Expert Commentary

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.

Visit the NAMS annual meetings website

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.

Visit the NAMS annual meetings website

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.

Visit the NAMS annual meetings website

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.

Click here to download

Click here to download

Click here to download

EXPERT COMMENTARY

Influenza can be a serious, even life-threatening infection, especially in pregnant women and their newborn infants.¹ For that reason, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) strongly recommend that all pregnant women receive the inactivated influenza vaccine at the start of each flu season, regardless of trimester of exposure.

The most widely-used vaccine in the United States is the inactivated quadrivalent vaccine, which is intended for intramuscular administration in a single dose. The 2017-2018 version of this vaccine includes 2 influenza A antigens and 2 influenza B antigens. The first of the A antigens differs from last year's vaccine. The other 3 antigens are the same as in the 2016-2017 vaccine:

• A/Michigan/45/2015 (H1N1) pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus  
• B/Brisbane/60/2008-like virus
• B/Phuket/3073/2013-like virus (B/Yamagota)

Several recent reports in large, diverse populations^2-5 have demonstrated that the vaccine does not increase the risk of spontaneous abortion, stillbirth, preterm delivery, or congenital anomalies. Therefore, a recent report by Donahue and colleagues⁶ is surprising and is certainly worthy of our attention. 

Related article:
Does influenza immunization during pregnancy confer flu protection to newborns?

Details of the study

Donahue and colleagues, experienced investigators, were tasked by the CDC with using information from the Vaccine Safety Datalink to specifically assess the safety of the influenza vaccine when administered early in pregnancy. They evaluated 485 women who had experienced a spontaneous abortion in 1 of 2 time periods: September 1, 2010 to April 28, 2011 and September 1, 2011 to April 28, 2012. These women were matched by last menstrual period with controls who subsequently had a liveborn infant or stillbirth at greater than 20 weeks of gestation. The exposure of interest was receipt of the monovalent H1N1 vaccine (H1N1pdm09), the inactivated trivalent vaccine (A/California/7/2009 H1N1 pdm09-like, A/Perth/16/2009 H3N2-like, and B/Brisbane/60/2008-like), or both in the 28 days immediately preceding the spontaneous abortion. The investigators also considered 2 other windows of exposure: 29 to 56 days and greater than 56 days. In addition, they controlled for the following potential confounding variables: maternal age, smoking history, presence of type 1 or 2 diabetes, prepregnancy BMI, and previous health care utilization. 

Cases were significantly older than controls. They also were more likely to be African-American, to have had a history of greater than or equal to 2 spontaneous abortions, and to have smoked during pregnancy. The median gestational age at the time of spontaneous abortion was 7 weeks. Overall, the adjusted odds ratio (aOR) of spontaneous abortion within the 1- to 28-day window was 2.0 (95% confidence interval [CI], 1.1-3.6). There was not even a weak association in the other 2 windows of exposure. However, in women who received the pH1N1 vaccine in the previous flu season, the aOR was 7.7 (95% CI, 2.2-27.3). When women who had experienced 2 or more spontaneous abortions were excluded, the aOR remained significantly elevated at 6.5 (95% CI, 1.7-24.3). The aOR was 1.3 (95% CI, 0.7-2.7) in women who were not vaccinated with the pH1N1 vaccine in the previous flu season.

Donahue and colleagues⁶ offered several possible explanations for their observations. They noted that the pH1N1 vaccine seemed to cause at least mild increases in pro-inflammatory cytokines, particularly in pregnant compared with nonpregnant women. In addition, infection with the pH1N1 virus or vaccination with the pH1N1 vaccine induces an increase in T helper type-1 cells, which exert a pro-inflammatory effect. Excessive inflammation, in turn, may cause spontaneous abortion.

Related article:
5 ways to reduce infection risk during pregnancy

Study limitations

This study has several important limitations. First, the vaccine used in the investigation is not identical to the one used most commonly today. Second, although the number of women with spontaneous abortions is relatively large, the number who received the pH1N1-containing vaccine in consecutive years was relatively small. Third, this case-control study was able to estimate an odds ratio for the adverse outcome, but it could not prove causation, nor could it provide a precise estimate of absolute risk for a spontaneous miscarriage following the influenza vaccine. Finally, the authors, understandably,were unable to control for all the myriad factors that may increase the risk for spontaneous abortion.

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

Influenza can be a serious, even life-threatening infection, especially in pregnant women and their newborn infants.¹ For that reason, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) strongly recommend that all pregnant women receive the inactivated influenza vaccine at the start of each flu season, regardless of trimester of exposure.

The most widely-used vaccine in the United States is the inactivated quadrivalent vaccine, which is intended for intramuscular administration in a single dose. The 2017-2018 version of this vaccine includes 2 influenza A antigens and 2 influenza B antigens. The first of the A antigens differs from last year's vaccine. The other 3 antigens are the same as in the 2016-2017 vaccine:

• A/Michigan/45/2015 (H1N1) pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus  
• B/Brisbane/60/2008-like virus
• B/Phuket/3073/2013-like virus (B/Yamagota)

Several recent reports in large, diverse populations^2-5 have demonstrated that the vaccine does not increase the risk of spontaneous abortion, stillbirth, preterm delivery, or congenital anomalies. Therefore, a recent report by Donahue and colleagues⁶ is surprising and is certainly worthy of our attention. 

