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Discussion: ‘Risk of repeat clinical chorioamnionitis,' by Cohen-Cline et al
Journal Club Roundtable
www. AJOG.org
Discussion: ‘Risk of repeat clinical chorioamnionitis,’ by Cohen-Cline et al In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Cohen-Cline HN, Kahn TR, Hutter, CM. A population-based study of the risk of repeat clinical chorioamnionitis in Washington State, 1989 –2008. Am J Obstet Gynecol 2012;207:473.e1-7.
DISCUSSION QUESTIONS
Why is this study question important?
What is your opinion of the dataset?
Were inclusion and exclusion criteria clearly described? Why employ 4 unexposed subjects for each exposed subject? What information is contained in the tables? What can we take away from this study?
From the Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO:
Moderator George A. Macones, MD, MSCE Mitchell and Elaine Yanow Professor and Head Discussants Alison Cahill, MD Assistant Professor Anthony Odibo, MD Associate Professor The authors report no conflict of interest. 0002-9378/$36.00 © 2012 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2012.10.870
See related article, page 473 For a summary and analysis of this discussion, see page 515
I NTRODUCTION Chorioamnionitis complicates pregnancy, though severe problems are uncommon among women who receive timely antibiotics. Even so, some 10% can develop bacteremia, and risks for postpartum hemorrhage, cesarean section, and surgical complications rise. Infants are at greater peril because their odds for consequences like cerebral palsy (CP), neonatal sepsis, or pneumonia climb. For example, chorioamnionitis boosts the incidence of CP from 3/1000 to 8/1000 live term births. When the membranes rupture before 37 weeks’ gestation, neonates exposed to infection and inflammation have more than 3 times the mortality rate of those who are not. A new study indicates that an episode makes women more susceptible to recurrence. George A. Macones, MD, MSCE, Associate Editor
B ACKGROUND Macones: Thank you for joining this discussion of a new paper on the risk of recurrent chorioamnionitis. What did you think of this research question? Cahill: I liked it. First, there has not been very much work on this topic in the past. Second, chorioamnionitis is associated with important adverse outcomes for the infant— essentially, preterm birth, CP, neonatal sepsis, and pneumonia. Thus, furthering our understanding of risk factors for these outcomes may lead to biologically-driven treatments in the future. I also liked that this question had clinical and biologic aspects.
S TUDY D ESIGN Macones: Great. I agree. What dataset was used? Was it appropriate?
Cahill: To address this specific research question, the authors used the well-established Washington State linked birth certificate-hospital discharge dataset. This dataset, which I believe is unique to Washington State, links demographic information from birth certificates to discharge diagnoses (ICD-9 codes). The dataset was a good choice for this specific research question. I know some are skeptical of administrative databases for clinical research, but I think there are times where the need for large numbers of subjects outweighs the theoretical disadvantages of random misclassification that might be present. And I always think skeptics should be challenged to figure out a better way to answer a question rather than just dismissing something out of hand. Still, the main disadvantage is that diagnoses are labeled with ICD-9 codes, which are generally identified by hospital-employed “coders.” Thus, the potential for random misclassification exists for many outcomes. The first advantage is the large number of observations provided. Second, I think using discharge diagnoses is likely a more valid method than using outcomes recorded on birth certificates. Macones: I agree with you completely. I think there is a time and place for administrative datasets in clinical research, and this seems like an appropriate application. Macones: Were descriptions of the study population and inclusion/ exclusion rationale clear? Odibo: Absolutely yes. In fact, this was one of the best-reported manuscripts I have read recently. The authors did an excellent job in describing who was in the study, and why they chose to include
DECEMBER 2012 American Journal of Obstetrics & Gynecology
e1
