- Email: [email protected]
Severe placental abruption: clinical definition and associations with maternal complications
Accepted Manuscript Severe Placental Abruption: Clinical Definition and Associations with Maternal Complications Cande V. Ananth, PhD, MPH, Jessica A. Lavery, MS, Anthony M. Vintzileos, MD, Daniel W. Skupski, MD, Michael Varner, MD, George Saade, MD, Joseph Biggio, MD, Michelle A. Williams, ScD, Ronald J. Wapner, MD, Jason D. Wright, MD PII:
S0002-9378(15)01120-5
DOI:
10.1016/j.ajog.2015.09.069
Reference:
YMOB 10657
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 31 August 2015 Accepted Date: 14 September 2015
Please cite this article as: Ananth CV, Lavery JA, Vintzileos AM, Skupski DW, Varner M, Saade G, Biggio J, Williams MA, Wapner RJ, Wright JD, Severe Placental Abruption: Clinical Definition and Associations with Maternal Complications, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.09.069. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Severe Placental Abruption: Clinical Definition and Associations with Maternal Complications
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Cande V. ANANTH, PhD, MPH,1,2,3 Jessica A. LAVERY, MS,1,2 Anthony M. VINTZILEOS, MD,4 Daniel W. SKUPSKI, MD,5 Michael VARNER, MD,6 George SAADE, MD,7
Joseph BIGGIO, MD,8 Michelle A. WILLIAMS, ScD,9
Author affiliations
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Ronald J. WAPNER, MD,1 Jason D. WRIGHT, MD1
1. Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY
2. Biostatistics Coordinating Center, Department of Obstetrics and Gynecology, College of
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Physicians and Surgeons, Columbia University, New York, NY
3. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
4. Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, NY
New York, NY
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5. Department of Obstetrics and Gynecology, Weill Medical College of Cornell University,
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6. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT 7. Department of Obstetrics and Gynecology, University of Texas, Galveston, TX 8. Department of Obstetrics and Gynecology, University of Alabama, Birmingham, AL 9. Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA
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Correspondence Cande V. Ananth Department of Obstetrics and Gynecology
Columbia University
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College of Physicians and Surgeons
622 West 168th Street, New York NY 10032
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Email: [email protected]
Abstract 499; Text 2,819; Tables 3; Figures 1; Online tables 1
Running head
Mild versus severe placental abruption
Funding
None
Conflicts
None declared
Print version
Please use figure 1
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Word count
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Condensation Severe placental abruption is clinically more homogeneous and is associated with substantially
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increased risks of serious maternal complications compared to mild abruptions.
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Abstract Background: Placental abruption is traditionally defined as the premature separation of the
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implanted placenta prior to the delivery of the fetus. The existing clinical criteria of severity rely exclusively on fetal (fetal distress or fetal death) and maternal complications without
consideration of neonatal or preterm delivery-related complications. However, two-thirds of
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abruption cases are accompanied by fetal or neonatal complications, including preterm
delivery. A clinically meaningful classification for abruption should therefore include not only
growth restriction and preterm delivery.
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maternal complications, but also adverse fetal and neonatal outcomes including intrauterine
Objectives: To define severe placental abruption and to compare serious maternal morbidity
abruptions.
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profiles of such cases to all other cases of abruption (i.e., mild abruption) as well as non-
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Study design: We performed a retrospective cohort analysis using the Premier database of hospitalizations resulting in singleton births in the US between 2006 and 2012 (n=27,796,465).
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Severe abruption was defined as abruption accompanied by at least one of the following: maternal (DIC, hypovolemic shock, blood transfusion, hysterectomy, renal failure or in-hospital death), fetal (non-reassuring fetal status, intrauterine growth restriction or fetal death) or neonatal (preterm delivery or small for gestational age) complications. Abruption cases that did not qualify as being severe were classified as mild abruptions. Morbidity profile included amniotic fluid embolism, pulmonary edema, acute respiratory or heart failure, acute myocardial
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infarction, cardiomyopathy, puerperal cerebrovascular disorders or coma. Associations were expressed as rate ratio (RR) with 95% confidence interval (CI) derived from fitting log-linear
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Poisson regression models.