Related article:
Does influenza immunization during pregnancy confer flu protection to newborns?

Details of the study

Donahue and colleagues, experienced investigators, were tasked by the CDC with using information from the Vaccine Safety Datalink to specifically assess the safety of the influenza vaccine when administered early in pregnancy. They evaluated 485 women who had experienced a spontaneous abortion in 1 of 2 time periods: September 1, 2010 to April 28, 2011 and September 1, 2011 to April 28, 2012. These women were matched by last menstrual period with controls who subsequently had a liveborn infant or stillbirth at greater than 20 weeks of gestation. The exposure of interest was receipt of the monovalent H1N1 vaccine (H1N1pdm09), the inactivated trivalent vaccine (A/California/7/2009 H1N1 pdm09-like, A/Perth/16/2009 H3N2-like, and B/Brisbane/60/2008-like), or both in the 28 days immediately preceding the spontaneous abortion. The investigators also considered 2 other windows of exposure: 29 to 56 days and greater than 56 days. In addition, they controlled for the following potential confounding variables: maternal age, smoking history, presence of type 1 or 2 diabetes, prepregnancy BMI, and previous health care utilization. 

Cases were significantly older than controls. They also were more likely to be African-American, to have had a history of greater than or equal to 2 spontaneous abortions, and to have smoked during pregnancy. The median gestational age at the time of spontaneous abortion was 7 weeks. Overall, the adjusted odds ratio (aOR) of spontaneous abortion within the 1- to 28-day window was 2.0 (95% confidence interval [CI], 1.1-3.6). There was not even a weak association in the other 2 windows of exposure. However, in women who received the pH1N1 vaccine in the previous flu season, the aOR was 7.7 (95% CI, 2.2-27.3). When women who had experienced 2 or more spontaneous abortions were excluded, the aOR remained significantly elevated at 6.5 (95% CI, 1.7-24.3). The aOR was 1.3 (95% CI, 0.7-2.7) in women who were not vaccinated with the pH1N1 vaccine in the previous flu season.

Donahue and colleagues⁶ offered several possible explanations for their observations. They noted that the pH1N1 vaccine seemed to cause at least mild increases in pro-inflammatory cytokines, particularly in pregnant compared with nonpregnant women. In addition, infection with the pH1N1 virus or vaccination with the pH1N1 vaccine induces an increase in T helper type-1 cells, which exert a pro-inflammatory effect. Excessive inflammation, in turn, may cause spontaneous abortion.

Related article:
5 ways to reduce infection risk during pregnancy

Study limitations

This study has several important limitations. First, the vaccine used in the investigation is not identical to the one used most commonly today. Second, although the number of women with spontaneous abortions is relatively large, the number who received the pH1N1-containing vaccine in consecutive years was relatively small. Third, this case-control study was able to estimate an odds ratio for the adverse outcome, but it could not prove causation, nor could it provide a precise estimate of absolute risk for a spontaneous miscarriage following the influenza vaccine. Finally, the authors, understandably,were unable to control for all the myriad factors that may increase the risk for spontaneous abortion.

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

Influenza can be a serious, even life-threatening infection, especially in pregnant women and their newborn infants.¹ For that reason, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) strongly recommend that all pregnant women receive the inactivated influenza vaccine at the start of each flu season, regardless of trimester of exposure.

The most widely-used vaccine in the United States is the inactivated quadrivalent vaccine, which is intended for intramuscular administration in a single dose. The 2017-2018 version of this vaccine includes 2 influenza A antigens and 2 influenza B antigens. The first of the A antigens differs from last year's vaccine. The other 3 antigens are the same as in the 2016-2017 vaccine:

• A/Michigan/45/2015 (H1N1) pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus  
• B/Brisbane/60/2008-like virus
• B/Phuket/3073/2013-like virus (B/Yamagota)

Several recent reports in large, diverse populations^2-5 have demonstrated that the vaccine does not increase the risk of spontaneous abortion, stillbirth, preterm delivery, or congenital anomalies. Therefore, a recent report by Donahue and colleagues⁶ is surprising and is certainly worthy of our attention. 

Related article:
Does influenza immunization during pregnancy confer flu protection to newborns?

Details of the study

Donahue and colleagues, experienced investigators, were tasked by the CDC with using information from the Vaccine Safety Datalink to specifically assess the safety of the influenza vaccine when administered early in pregnancy. They evaluated 485 women who had experienced a spontaneous abortion in 1 of 2 time periods: September 1, 2010 to April 28, 2011 and September 1, 2011 to April 28, 2012. These women were matched by last menstrual period with controls who subsequently had a liveborn infant or stillbirth at greater than 20 weeks of gestation. The exposure of interest was receipt of the monovalent H1N1 vaccine (H1N1pdm09), the inactivated trivalent vaccine (A/California/7/2009 H1N1 pdm09-like, A/Perth/16/2009 H3N2-like, and B/Brisbane/60/2008-like), or both in the 28 days immediately preceding the spontaneous abortion. The investigators also considered 2 other windows of exposure: 29 to 56 days and greater than 56 days. In addition, they controlled for the following potential confounding variables: maternal age, smoking history, presence of type 1 or 2 diabetes, prepregnancy BMI, and previous health care utilization. 