Journal Club Roundtable or exclude certain subjects. The population, drawn from 306,769 women, had a first pregnancy between 1989 and 2008 and at least 2 consecutive live singleton births. Because studies show a higher incidence of chorioamnionitis in the first pregnancy, compared to the second pregnancy, the researchers only included women who were nulliparous at the first recorded birth. The exposed group had a diagnosis of chorioamnionitis at their first birth; the comparison group did not. Macones: How can readers judge whether the population was suitably chosen? Odibo: Specifically, I consider whether I could completely reproduce what was done in the study if I had the same dataset. In this case, there is no question that I could. I am usually not as confident, but the study methods were so skillfully reported that I feel like I could. Macones: That’s a great tip and one we should keep in mind when we write our own papers. So to summarize the overall design, the authors performed a cohort study to identify the recurrence of chorioamnionitis. The exposed group consisted of women with chorioamnionitis in their first pregnancy, while the unexposed group was made up of women without chorioamnionitis in their first pregnancy. Macones: I saw an interesting fact— the authors chose to use 4 unexposed subjects per exposed subject. Why was that? Cahill: It’s all about power. I think many readers know the fundamentals of sample-size estimates, but 1 overlooked feature is the ratio of unexposed to exposed subjects. In general, to a point, you can increase statistical power by increasing this ratio. After a ratio of 4:1, the gains in power are relatively small with further increases. So the authors wisely chose the ratio of 4:1. But I think it is important to consider logistics when making this decision. In this study, it was relatively easy to use a 4:1 ratio, as this administrative
e2
data had already been collected. There may be cases where increasing this ratio beyond 1:1 could be logistically difficult. Macones: That’s a great explanation. Was there anything unusual about the analysis? Odibo: Not really, but that isn’t a negative comment. The authors used logistic regression to estimate their association of interest, and that is totally appropriate. They also clearly described what was in the model and why. One interesting piece was that they explored whether smoking was an effect modifier. Macones: Can you explain? Odibo: Sure. Essentially, the authors’ a priori assumption was that the recurrence of clinical chorioamnionitis might be increased in smokers. It turns out that their guess was wrong, which I thought was quite intriguing.
R ESULTS Macones: Table 1 is a fairly standard table of demographics, but the meat of the results is in Table 2. What information is contained there? Cahill: I think the main result is in the first line, where you can see that after adjustments are made, chorioamnionitis in the first pregnancy was associated with more than a 3-fold increase in the risk for recurrence in the second pregnancy. That is the heart of this study. But there were other interesting findings. First, internal monitoring is associated with chorioamnionitis. I think that is potentially a confounder, so I am not sure I am confident of that association. But the very interesting finding is that the interaction between smoking and chorioamnionitis is significant. Macones: Yes, Dr Odibo was interested in that. Odibo: What is very interesting is that the direction of the interaction is the opposite of what the authors had hypothesized. Specifically, the odds ratio (OR) for the association between first pregnancy chorioamnionitis and second pregnancy chorioamnionitis is actually
American Journal of Obstetrics & Gynecology DECEMBER 2012
www.AJOG.org higher in the nonsmokers. That is in the next table. When the researchers did not adjust for smoking status, the OR for recurrence in women who had chorioamnionitis in the first pregnancy was 3.43. When smoking was included as a variable, the OR for recurrence was 3.80 among women who did not smoke during the second pregnancy and 2.41 among those who did. Macones: It does seem counterintuitive to me also, but I must say that the authors had some very solid hypotheses about why they may have seen that interaction. Cahill: That raises a general point about this manuscript—the authors did a great job in discussing strengths and limitations of the study and helping readers to understand how misclassification and different biases may have influenced their results. That part of the manuscript is beautifully done. I think everyone interested in clinical research should read the discussion section.
C ONCLUSIONS Macones: I agree completely. As I was reading this, every question I had about the strengths and limitations was answered in the discussion. So what can we take away from this work? Odibo: First, I think the discussion is a must-read for people who want to do clinical research and report it well. Clinically, this study provides good evidence that chorioamnionitis in a first pregnancy increases the risk in subsequent pregnancies. This could have some important clinical implications, such as increased vigilance in subsequent pregnancies. Cahill: I would add that it is also biologically interesting. Perhaps, as the authors suggest, there may be a genetic predisposition to chorioamnionitis. Macones: I couldn’t agree more. Thanks for a great discussion on this very interesting paper. f
www. AJOG.org
Discussion: ‘Risk of repeat clinical chorioamnionitis,’ by Cohen-Cline et al In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Cohen-Cline HN, Kahn TR, Hutter, CM. A population-based study of the risk of repeat clinical chorioamnionitis in Washington State, 1989 –2008. Am J Obstet Gynecol 2012;207:473.e1-7.