Results: The overall prevalence rate of abruption was 9.6 per 1000, of which two-thirds were
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classified as being severe (6.5 per 1000). Serious maternal complications occurred in 15.4, 33.3 and 141.7 per 10,000 among non-abruption, and mild and severe abruption, respectively. In
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comparison to no abruptions, the RR for serious maternal complications were 1.51 (95% CI 1.34, 1.71) and 3.93 (95% CI 3.77, 4.10) in women with mild and severe placental abruption, respectively. RRs for the individual complications were 2 to 7-fold higher among severe abruptions. Furthermore, the RR’s for serious maternal complications among severe abruption
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compared to mild abruption was 3.47 (95% CI 3.05, 3.95). This association was considerably stronger for virtually all maternal complications among severe abruption compared to mild
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abruption.
Annual rates of mild and severe abruption were fairly constant during the study period (figure).
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While the maternal complication rate among non-abruption births was stable between 2006 and 2012, the rate of complications among mild abruption dropped between 2006 and 2008 and then leveled off thereafter. In contrast, the rate of serious complications among severe abruption remained fairly stable between 2006 and 2010, and increased sharply thereafter.
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Conclusions: Severe abruption was associated with a distinctively higher morbidity risk profile as compared to the other two groups. The clinical characteristics and morbidity profile of mild
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abruption was more similar to those of women without an abruption. These findings suggest that the definition of severe placental abruption based on the proposed specific criteria is
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clinically relevant and may facilitate epidemiological and genetic research.
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Key words
Placental abruption; maternal complications; ischemic placental disease; IUGR; preterm
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delivery; fetal death; DIC; blood transfusion
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Introduction Placental abruption is traditionally defined as the premature separation of the implanted
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placenta prior to the delivery of the fetus. The existing clinical criteria of severity rely exclusively on fetal (fetal distress or fetal death) and maternal complications without
consideration of neonatal or preterm delivery-related complications.1 However, two-thirds of
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abruption cases are accompanied by fetal or neonatal complications, including preterm
delivery. A clinically meaningful classification for abruption should therefore include not only
growth restriction and preterm delivery.
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maternal complications, but also adverse fetal and neonatal outcomes including intrauterine
We hypothesized that the criteria to define placental abruption as “severe” should be clinically
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meaningful and should include at least one of maternal (disseminated intravascular coagulation, hypovolemic shock, blood transfusion, hysterectomy, renal failure or in-hospital death), fetal (non-reassuring fetal status, intrauterine growth restriction or fetal death) or
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neonatal (preterm delivery or fetal growth restriction [FGR]) complications. The intrinsic motivation for this hypothesis was that abruption cases with one or more of the above criteria
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will identify a distinct subset of women with very high risks of serious maternal complications, in comparison to women with mild abruption or no abruption. We test this hypothesis in a large cohort of almost 28 million singleton pregnancies in the United States.
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Methods Premier data
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We performed a retrospective cohort analysis of data from the Premier database (www.premierinc.com) to obtain all maternal hospital records for deliveries that occurred from 2006 to 2012. The data includes hospitalizations from in-patient, ambulatory and emergency
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admissions in about 500 hospitals each year in the US. These hospitals are chosen to provide representation of hospitalizations across the US. The Premier data can be purchased from
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Premier, Inc. All diagnosis and procedure codes in the Premier data were coded based on the International Classification of Disease, 9th version (ICD-9), and the codes used for conditions in this study are listed in the supplemental table 1. We sought and obtained approval from the
Placental abruption
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Institutional Review Board as an exempt protocol from Columbia University Medical Center, NY.