Cases were significantly older than controls. They also were more likely to be African-American, to have had a history of greater than or equal to 2 spontaneous abortions, and to have smoked during pregnancy. The median gestational age at the time of spontaneous abortion was 7 weeks. Overall, the adjusted odds ratio (aOR) of spontaneous abortion within the 1- to 28-day window was 2.0 (95% confidence interval [CI], 1.1-3.6). There was not even a weak association in the other 2 windows of exposure. However, in women who received the pH1N1 vaccine in the previous flu season, the aOR was 7.7 (95% CI, 2.2-27.3). When women who had experienced 2 or more spontaneous abortions were excluded, the aOR remained significantly elevated at 6.5 (95% CI, 1.7-24.3). The aOR was 1.3 (95% CI, 0.7-2.7) in women who were not vaccinated with the pH1N1 vaccine in the previous flu season.

Donahue and colleagues⁶ offered several possible explanations for their observations. They noted that the pH1N1 vaccine seemed to cause at least mild increases in pro-inflammatory cytokines, particularly in pregnant compared with nonpregnant women. In addition, infection with the pH1N1 virus or vaccination with the pH1N1 vaccine induces an increase in T helper type-1 cells, which exert a pro-inflammatory effect. Excessive inflammation, in turn, may cause spontaneous abortion.

Related article:
5 ways to reduce infection risk during pregnancy

Study limitations

This study has several important limitations. First, the vaccine used in the investigation is not identical to the one used most commonly today. Second, although the number of women with spontaneous abortions is relatively large, the number who received the pH1N1-containing vaccine in consecutive years was relatively small. Third, this case-control study was able to estimate an odds ratio for the adverse outcome, but it could not prove causation, nor could it provide a precise estimate of absolute risk for a spontaneous miscarriage following the influenza vaccine. Finally, the authors, understandably,were unable to control for all the myriad factors that may increase the risk for spontaneous abortion.

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.

To date, efforts to translate exciting laboratory findings into clinical trials for Parkinson’s disease have not met with much success. However, the latest exenatide study results offer another chance for improving this situation. This randomized, placebo-controlled trial also highlights how a medication already in human use might be repurposed for a novel application.

Whether this study actually proved its concept will require confirmation by further clinical investigation. The biggest challenge presented by this study has to do with studying patients with Parkinson’s disease who already are receiving symptomatic therapy with dopaminergic drugs. The study plan was to eliminate this effect by an overnight washout of Parkinson’s disease drugs. But waiting for a day or two after stopping medication, even for a short-acting drug like levodopa, does not necessarily abolish all of its symptomatic effects. If exenatide acted by enhancing the temporary relief of parkinsonism offered by medications rather than by protecting against further neurodegeneration, study ratings would not be able to discern this difference. Similarly, if exenatide exerts a trophic effect on striatal dopamine transporters, the observed reduction of decline in dopamine transporter (DAT) scan readings would not necessarily reflect sparing of further dopaminergic neuron loss.

Another potentially confounding factor was that during the course of the trial, the exenatide group increased its concomitant dopaminergic therapy more than the placebo-treated controls did. In a study of only 62 subjects who were already advanced in the course of Parkinson’s disease and experiencing motor fluctuations, any imbalance between treatment and placebo groups might impart uncertainties for which it may be difficult to correct.

Despite all the reasonable objections that might detract from a definitive interpretation of this study, its results make a credible argument for a neuroprotection outcome. The happenstance of two seemingly independent indicators of disease modification—in this case, the washout ratings of parkinsonian features and the DAT scan results—provides grounds for optimism. In the quest for halting the advance of Parkinson’s disease, the perfect study has yet to emerge. The exenatide investigators’ careful attention to detail and collection of other study information and biomarker specimens will serve well the next researchers who explore the potential for glucagon-like peptide-1 treatments.

—Peter A. LeWitt, MD
Professor of Neurology
Wayne State University School of Medicine
Director, Parkinson's Disease and Movement Disorders Program
Henry Ford Hospital West Bloomfield
West Bloomfield, Michigan

To date, efforts to translate exciting laboratory findings into clinical trials for Parkinson’s disease have not met with much success. However, the latest exenatide study results offer another chance for improving this situation. This randomized, placebo-controlled trial also highlights how a medication already in human use might be repurposed for a novel application.

Whether this study actually proved its concept will require confirmation by further clinical investigation. The biggest challenge presented by this study has to do with studying patients with Parkinson’s disease who already are receiving symptomatic therapy with dopaminergic drugs. The study plan was to eliminate this effect by an overnight washout of Parkinson’s disease drugs. But waiting for a day or two after stopping medication, even for a short-acting drug like levodopa, does not necessarily abolish all of its symptomatic effects. If exenatide acted by enhancing the temporary relief of parkinsonism offered by medications rather than by protecting against further neurodegeneration, study ratings would not be able to discern this difference. Similarly, if exenatide exerts a trophic effect on striatal dopamine transporters, the observed reduction of decline in dopamine transporter (DAT) scan readings would not necessarily reflect sparing of further dopaminergic neuron loss.

