealing that ELA deficiency leads to preeclampsia and placental abnormalities in pregnant mice. How ELA acts in humans and human pregnancy, however, has yet to be explored.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Preeclampsia is a disorder of impaired placentation. ELABELA (ELA) encodes an endogenous ligand for the apelin receptor and is detected in preimplantation human blastocysts and in 2 organs in adults: the placenta and kidney. Recently, an international team of researchers described their study findings on ELA and its role in placental vascular development and preeclampsia in mice.

Details of the study

To delineate the contribution of ELA to mammalian development, Ho and colleagues generated Ela knockout mice. The investigators showed that during development, the ELA protein is first detected in the early placenta and becomes abundant later in placenta formation. They also demonstrated that ELA is a pregnancy hormone that circulates in the blood of pregnant, but not nonpregnant, mice.

Placental structure. The Ela knockout mice had placentas that demonstrated thin labyrinths, with poor vascularization, increased apoptosis, and reduced proliferation. Further, RNA analysis of ELA-lacking placentas revealed a gene expression profile indicative of hypoxia, including the upregulation of certain genes involved in blood vessel building. Placental vessels showed overall stunted architecture characterized by little or no extension and branching of angiogenic sprouts and impaired formation of the adequate labyrinth network required for proper perfusion in the placenta.

Given these gene expression findings and the fact that placental and vascular abnormalities have long been suspected to underlie preeclampsia, the investigators sought to determine if ELA-lacking mice exhibit preeclampsia. Evidence indicated they do.

Indicators of preeclampsia. Pregnant ELA-lacking mice had significantly higher levels of proteinuria and significantly higher blood pressure than either pregnant wild-type mice or nonpregnant ELA-lacking mice. Further, at the end of pregnancy, histology and transmission electron microscopy of kidney glomerular sections from ELA-lacking pregnant mice revealed signs of endotheliosis, a unique renal pathology that is also observed in women with preeclampsia. Pups of ELA-lacking mothers tended to weigh less than those of wild-type mothers, a situation that may be similar to the fetal intrauterine growth restriction commonly seen in women with preeclampsia.

Angiogenic factors. The authors then looked at levels of angiogenic proteins implicated in the pathogenesis of preeclampsia to determine if ELA is upstream. They found that ELA-lacking mice placentas had increased levels of sFlt1, Vegfa, and Plgf mRNA; these transcriptional changes, however, did not translate into significantly elevated plasma levels of the respective proteins. Thus, these findings indicate that ELA acts independently of, and possibly earlier than, angiogenic factors in the pathogenesis of preeclampsia.

Experimental treatment. The authors further showed that infusing recombinant ELA protein could alleviate symptoms of preeclampsia in mice. Injection of ELA protein in ELA-lacking mice led to reduction of blood pressure, reversal of glomerular endotheliosis, and rescue of fetal growth restriction.

Study strengths and weaknesses

This animal study contributes compelling molecular evidence of ELA’s role in mammalian placental development and angiogenesis, revealing that ELA deficiency leads to preeclampsia and placental abnormalities in pregnant mice. How ELA acts in humans and human pregnancy, however, has yet to be explored.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Preeclampsia is a disorder of impaired placentation. ELABELA (ELA) encodes an endogenous ligand for the apelin receptor and is detected in preimplantation human blastocysts and in 2 organs in adults: the placenta and kidney. Recently, an international team of researchers described their study findings on ELA and its role in placental vascular development and preeclampsia in mice.

Details of the study

To delineate the contribution of ELA to mammalian development, Ho and colleagues generated Ela knockout mice. The investigators showed that during development, the ELA protein is first detected in the early placenta and becomes abundant later in placenta formation. They also demonstrated that ELA is a pregnancy hormone that circulates in the blood of pregnant, but not nonpregnant, mice.

Placental structure. The Ela knockout mice had placentas that demonstrated thin labyrinths, with poor vascularization, increased apoptosis, and reduced proliferation. Further, RNA analysis of ELA-lacking placentas revealed a gene expression profile indicative of hypoxia, including the upregulation of certain genes involved in blood vessel building. Placental vessels showed overall stunted architecture characterized by little or no extension and branching of angiogenic sprouts and impaired formation of the adequate labyrinth network required for proper perfusion in the placenta.

Given these gene expression findings and the fact that placental and vascular abnormalities have long been suspected to underlie preeclampsia, the investigators sought to determine if ELA-lacking mice exhibit preeclampsia. Evidence indicated they do.

Indicators of preeclampsia. Pregnant ELA-lacking mice had significantly higher levels of proteinuria and significantly higher blood pressure than either pregnant wild-type mice or nonpregnant ELA-lacking mice. Further, at the end of pregnancy, histology and transmission electron microscopy of kidney glomerular sections from ELA-lacking pregnant mice revealed signs of endotheliosis, a unique renal pathology that is also observed in women with preeclampsia. Pups of ELA-lacking mothers tended to weigh less than those of wild-type mothers, a situation that may be similar to the fetal intrauterine growth restriction commonly seen in women with preeclampsia.

Angiogenic factors. The authors then looked at levels of angiogenic proteins implicated in the pathogenesis of preeclampsia to determine if ELA is upstream. They found that ELA-lacking mice placentas had increased levels of sFlt1, Vegfa, and Plgf mRNA; these transcriptional changes, however, did not translate into significantly elevated plasma levels of the respective proteins. Thus, these findings indicate that ELA acts independently of, and possibly earlier than, angiogenic factors in the pathogenesis of preeclampsia.

Experimental treatment. The authors further showed that infusing recombinant ELA protein could alleviate symptoms of preeclampsia in mice. Injection of ELA protein in ELA-lacking mice led to reduction of blood pressure, reversal of glomerular endotheliosis, and rescue of fetal growth restriction.

Study strengths and weaknesses

This animal study contributes compelling molecular evidence of ELA’s role in mammalian placental development and angiogenesis, revealing that ELA deficiency leads to preeclampsia and placental abnormalities in pregnant mice. How ELA acts in humans and human pregnancy, however, has yet to be explored.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.