A diagnosis of placental abruption was based on clinical symptoms that include vaginal bleeding
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accompanied with severe abdominal pain, uterine tenderness, or tetanic contractions. Severe placental abruption was defined as a delivery with an abruption accompanied by one or more
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of the following maternal, fetal or neonatal complications. Maternal complications included disseminated intravascular coagulation, hypovolemic shock, blood transfusion, hysterectomy, and renal failure and in-hospital death. Fetal complications included non-reassuring fetal status, fetal growth restriction or fetal death, and neonatal complications included neonatal death, preterm delivery and small for gestational age (SGA) births. Although the risk of some of the severe maternal morbidity, such as pulmonary edema or cardiomyopathy, are expected to be
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higher among pregnancies complicated by abruption, these conditions are not the typical complications following abruption; therefore we do not consider these variables in the
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definition of severe abruption.2-4 Abruption cases that did not qualify as being severe were classified as mild abruptions.
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Maternal morbidity profile
The primary endpoint was a composite morbidity outcome comprised of serious maternal
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complications including pulmonary edema, acute respiratory failure, acute heart failure, acute myocardial infarction, cardiomyopathy, puerperal cerebrovascular disorder, and coma and amniotic fluid embolism. In addition, we also examined the associations between abruption and
Clinical characteristics
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each of these serious maternal complications.
We examined the rates of mild and severe abruption across patient characteristics. Maternal
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sociodemographic and behavioral characteristics included year of delivery (2006-2012), maternal age, single marital status, and insurance status, as well as tobacco, drug or alcohol
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use. Maternal comorbidities included hypertensive diseases (chronic hypertension, gestational hypertension, or preeclampsia/eclampsia), pregestational diabetes, gestational diabetes, chronic renal disease, asthma, and congenital cardiac disease. Intrapartum and labor characteristics included premature rupture of membranes (at preterm or term gestations), anemia, intrapartum fever, polyhydramnios, oligohydramnios, and chorioamnionitis. SGA was used as a proxy for intrauterine growth restriction.
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Statistical analysis
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Two sets of log-linear regression models (with a Poisson distribution and a log-link function) were fit: the first was to evaluate the maternal characteristics associated with mild and severe placental abruption; and second, to estimate the association of serious maternal complications
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(morbidity profile) associated with mild and severe abruptions compared to non-abruption births, as well as a comparison of serious maternal complications between severe versus mild
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(reference) abruptions. For evaluating risk factors for mild and severe abruptions, we first estimated the unadjusted rate ratio (RR) and 95% confidence interval (CI). From this analysis, we chose risk factors that had RRs either above 1.2 or below 0.8 for mild and severe abruption; risk factors that met this criterion were entered in the final multivariable log linear Poisson
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regression models from which we evaluated the associations.
Rate ratios (RR) and 95% confidence intervals (CI) were calculated for the composite serious
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maternal morbidity profile, as well as for each severe maternal outcome individually. In this analysis, we adjusted for all maternal characteristics as potential confounding factors. All
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analyses were weighted based on the weights provided in Premier in order to generate national estimates.
Cohort composition From 28,504,661 (weighted) singleton deliveries identified in the Perspectives database, twins and higher-order multiple births (n=530,091; unweighted 79,594) and women younger than 15
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or older than 59 years were excluded (n=30,940; unweighted 5,187). We additionally excluded women diagnosed with placenta previa (n=141,135; unweighted 22,241). After all exclusions,
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the analysis cohort was composed of 27,796,465 (3,961,031 unweighted) women.
Results
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In this cohort of 27,796,465 singleton births, the prevalence rates of mild and severe abruption were 3.1 and 6.5 per 1000, respectively (overall prevalence rate of 9.6 per 1000). The
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distribution of clinical characteristics among the three groups of non-abruption, mild abruption and severe abruption is shown in table 1. Maternal age 40 years or older, black race, cigarette smoking status and use of drugs or alcohol were associated with increased rates of abruption, with a stark contrast in rates observed for mild versus severe abruption cases. Compared to
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non-abruption births, the prevalence rates of hypertensive disorders were increased among women with mild abruption but were substantially higher among women with severe abruption. Similarly, rates of premature rupture of membranes, polyhydramnios and
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oligohydramnios were also relatively higher among severe abruption.