Another potentially confounding factor was that during the course of the trial, the exenatide group increased its concomitant dopaminergic therapy more than the placebo-treated controls did. In a study of only 62 subjects who were already advanced in the course of Parkinson’s disease and experiencing motor fluctuations, any imbalance between treatment and placebo groups might impart uncertainties for which it may be difficult to correct.

Despite all the reasonable objections that might detract from a definitive interpretation of this study, its results make a credible argument for a neuroprotection outcome. The happenstance of two seemingly independent indicators of disease modification—in this case, the washout ratings of parkinsonian features and the DAT scan results—provides grounds for optimism. In the quest for halting the advance of Parkinson’s disease, the perfect study has yet to emerge. The exenatide investigators’ careful attention to detail and collection of other study information and biomarker specimens will serve well the next researchers who explore the potential for glucagon-like peptide-1 treatments.

—Peter A. LeWitt, MD
Professor of Neurology
Wayne State University School of Medicine
Director, Parkinson's Disease and Movement Disorders Program
Henry Ford Hospital West Bloomfield
West Bloomfield, Michigan

To date, efforts to translate exciting laboratory findings into clinical trials for Parkinson’s disease have not met with much success. However, the latest exenatide study results offer another chance for improving this situation. This randomized, placebo-controlled trial also highlights how a medication already in human use might be repurposed for a novel application.

Whether this study actually proved its concept will require confirmation by further clinical investigation. The biggest challenge presented by this study has to do with studying patients with Parkinson’s disease who already are receiving symptomatic therapy with dopaminergic drugs. The study plan was to eliminate this effect by an overnight washout of Parkinson’s disease drugs. But waiting for a day or two after stopping medication, even for a short-acting drug like levodopa, does not necessarily abolish all of its symptomatic effects. If exenatide acted by enhancing the temporary relief of parkinsonism offered by medications rather than by protecting against further neurodegeneration, study ratings would not be able to discern this difference. Similarly, if exenatide exerts a trophic effect on striatal dopamine transporters, the observed reduction of decline in dopamine transporter (DAT) scan readings would not necessarily reflect sparing of further dopaminergic neuron loss.

Another potentially confounding factor was that during the course of the trial, the exenatide group increased its concomitant dopaminergic therapy more than the placebo-treated controls did. In a study of only 62 subjects who were already advanced in the course of Parkinson’s disease and experiencing motor fluctuations, any imbalance between treatment and placebo groups might impart uncertainties for which it may be difficult to correct.

Despite all the reasonable objections that might detract from a definitive interpretation of this study, its results make a credible argument for a neuroprotection outcome. The happenstance of two seemingly independent indicators of disease modification—in this case, the washout ratings of parkinsonian features and the DAT scan results—provides grounds for optimism. In the quest for halting the advance of Parkinson’s disease, the perfect study has yet to emerge. The exenatide investigators’ careful attention to detail and collection of other study information and biomarker specimens will serve well the next researchers who explore the potential for glucagon-like peptide-1 treatments.

—Peter A. LeWitt, MD
Professor of Neurology
Wayne State University School of Medicine
Director, Parkinson's Disease and Movement Disorders Program
Henry Ford Hospital West Bloomfield
West Bloomfield, Michigan

Photo: Shutterstock

Many hospitals across the country have received designation as “Baby Friendly”; many other hospitals are in the process of seeking this designation. In order to be Baby Friendly, a hospital or birth center must prove they have implemented a set of 10 rules to encourage breastfeeding. As Baby Friendly USA puts it in their byline, it has become the gold standard of care.

Importantly, Baby Friendly fails to recognize that there is another equally crucial participant in any childbirth experience—the woman. Although childbirth is natural and usually healthy, it is not easy. Women commonly lose up to 1 L of blood during childbirth.¹ Labor can take 18 to 24 hours for a first-timer and about 12 to 18 hours for an encore performance, often disrupting at least1 entire night of sleep. The minimally invasive cesarean delivery continues to elude us, and women undergoing cesarean delivery must contend with a sizable incision and the additional pain and associated recovery.

Hospitals adopting the Baby Friendly rules must not allow formula, must prohibit pacifier use, and must go to great lengths to encourage rooming-in. Rooming-in means that the baby shares the same room as the new mother around-the-clock, which is reported to help the new mother distinguish sounds that indicate “feed me” from those that indicate a cool breeze. Rooming-in has been shown to be associated with a modest increase in breastfeeding²; however, women who are committed to breastfeeding likely room-in more often than women less committed to breastfeeding. Whether or not forcing the woman who is less committed to breastfeeding or the woman highly committed to breastfeeding who just wants a good night’s rest to room-in with her baby has a meaningful impact on breastfeeding remains unknown.

Are we violating ethics rules?