DISCUSSION QUESTIONS
Why is this study question important?
What is your opinion of the dataset?
Were inclusion and exclusion criteria clearly described? Why employ 4 unexposed subjects for each exposed subject? What information is contained in the tables? What can we take away from this study?
From the Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO:
Moderator George A. Macones, MD, MSCE Mitchell and Elaine Yanow Professor and Head Discussants Alison Cahill, MD Assistant Professor Anthony Odibo, MD Associate Professor The authors report no conflict of interest. 0002-9378/$36.00 © 2012 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2012.10.870
See related article, page 473 For a summary and analysis of this discussion, see page 515
I NTRODUCTION Chorioamnionitis complicates pregnancy, though severe problems are uncommon among women who receive timely antibiotics. Even so, some 10% can develop bacteremia, and risks for postpartum hemorrhage, cesarean section, and surgical complications rise. Infants are at greater peril because their odds for consequences like cerebral palsy (CP), neonatal sepsis, or pneumonia climb. For example, chorioamnionitis boosts the incidence of CP from 3/1000 to 8/1000 live term births. When the membranes rupture before 37 weeks’ gestation, neonates exposed to infection and inflammation have more than 3 times the mortality rate of those who are not. A new study indicates that an episode makes women more susceptible to recurrence. George A. Macones, MD, MSCE, Associate Editor
B ACKGROUND Macones: Thank you for joining this discussion of a new paper on the risk of recurrent chorioamnionitis. What did you think of this research question? Cahill: I liked it. First, there has not been very much work on this topic in the past. Second, chorioamnionitis is associated with important adverse outcomes for the infant— essentially, preterm birth, CP, neonatal sepsis, and pneumonia. Thus, furthering our understanding of risk factors for these outcomes may lead to biologically-driven treatments in the future. I also liked that this question had clinical and biologic aspects.
S TUDY D ESIGN Macones: Great. I agree. What dataset was used? Was it appropriate?
Cahill: To address this specific research question, the authors used the well-established Washington State linked birth certificate-hospital discharge dataset. This dataset, which I believe is unique to Washington State, links demographic information from birth certificates to discharge diagnoses (ICD-9 codes). The dataset was a good choice for this specific research question. I know some are skeptical of administrative databases for clinical research, but I think there are times where the need for large numbers of subjects outweighs the theoretical disadvantages of random misclassification that might be present. And I always think skeptics should be challenged to figure out a better way to answer a question rather than just dismissing something out of hand. Still, the main disadvantage is that diagnoses are labeled with ICD-9 codes, which are generally identified by hospital-employed “coders.” Thus, the potential for random misclassification exists for many outcomes. The first advantage is the large number of observations provided. Second, I think using discharge diagnoses is likely a more valid method than using outcomes recorded on birth certificates. Macones: I agree with you completely. I think there is a time and place for administrative datasets in clinical research, and this seems like an appropriate application. Macones: Were descriptions of the study population and inclusion/ exclusion rationale clear? Odibo: Absolutely yes. In fact, this was one of the best-reported manuscripts I have read recently. The authors did an excellent job in describing who was in the study, and why they chose to include
DECEMBER 2012 American Journal of Obstetrics & Gynecology
e1
Journal Club Roundtable or exclude certain subjects. The population, drawn from 306,769 women, had a first pregnancy between 1989 and 2008 and at least 2 consecutive live singleton births. Because studies show a higher incidence of chorioamnionitis in the first pregnancy, compared to the second pregnancy, the researchers only included women who were nulliparous at the first recorded birth. The exposed group had a diagnosis of chorioamnionitis at their first birth; the comparison group did not. Macones: How can readers judge whether the population was suitably chosen? Odibo: Specifically, I consider whether I could completely reproduce what was done in the study if I had the same dataset. In this case, there is no question that I could. I am usually not as confident, but the study methods were