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The associations between the clinical characteristics and mild and severe placental abruption are shown in Table 2. Several differences were found between mild versus severe abruption. For instance, compared to women 25-29 years (reference), maternal age up to 45 years showed stronger associations with mild abruption, whereas the risk among women ≥45 years higher among severe abruption. Rate ratios were higher for severe than mild abruption for black race, single marital status, tobacco use. The risk of severe abruption was substantially higher than
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mild abruption in relation to chronic hypertension (RRs 1.64 versus 1.35), mild preeclampsia (2.06 versus 1.69) and severe preeclampsia (4.21 versus 2.00). In contrast, the RRs of mild
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abruption were higher compared to severe abruption among gestational hypertensive women (1.47 versus 1.21). The RRs for severe abruption were higher than mild abruption in relation to premature rupture of membranes, anemia, polyhydramnios, oligohydramnios, and
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chorioamnionitis.
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The morbidity profile and the rates of individual maternal complications in mild and severe abruption, as well as the adjusted RR for these complications are shown in Table 3. Serious maternal complications occurred in 15.4 per 10,000 among non-abruption births, and in 33.3 and 141.7 per 10,000 in women with mild and severe abruption. After adjusting for
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confounders, compared to women without abruption, the RR for maternal complications was 2.14 (95% CI 1.89, 2.41) in women with mild abruption and 4.29 (95% CI 4.11, 4.47) in women with severe abruption. RRs for many of the individual complications were moderately increased
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in women with mild abruption, but were 2 to 7-fold higher among severe abruptions. In fact, the RR of the composite serious maternal complications in relation to severe abruption was
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3.47 (95% CI 3.05, 3.95) (Table 3). Similarly, the RRs for pulmonary edema (RR 2.40, 95% CI 1.82, 3.17), acute heart failure (RR 4.20, 95% CI 3.08, 5.74), and acute respiratory failure (RR 5.47, 95% CI 4.48, 6.68) were all considerably higher in women with severe abruptions.
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The rate ratio for serious maternal complications among severe abruption compared to mild abruption was 3.47 (95% CI 3.05, 3.95). The associations were considerably stronger for
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virtually all maternal complications among severe abruption than among mild abruption.
Rates of mild and severe abruption between 2006 and 2012 and the corresponding rates of
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serious maternal complications in relations to abruption are shown in Figure 1. Rates of mild and severe abruption were fairly constant during the study period. While the maternal
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complication rate among non-abruption births was stable between 2006 and 2012, the rate of complications among mild abruption dropped between 2006 and 2008 and then leveled off thereafter. In contrast, the rate of serious complications among severe abruption remained
Comment
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fairly stable between 2006 and 2010, and increased sharply thereafter.
Placental abruption is a serious and often a life threatening condition to the fetus and, to a
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lesser extent, to the woman.5-13 We show that the clinical characteristics for abruption differ substantially between mild and severe forms of the condition and with varying strengths of
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associations. The choices of maternal conditions that constitute a diagnosis of severe abruption were not different than those previously reported in the obstetrical literature. The maternal morbidity profile that we chose includes extreme maternal conditions that are not typically seen with abruption and are not typically included in the definition of abruption. Under maternal morbidity profile we included cardiomyopathy, myocardial infarction and respiratory failure, which are conditions, associated with severe, prolonged hypoxia. Amniotic fluid
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embolism was also included in the maternal morbidity profile since it is not typical for the diagnosis but its association with abruption has been well documented.2-4, 14 These conditions
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are extremely serious but not typical of abruption and this was the reason that we included them in the maternal morbidity profile rather than in the definition of severe abruption.
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The morbidity profile and rates of serious maternal complications are profoundly different between mild and severe abruptions, with the rates being substantially higher among severe
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(141.7 per 10,000) than mild (33.3 per 10,000) abruptions. Importantly, severe abruptions comprise two-thirds of all abruptions mainly because preterm delivery and SGA were included in the definition of severe abruption even in the absence of severe maternal symptomatology. Taken together, these findings suggest that severe abruptions are the distinct group of really
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sick patients and that combining mild and severe forms of the disease may introduce substantial heterogeneity in clinical research.