When hospitals adopt the Baby Friendly rules—policies that limit women’s choices for themselves and for their baby—we violate medical ethics principles regarding respect for autonomy, beneficence, and truthfulness. For instance, women are told that if they breastfeed their babies will be smarter, healthier, and have stronger emotional bonds. However, when research studies control for factors such as mothers’ education level or the amount of time spent talking to the baby, the effect of breastfeeding on intelligence “washes out.”³ Babies who are formula-fed but cuddled experience the same degree of bonding with their mothers as breast-fed babies.^4,5

Although breast is best, the reported benefits that underlie Baby Friendly are overblown and oversold. When we explain to a woman why her newborn cannot spend a few hours in the nursery or why we cannot allow a pacifier, we are denying her the right to parent and make choices for herself and her baby, not acting in the best interest of the woman. We are in fact misrepresenting the truth. We are also acting paternalistic, propagating the long tradition of telling women that we know better about their reproductive health and choices.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Breastfeeding still not fully accepted outside the hospital

The Baby Friendly rules restrict autonomy and prod women to breastfeed for the few days that they remain in the hospital postpartum. However, these women go home to societal and institutional systems that are deeply unsupportive of breastfeeding. In addition to being the birthplace for 98% of babies born in the United States, the health care industry is the single largest employer of US women.^6,7 There are 5 academic hospitals in the Boston area. After contacting the human resources department at each, I found that only 1 has a policy for their breastfeeding employees.

Women should not be forced to choose between breastfeeding and working, between taking a longer maternity leave (often unpaid and professionally detrimental) and shelving the breast pump. What we invest in reveals our values. When we require women to room-in without respecting their choices or needs, and when workplaces fail to provide reasonable flexibility and private space for breast-pumping employees, our values as a society are revealed.

Women and men, hospital users and hospital employees, need to insist that the principles of autonomy, respect for persons, truthfulness, and justice guide breastfeeding policy both within our hospitals and within our workplaces. We need to respect women and the choices that they make for themselves and their families. We need to allow women to decide to recover from their delivery without their baby constantly in arms’ reach. We need to ensure that our counseling and our policies are rooted in sound science and not influenced by passionate but biased perspectives.

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.

Photo: Shutterstock

Many hospitals across the country have received designation as “Baby Friendly”; many other hospitals are in the process of seeking this designation. In order to be Baby Friendly, a hospital or birth center must prove they have implemented a set of 10 rules to encourage breastfeeding. As Baby Friendly USA puts it in their byline, it has become the gold standard of care.

Importantly, Baby Friendly fails to recognize that there is another equally crucial participant in any childbirth experience—the woman. Although childbirth is natural and usually healthy, it is not easy. Women commonly lose up to 1 L of blood during childbirth.¹ Labor can take 18 to 24 hours for a first-timer and about 12 to 18 hours for an encore performance, often disrupting at least1 entire night of sleep. The minimally invasive cesarean delivery continues to elude us, and women undergoing cesarean delivery must contend with a sizable incision and the additional pain and associated recovery.

Hospitals adopting the Baby Friendly rules must not allow formula, must prohibit pacifier use, and must go to great lengths to encourage rooming-in. Rooming-in means that the baby shares the same room as the new mother around-the-clock, which is reported to help the new mother distinguish sounds that indicate “feed me” from those that indicate a cool breeze. Rooming-in has been shown to be associated with a modest increase in breastfeeding²; however, women who are committed to breastfeeding likely room-in more often than women less committed to breastfeeding. Whether or not forcing the woman who is less committed to breastfeeding or the woman highly committed to breastfeeding who just wants a good night’s rest to room-in with her baby has a meaningful impact on breastfeeding remains unknown.

Are we violating ethics rules?

When hospitals adopt the Baby Friendly rules—policies that limit women’s choices for themselves and for their baby—we violate medical ethics principles regarding respect for autonomy, beneficence, and truthfulness. For instance, women are told that if they breastfeed their babies will be smarter, healthier, and have stronger emotional bonds. However, when research studies control for factors such as mothers’ education level or the amount of time spent talking to the baby, the effect of breastfeeding on intelligence “washes out.”³ Babies who are formula-fed but cuddled experience the same degree of bonding with their mothers as breast-fed babies.^4,5

Although breast is best, the reported benefits that underlie Baby Friendly are overblown and oversold. When we explain to a woman why her newborn cannot spend a few hours in the nursery or why we cannot allow a pacifier, we are denying her the right to parent and make choices for herself and her baby, not acting in the best interest of the woman. We are in fact misrepresenting the truth. We are also acting paternalistic, propagating the long tradition of telling women that we know better about their reproductive health and choices.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Breastfeeding still not fully accepted outside the hospital

The Baby Friendly rules restrict autonomy and prod women to breastfeed for the few days that they remain in the hospital postpartum. However, these women go home to societal and institutional systems that are deeply unsupportive of breastfeeding. In addition to being the birthplace for 98% of babies born in the United States, the health care industry is the single largest employer of US women.^6,7 There are 5 academic hospitals in the Boston area. After contacting the human resources department at each, I found that only 1 has a policy for their breastfeeding employees.