so skillfully reported that I feel like I could. Macones: That’s a great tip and one we should keep in mind when we write our own papers. So to summarize the overall design, the authors performed a cohort study to identify the recurrence of chorioamnionitis. The exposed group consisted of women with chorioamnionitis in their first pregnancy, while the unexposed group was made up of women without chorioamnionitis in their first pregnancy. Macones: I saw an interesting fact— the authors chose to use 4 unexposed subjects per exposed subject. Why was that? Cahill: It’s all about power. I think many readers know the fundamentals of sample-size estimates, but 1 overlooked feature is the ratio of unexposed to exposed subjects. In general, to a point, you can increase statistical power by increasing this ratio. After a ratio of 4:1, the gains in power are relatively small with further increases. So the authors wisely chose the ratio of 4:1. But I think it is important to consider logistics when making this decision. In this study, it was relatively easy to use a 4:1 ratio, as this administrative
e2
data had already been collected. There may be cases where increasing this ratio beyond 1:1 could be logistically difficult. Macones: That’s a great explanation. Was there anything unusual about the analysis? Odibo: Not really, but that isn’t a negative comment. The authors used logistic regression to estimate their association of interest, and that is totally appropriate. They also clearly described what was in the model and why. One interesting piece was that they explored whether smoking was an effect modifier. Macones: Can you explain? Odibo: Sure. Essentially, the authors’ a priori assumption was that the recurrence of clinical chorioamnionitis might be increased in smokers. It turns out that their guess was wrong, which I thought was quite intriguing.
R ESULTS Macones: Table 1 is a fairly standard table of demographics, but the meat of the results is in Table 2. What information is contained there? Cahill: I think the main result is in the first line, where you can see that after adjustments are made, chorioamnionitis in the first pregnancy was associated with more than a 3-fold increase in the risk for recurrence in the second pregnancy. That is the heart of this study. But there were other interesting findings. First, internal monitoring is associated with chorioamnionitis. I think that is potentially a confounder, so I am not sure I am confident of that association. But the very interesting finding is that the interaction between smoking and chorioamnionitis is significant. Macones: Yes, Dr Odibo was interested in that. Odibo: What is very interesting is that the direction of the interaction is the opposite of what the authors had hypothesized. Specifically, the odds ratio (OR) for the association between first pregnancy chorioamnionitis and second pregnancy chorioamnionitis is actually
American Journal of Obstetrics & Gynecology DECEMBER 2012
www.AJOG.org higher in the nonsmokers. That is in the next table. When the researchers did not adjust for smoking status, the OR for recurrence in women who had chorioamnionitis in the first pregnancy was 3.43. When smoking was included as a variable, the OR for recurrence was 3.80 among women who did not smoke during the second pregnancy and 2.41 among those who did. Macones: It does seem counterintuitive to me also, but I must say that the authors had some very solid hypotheses about why they may have seen that interaction. Cahill: That raises a general point about this manuscript—the authors did a great job in discussing strengths and limitations of the study and helping readers to understand how misclassification and different biases may have influenced their results. That part of the manuscript is beautifully done. I think everyone interested in clinical research should read the discussion section.
C ONCLUSIONS Macones: I agree completely. As I was reading this, every question I had about the strengths and limitations was answered in the discussion. So what can we take away from this work? Odibo: First, I think the discussion is a must-read for people who want to do clinical research and report it well. Clinically, this study provides good evidence that chorioamnionitis in a first pregnancy increases the risk in subsequent pregnancies. This could have some important clinical implications, such as increased vigilance in subsequent pregnancies. Cahill: I would add that it is also biologically interesting. Perhaps, as the authors suggest, there may be a genetic predisposition to chorioamnionitis. Macones: I couldn’t agree more. Thanks for a great discussion on this very interesting paper. f