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In this study the diagnosis of placental abruption was based on clinical criteria rather than placental pathology reports (which were unavailable). However, in our view, pathology reports
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may not be necessary for three reasons: (i) epidemiologic database very rarely, if ever, have data regarding pathology reports; (ii) there are very few experts in placental pathology, so any definition using reliable placental pathology information may affect generalizability; and (iii) the prevalence rate of abruption of 9.6 per 1000 in this study is within the range reported in other population-based studies.5, 15-17 This suggests that we have not missed a significant number of
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cases due to lack of placental pathology data. However, the data allowed for distinguishing
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preterm from term births despite the lack of data on the individual gestational age.
Limitations of the data
Despite the interesting observations, the findings must be interpreted with some caution.
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Primarily, the Premier data includes data on large number of deliveries, but data on few
socioeconomic and behavioral characteristics (such as maternal education, prepregnancy body-
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mass index, and weight gain during pregnancy) are lacking, so the possibility of the associations being affected by unmeasured confounders remain. There is also some possibility of misclassification of abruption cases. However, we believe that such misclassification, if present, is likely more common for the milder forms of the condition. Women with severe abruption are
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the really sick patients with more than one serious complication and it is very unlikely that abruption status will be misclassified in this group.
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Strengths of the study
The strengths of the study include the large study size with data from hospitalizations
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associated with over 27 million singleton deliveries from 441 hospitals over a seven-year period (2006-2012) in the US. All analyses were weighted by the sampling weights of deliveries permitting generalizability of the findings. The associations we report are adjusted for a variety of confounding factors.
Interpretation of findings
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Over four decades ago, Pritchard and colleagues18 proposed that severe abruptions are those that are accompanied by one or more of short umbilical cord, external trauma, sudden uterine
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decomposition, uterine anomaly or tumor, occlusion of the inferior vena cava, maternal folate deficiency, maternal vascular disease, high parity, and previous abruption. A second
classification was based on a system that assigns a score ranging from 0 to 3, with 0 indicating
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asymptomatic women with evidence of small retroplacental clots on the placental surface on pathologic examination after delivery, 1 denoting those with bleeding and uterine tenderness
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or tetanic contractions, 2 denoting bleeding with fetal distress (but no signs of maternal shock) and 3 denoting bleeding with uterine tetany, persistent abdominal pain, and maternal shock and fetal demise.19
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The classification for severe placental abruption that we propose is broad and encompasses more objective criteria of clinically meaningful abruption. In fact, the conditions used to define severe abruption are based on serious co-occurring maternal, fetal and neonatal clinical
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complications. The grading system to classify abruption severity19 is restrictive since even the grade 0 abruption that results in preterm delivery will be deemed as being “severe” based on
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this classification system. Based on this definition, two-thirds of all clinically diagnosed abruption cases were classified as being severe. Furthermore, fetal growth restriction and abruption are both largely a chronic process that share strong similarities and are driven by uteroplacental ischemia,20, 21 and this provides further support that both preterm delivery and fetal growth restriction should be considered in the definition of severe abruptions. This classification not only identifies women with severe abruption with substantially higher risk of
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serious morbidity, but also acknowledges that women with severe abruption are distinctly
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different than those with milder forms of the complication.
Virtually all studies on placental abruption have focused exclusively on assessing risks in the perinatal period and during infancy,22-26 and evaluation of maternal risks associated with this
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condition are sparse. Furthermore, we are unaware of any study that has attempted to
separate mild from severe forms of abruption. In fact, the inclusion of neonatal complications
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(preterm delivery and SGA) in the definition of severe abruption results in two-thirds of all abruptions being classified as being severe.
Risk factors for severe abruption appear largely driven by inflammation and, to a lesser extent,
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infection-related pathways.27 That tobacco and drug use are stronger risk factors for severe than mild abruptions suggest that chronic hypoxia leading to uteroplacental underperfusion as a result of tobacco smoke11, 28-30 appears to shape the risk of severe abruption. Other
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pathological chronic conditions including chronic hypertension,12, 31-33 preeclampsia,34, 35 premature rupture of membranes,36 anemia,37 oligohydramnios38 and infection-related
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conditions such as chorioamnionitis38, 39 are stronger risk factors for severe than mild abruptions. Interestingly, asthma and intrapartum fever showed stronger associations with mild than with severe abruptions.