Women should not be forced to choose between breastfeeding and working, between taking a longer maternity leave (often unpaid and professionally detrimental) and shelving the breast pump. What we invest in reveals our values. When we require women to room-in without respecting their choices or needs, and when workplaces fail to provide reasonable flexibility and private space for breast-pumping employees, our values as a society are revealed.

Women and men, hospital users and hospital employees, need to insist that the principles of autonomy, respect for persons, truthfulness, and justice guide breastfeeding policy both within our hospitals and within our workplaces. We need to respect women and the choices that they make for themselves and their families. We need to allow women to decide to recover from their delivery without their baby constantly in arms’ reach. We need to ensure that our counseling and our policies are rooted in sound science and not influenced by passionate but biased perspectives.

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.

Photo: Shutterstock

Many hospitals across the country have received designation as “Baby Friendly”; many other hospitals are in the process of seeking this designation. In order to be Baby Friendly, a hospital or birth center must prove they have implemented a set of 10 rules to encourage breastfeeding. As Baby Friendly USA puts it in their byline, it has become the gold standard of care.

Importantly, Baby Friendly fails to recognize that there is another equally crucial participant in any childbirth experience—the woman. Although childbirth is natural and usually healthy, it is not easy. Women commonly lose up to 1 L of blood during childbirth.¹ Labor can take 18 to 24 hours for a first-timer and about 12 to 18 hours for an encore performance, often disrupting at least1 entire night of sleep. The minimally invasive cesarean delivery continues to elude us, and women undergoing cesarean delivery must contend with a sizable incision and the additional pain and associated recovery.

Hospitals adopting the Baby Friendly rules must not allow formula, must prohibit pacifier use, and must go to great lengths to encourage rooming-in. Rooming-in means that the baby shares the same room as the new mother around-the-clock, which is reported to help the new mother distinguish sounds that indicate “feed me” from those that indicate a cool breeze. Rooming-in has been shown to be associated with a modest increase in breastfeeding²; however, women who are committed to breastfeeding likely room-in more often than women less committed to breastfeeding. Whether or not forcing the woman who is less committed to breastfeeding or the woman highly committed to breastfeeding who just wants a good night’s rest to room-in with her baby has a meaningful impact on breastfeeding remains unknown.

Are we violating ethics rules?

When hospitals adopt the Baby Friendly rules—policies that limit women’s choices for themselves and for their baby—we violate medical ethics principles regarding respect for autonomy, beneficence, and truthfulness. For instance, women are told that if they breastfeed their babies will be smarter, healthier, and have stronger emotional bonds. However, when research studies control for factors such as mothers’ education level or the amount of time spent talking to the baby, the effect of breastfeeding on intelligence “washes out.”³ Babies who are formula-fed but cuddled experience the same degree of bonding with their mothers as breast-fed babies.^4,5

Although breast is best, the reported benefits that underlie Baby Friendly are overblown and oversold. When we explain to a woman why her newborn cannot spend a few hours in the nursery or why we cannot allow a pacifier, we are denying her the right to parent and make choices for herself and her baby, not acting in the best interest of the woman. We are in fact misrepresenting the truth. We are also acting paternalistic, propagating the long tradition of telling women that we know better about their reproductive health and choices.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Breastfeeding still not fully accepted outside the hospital

The Baby Friendly rules restrict autonomy and prod women to breastfeed for the few days that they remain in the hospital postpartum. However, these women go home to societal and institutional systems that are deeply unsupportive of breastfeeding. In addition to being the birthplace for 98% of babies born in the United States, the health care industry is the single largest employer of US women.^6,7 There are 5 academic hospitals in the Boston area. After contacting the human resources department at each, I found that only 1 has a policy for their breastfeeding employees.

Women should not be forced to choose between breastfeeding and working, between taking a longer maternity leave (often unpaid and professionally detrimental) and shelving the breast pump. What we invest in reveals our values. When we require women to room-in without respecting their choices or needs, and when workplaces fail to provide reasonable flexibility and private space for breast-pumping employees, our values as a society are revealed.

Women and men, hospital users and hospital employees, need to insist that the principles of autonomy, respect for persons, truthfulness, and justice guide breastfeeding policy both within our hospitals and within our workplaces. We need to respect women and the choices that they make for themselves and their families. We need to allow women to decide to recover from their delivery without their baby constantly in arms’ reach. We need to ensure that our counseling and our policies are rooted in sound science and not influenced by passionate but biased perspectives.

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

The American Society for Colposcopy and Cervical Pathology (ASCCP) has recommended HPV triage for ASC-US cytology for more than 15 years. Since the ALTS trial demonstrated improved detection of CIN2+ in women with ASC-US cytology, HPV testing has become the preferred triage strategy for women with ASC-US cytology, except for women under age 25.¹ However, we do not know the long-term outcomes for these women. The study by Cuzick and colleagues uniquely addresses this question.