The long-term risk of mortality and morbidity from premature cardiovascular disease are about 2 to 6-fold higher among women with abruption compared to otherwise normal pregnancies.40-
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In addition, this study suggests that the risks of serious maternal cardiovascular complications
also remain substantially higher among women with severe than mild abruptions. Acute
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complications such as myocardial infarction and respiratory failure are about 7-fold higher among women with severe abruption. These findings provide support to available data showing that ischemic conditions during pregnancy such as preeclampsia,44, 45 fetal growth restriction,46, preterm delivery48, 49 and placental abruption40, 41, 43 may be linked to future cardiovascular
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disease in women later in life. One of the intriguing and unexpected finding is the temporal
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increase in the rate of serious maternal complications among women with severe abruption since 2010 (Figure 1), but this increase remains clinically insignificant.
Conclusions
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This large population-based study suggests that the frequency of maternal clinical risk factors is different between mild versus severe abruptions. Furthermore, the associated serious morbidity profile of women diagnosed with severe abruption is considerably worse than in
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those with mild abruption. These findings underscore a substantial heterogeneity in both risk factor profile and serious adverse maternal complications. Importantly, the definition of severe
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that we propose is based on objective data that includes maternal, fetal and neonatal complications. Although this proposed definition is not one that can be used prospectively because it includes outcome data in the definition of severe abruption, these observations underscore that future studies on placental abruption should attempt to separate mild from severe forms, when feasible. This recommendation will be particularly helpful for studies that seek to understand the genetic imprints and gene-environment interactions on abruption risk.
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Research to unravel the etiology may also benefit from separating mild from severe placental
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abruption.
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SHER G, STATLAND BE. Abruptio placentae with coagulopathy: a rational basis for management. Clinical obstetrics and gynecology 1985;28:15-23. ANANTH CV, VINTZILEOS AM. Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth. Am J Obstet Gynecol 2006;195:1557-63. ANANTH CV, VINTZILEOS AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006;19:773-82. KYRKLUND-BLOMBERG NB, GENNSER G, CNATTINGIUS S. Placental abruption and perinatal death. Paediatr Perinat Epidemiol 2001;15:290-7. RASMUSSEN S, IRGENS LM, BERGSJO P, DALAKER K. Perinatal mortality and case fatality after placental abruption in Norway 1967-1991. Acta Obstet Gynecol Scand 1996;75:229-34. ANANTH CV, BERKOWITZ GS, SAVITZ DA, LAPINSKI RH. Placental abruption and adverse perinatal outcomes. JAMA 1999;282:1646-51. ANANTH CV, WILCOX AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001;153:332-7. TIKKANEN M, LUUKKAALA T, GISSLER M, et al. Decreasing perinatal mortality in placental abruption. Acta Obstet Gynecol Scand 2013;92:298-305. ANANTH CV, GETAHUN D, PELTIER MR, SMULIAN JC. Placental abruption in term and preterm gestations: evidence for heterogeneity in clinical pathways. Obstet Gynecol 2006;107:785-92. CHRISTIANSON RE. Gross differences observed in the placentas of smokers and nonsmokers. Am J Epidemiol 1979;110:178-87. ANANTH CV, SAVITZ DA, LUTHER ER. Maternal cigarette smoking as a risk factor for placental abruption, placenta previa, and uterine bleeding in pregnancy. Am J Epidemiol 1996;144:881-9. CNATTINGIUS S. Maternal age modifies the effect of maternal smoking on intrauterine growth retardation but not on late fetal death and placental abruption. Am J Epidemiol 1997;145:319-23. WILLIAMS MA, MITTENDORF R, MONSON RR. Chronic hypertension, cigarette smoking, and abruptio placentae. Epidemiology 1991;2:450-3. ANANTH CV, PELTIER MR, KINZLER WL, SMULIAN JC, VINTZILEOS AM. Chronic hypertension and risk of placental abruption: Is the association modified by ischemic placental disease? Am J Obstet Gynecol 2007;197:273 e1-7. MISRA DP, ANANTH CV. Risk factor profiles of placental abruption in first and second pregnancies: heterogeneous etiologies. J Clin Epidemiol 1999;52:453-61. ANANTH CV, PELTIER MR, CHAVEZ MR, KIRBY RS, GETAHUN D, VINTZILEOS AM. Recurrence of ischemic placental disease. Obstet Gynecol 2007;110:128-33. CNATTINGIUS S, MILLS JL, YUEN J, ERIKSSON O, SALONEN H. The paradoxical effect of smoking in preeclamptic pregnancies: smoking reduces the incidence but increases the rates of perinatal mortality, abruptio placentae, and intrauterine growth restriction. Am J Obstet Gynecol 1997;177:156-61. VINTZILEOS AM, CAMPBELL WA, NOCHIMSON DJ, WEINBAUM PJ. Preterm premature rupture of the membranes: a risk factor for the development of abruptio placentae. Am J Obstet Gynecol 1987;156:1235-8.