Details of the study

The retrospective review of data from the New Mexico HPV Pap Registry examined the influence of HPV testing on outcomes in 20,677 women with ASC-US cytology between 2008 and 2012. Of those women, 80.5% had an HPV test, and the authors estimated that 80.6% of those HPV tests were for triage after ASC-US cytology as opposed to co-testing (that is, cytology and HPV testing together). Of note, the majority of these Pap tests were performed prior to the 2012 ASCCP guidelines that recommend HPV co-testing for all women aged 30 to 64 years regardless of cytology. Of the HPV tests performed, 43.1% were positive. The investigators then examined rates of CIN in the interval between ASC-US cytology and biopsy-confirmed CIN, and rates of loop electrosurgical excision procedures (LEEP) and results at 5 years.

The investigators found a non–statistically significant increase in overall detection of CIN3 (relative risk [RR], 1.16; 95% confidence interval [CI], 0.92–1.45) in women who had been triaged with HPV testing, and a significant increase in overall detection of CIN2 (RR, 1.27; 95% CI, 1.06–1.53) and CIN1 (RR, 1.76; 95% CI, 1.56–2.00). CIN1, CIN2, and CIN3 were detected significantly earlier in patients with HPV testing. As expected, the majority of CIN2 and CIN3 was diagnosed in women who were HPV positive.

Related article:
2017 Update on cervical disease

The proportion of women undergoing either endocervical curettage or cervical biopsy was higher in those with HPV testing (32.1% vs 20.6%, P<.001), as were LEEP rates (4.9% vs 4.0%, P = .03). LEEP rates were highest in the year after a positive HPV test and were mostly attributable to CIN1 results. However, the overall ratio of LEEP to CIN3+ diagnosis was similar in women who were tested for HPV compared with those who were not. A larger proportion of patients with HPV testing had follow-up compared with those without HPV testing (84.1% vs 78.9%, P<.001).

The authors concluded that HPV testing in women with ASC-US cytology leads to detecting high-grade disease earlier, but that HPV positivity results in more interventions, largely due to an overdiagnosis of CIN1. They also confirmed that the majority of high-grade lesions are found in women with positive HPV tests.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Study strengths and weaknesses

This is the first comprehensive long-term look at women with ASC-US cytology and the impact of HPV testing. The New Mexico HPV Pap Registry is the only US state-based registry with comprehensive follow-up data. This study’s results build on previous data that showed sensitivity is increased with the addition of HPV testing to cervical cytology,¹ and they support current ASCCP guidelines that emphasize HPV triage or co-testing for women age 25 or older.

Potential bias. While this study has the benefit of a large cohort, it is limited by biases inherent in retrospective study design. One important potential bias is the differential utilization of HPV testing or procedures by providers. The authors acknowledge preliminary analyses that show that some clinics (rural, federally qualified health centers, public health clinics) serving underserved populations may underutilize or inappropriately utilize HPV testing.

Further, the 2008–2012 study period may make the results less generalizable to current practices since the ASCCP guidelines were adjusted to include more HPV testing in women aged 25 and older in 2012.

Finally, this study examines CIN but does not specifically look at the impact of HPV testing on the ultimate outcome of interest, cervical cancer rates.

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

The American Society for Colposcopy and Cervical Pathology (ASCCP) has recommended HPV triage for ASC-US cytology for more than 15 years. Since the ALTS trial demonstrated improved detection of CIN2+ in women with ASC-US cytology, HPV testing has become the preferred triage strategy for women with ASC-US cytology, except for women under age 25.¹ However, we do not know the long-term outcomes for these women. The study by Cuzick and colleagues uniquely addresses this question.

Details of the study

The retrospective review of data from the New Mexico HPV Pap Registry examined the influence of HPV testing on outcomes in 20,677 women with ASC-US cytology between 2008 and 2012. Of those women, 80.5% had an HPV test, and the authors estimated that 80.6% of those HPV tests were for triage after ASC-US cytology as opposed to co-testing (that is, cytology and HPV testing together). Of note, the majority of these Pap tests were performed prior to the 2012 ASCCP guidelines that recommend HPV co-testing for all women aged 30 to 64 years regardless of cytology. Of the HPV tests performed, 43.1% were positive. The investigators then examined rates of CIN in the interval between ASC-US cytology and biopsy-confirmed CIN, and rates of loop electrosurgical excision procedures (LEEP) and results at 5 years.

The investigators found a non–statistically significant increase in overall detection of CIN3 (relative risk [RR], 1.16; 95% confidence interval [CI], 0.92–1.45) in women who had been triaged with HPV testing, and a significant increase in overall detection of CIN2 (RR, 1.27; 95% CI, 1.06–1.53) and CIN1 (RR, 1.76; 95% CI, 1.56–2.00). CIN1, CIN2, and CIN3 were detected significantly earlier in patients with HPV testing. As expected, the majority of CIN2 and CIN3 was diagnosed in women who were HPV positive.

Related article:
2017 Update on cervical disease

The proportion of women undergoing either endocervical curettage or cervical biopsy was higher in those with HPV testing (32.1% vs 20.6%, P<.001), as were LEEP rates (4.9% vs 4.0%, P = .03). LEEP rates were highest in the year after a positive HPV test and were mostly attributable to CIN1 results. However, the overall ratio of LEEP to CIN3+ diagnosis was similar in women who were tested for HPV compared with those who were not. A larger proportion of patients with HPV testing had follow-up compared with those without HPV testing (84.1% vs 78.9%, P<.001).