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46. 47. 48. 49.
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HIBBARD BM. The role of folic acid in pregnancy; with particular reference to anaemia, abruption and abortion. J Obstet Gynaecol Br Commonw 1964;71:529-42. ANANTH CV, OYELESE Y, SRINIVAS N, YEO L, VINTZILEOS AM. Preterm premature rupture of membranes, intrauterine infection, and oligohydramnios: risk factors for placental abruption. Obstet Gynecol 2004;104:71-7. DARBY MJ, CARITIS SN, SHEN-SCHWARZ S. Placental abruption in the preterm gestation: an association with chorioamnionitis. Obstet Gynecol 1989;74:88-92. PARIENTE G, SHOHAM-VARDI I, KESSOUS R, SHERF M, SHEINER E. Placental abruption as a significant risk factor for long-term cardiovascular mortality in a follow-up period of more than a decade. Paediatr Perinat Epidemiol 2014;28:32-8. RAY JG, VERMEULEN MJ, SCHULL MJ, REDELMEIER DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005;366:1797-803. VEERBEEK JH, SMIT JG, KOSTER MP, et al. Maternal cardiovascular risk profile after placental abruption. Hypertension 2013;61:1297-301. DEROO L, SKJAERVEN R, WILCOX A, et al. Placental abruption and long-term maternal cardiovascular disease mortality: a population-based registry study in Norway and Sweden. Eur J Epidemiol 2015. IRGENS HU, REISAETER L, IRGENS LM, LIE RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323:1213-7. LYKKE JA, LANGHOFF-ROOS J, SIBAI BM, FUNAI EF, TRICHE EW, PAIDAS MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53:944-51. LYKKE JA, PAIDAS MJ, TRICHE EW, LANGHOFF-ROOS J. Fetal growth and later maternal death, cardiovascular disease and diabetes. Acta Obstet Gynecol Scand 2012;91:503-10. SMITH GD, WHITLEY E, GISSLER M, HEMMINKI E. Birth dimensions of offspring, premature birth, and the mortality of mothers. Lancet 2000;356:2066-7. CATOV JM, WU CS, OLSEN J, SUTTON-TYRRELL K, LI J, NOHR EA. Early or recurrent preterm birth and maternal cardiovascular disease risk. Ann Epidemiol 2010;20:604-9. RICH-EDWARDS JW, KLUNGSOYR K, WILCOX AJ, SKJAERVEN R. Duration of pregnancy, even at term, predicts long-term risk of coronary heart disease and stroke mortality in women: a population-based study. Am J Obstet Gynecol 2015.