The authors concluded that HPV testing in women with ASC-US cytology leads to detecting high-grade disease earlier, but that HPV positivity results in more interventions, largely due to an overdiagnosis of CIN1. They also confirmed that the majority of high-grade lesions are found in women with positive HPV tests.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Study strengths and weaknesses

This is the first comprehensive long-term look at women with ASC-US cytology and the impact of HPV testing. The New Mexico HPV Pap Registry is the only US state-based registry with comprehensive follow-up data. This study’s results build on previous data that showed sensitivity is increased with the addition of HPV testing to cervical cytology,¹ and they support current ASCCP guidelines that emphasize HPV triage or co-testing for women age 25 or older.

Potential bias. While this study has the benefit of a large cohort, it is limited by biases inherent in retrospective study design. One important potential bias is the differential utilization of HPV testing or procedures by providers. The authors acknowledge preliminary analyses that show that some clinics (rural, federally qualified health centers, public health clinics) serving underserved populations may underutilize or inappropriately utilize HPV testing.

Further, the 2008–2012 study period may make the results less generalizable to current practices since the ASCCP guidelines were adjusted to include more HPV testing in women aged 25 and older in 2012.

Finally, this study examines CIN but does not specifically look at the impact of HPV testing on the ultimate outcome of interest, cervical cancer rates.

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

The American Society for Colposcopy and Cervical Pathology (ASCCP) has recommended HPV triage for ASC-US cytology for more than 15 years. Since the ALTS trial demonstrated improved detection of CIN2+ in women with ASC-US cytology, HPV testing has become the preferred triage strategy for women with ASC-US cytology, except for women under age 25.¹ However, we do not know the long-term outcomes for these women. The study by Cuzick and colleagues uniquely addresses this question.

Details of the study

The retrospective review of data from the New Mexico HPV Pap Registry examined the influence of HPV testing on outcomes in 20,677 women with ASC-US cytology between 2008 and 2012. Of those women, 80.5% had an HPV test, and the authors estimated that 80.6% of those HPV tests were for triage after ASC-US cytology as opposed to co-testing (that is, cytology and HPV testing together). Of note, the majority of these Pap tests were performed prior to the 2012 ASCCP guidelines that recommend HPV co-testing for all women aged 30 to 64 years regardless of cytology. Of the HPV tests performed, 43.1% were positive. The investigators then examined rates of CIN in the interval between ASC-US cytology and biopsy-confirmed CIN, and rates of loop electrosurgical excision procedures (LEEP) and results at 5 years.

The investigators found a non–statistically significant increase in overall detection of CIN3 (relative risk [RR], 1.16; 95% confidence interval [CI], 0.92–1.45) in women who had been triaged with HPV testing, and a significant increase in overall detection of CIN2 (RR, 1.27; 95% CI, 1.06–1.53) and CIN1 (RR, 1.76; 95% CI, 1.56–2.00). CIN1, CIN2, and CIN3 were detected significantly earlier in patients with HPV testing. As expected, the majority of CIN2 and CIN3 was diagnosed in women who were HPV positive.

Related article:
2017 Update on cervical disease

The proportion of women undergoing either endocervical curettage or cervical biopsy was higher in those with HPV testing (32.1% vs 20.6%, P<.001), as were LEEP rates (4.9% vs 4.0%, P = .03). LEEP rates were highest in the year after a positive HPV test and were mostly attributable to CIN1 results. However, the overall ratio of LEEP to CIN3+ diagnosis was similar in women who were tested for HPV compared with those who were not. A larger proportion of patients with HPV testing had follow-up compared with those without HPV testing (84.1% vs 78.9%, P<.001).

The authors concluded that HPV testing in women with ASC-US cytology leads to detecting high-grade disease earlier, but that HPV positivity results in more interventions, largely due to an overdiagnosis of CIN1. They also confirmed that the majority of high-grade lesions are found in women with positive HPV tests.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Study strengths and weaknesses

This is the first comprehensive long-term look at women with ASC-US cytology and the impact of HPV testing. The New Mexico HPV Pap Registry is the only US state-based registry with comprehensive follow-up data. This study’s results build on previous data that showed sensitivity is increased with the addition of HPV testing to cervical cytology,¹ and they support current ASCCP guidelines that emphasize HPV triage or co-testing for women age 25 or older.

Potential bias. While this study has the benefit of a large cohort, it is limited by biases inherent in retrospective study design. One important potential bias is the differential utilization of HPV testing or procedures by providers. The authors acknowledge preliminary analyses that show that some clinics (rural, federally qualified health centers, public health clinics) serving underserved populations may underutilize or inappropriately utilize HPV testing.

Further, the 2008–2012 study period may make the results less generalizable to current practices since the ASCCP guidelines were adjusted to include more HPV testing in women aged 25 and older in 2012.

Finally, this study examines CIN but does not specifically look at the impact of HPV testing on the ultimate outcome of interest, cervical cancer rates.

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.