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Table 1 Distribution of clinical characteristics based on mild and severe placental abruption Severe Abruption %
27,528,415
86,917 (3.1)
181,133 (6.5)
<20
9.0
20-24
23.5
25-29
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Maternal age (years)
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Mild Abruption %
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Number (abruption rate per 1000)
Non Abruption %
7.1
10.6
22.5
24.3
28.6
28.1
26.3
24.3
25.0
22.4
12.9
14.8
14.0
1.5
2.3
2.0
0.1
0.2
0.3
27.7 (6.0)
28.3 (6.1)
27.7 (6.4)
51.3
53.0
47.1
12.6
13.0
19.7
9.9
8.6
8.3
26.2
25.4
24.8
Married
49.7
48.7
41.3
Single
37.6
39.3
46.6
Unknown
12.7
12.1
12.1
Tobacco use
4.7
7.6
10.2
Alcohol use
0.1
0.3
0.4
30-34 35-39 40-44 ≥45
White Black Hispanic
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Other
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Maternal race
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Mean (standard deviation)
Marital status
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Mild Abruption %
Severe Abruption %
0.2
0.7
1.0
Insurance 52.1
Medicare
0.6
Medicaid
41.2
Uninsured
2.5
Unknown
3.6
48.7
43.7
0.7
0.8
43.6
47.8 3.4
3.9
4.2
91.4
86.7
82.2
1.8
2.5
3.2
3.2
4.5
3.5
1.8
2.9
3.5
1.8
3.4
7.6
0.8
0.7
1.2
5.5
5.3
5.1
Chronic renal disease
0.2
0.2
0.5
Asthma
2.9
3.5
3.9
Anemia
9.8
15.1
23.9
Congenital cardiac disease
0.1
0.0
0.1
Premature rupture of membranes
3.5
4.5
8.8
Intrapartum fever
0.1
0.1
0.1
Chorioamnionitis
1.4
2.2
4.1
Polyhydramnios
0.8
1.0
1.2
Hypertension status Normotensive Chronic hypertension Gestational hypertension
Severe preeclampsia
Pregestational diabetes
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Gestational diabetes
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Mild preeclampsia
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3.1
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Commercial
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Drug use
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Non Abruption %
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Non Abruption %
Mild Abruption %
Severe Abruption %
2.6
2.5
3.9
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Oligohydramnios
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Table 2 Association between clinical characteristics and risks of mild and severe placental abruption Adjusted Risk Ratio (95% Confidence Interval)
Maternal age (years) 0.70 (0.68, 0.72)
20-24
0.89 (0.87, 0.91)
25-29
1.00 (Reference)
30-34
1.10 (1.08, 1.13)
35-39
1.23 (1.21, 1.26)
0.97 (0.95, 0.99) 0.95 (0.94, 0.97)
1.00 (Reference) 1.11 (1.09, 1.12) 1.28 (1.26, 1.30)
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<20
Severe abruption
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Mild abruption
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Risk Factors
1.58 (1.51, 1.65)
1.47 (1.42, 1.52)
0.70 (0.68, 0.72)
0.97 (0.95, 0.99)
1.00 (Reference)
1.00 (Reference)
0.92 (0.90, 0.94)
1.31 (1.29, 1.33)
0.83 (0.81, 0.86)
0.89 (0.88, 0.91)
0.94 (0.92, 0.96)
1.01 (1.00, 1.02)
Single marital status
1.06 (1.04, 1.08)
1.20 (1.19, 1.22)
Tobacco use
1.49 (1.45, 1.53)
1.90 (1.87, 1.93)
Alcohol use
1.86 (1.63, 2.13)
1.78 (1.65, 1.92)
2.08 (1.91, 2.26)
2.32 (2.21, 2.44)
1.00 (Reference)
1.00 (Reference)
Medicare
1.14 (1.05, 1.24)
1.10 (1.04, 1.16)
Medicaid
1.21 (1.19, 1.23)
1.19 (1.18, 1.21)
Uninsured
1.43 (1.37, 1.49)
1.56 (1.52, 1.60)
40-44 ≥45
Maternal race White
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Black Hispanic
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Other
Drug use
Insurance
Commercial
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Hypertension status 1.00 (Reference)
Chronic hypertension
1.35 (1.29, 1.41)
1.64 (1.60, 1.69)
Gestational hypertension
1.47 (1.42, 1.52)
1.21 (1.18, 1.24)
Mild preeclampsia
1.69 (1.63, 1.77)
2.06 (2.01, 2.12)
Severe preeclampsia
2.00 (1.92, 2.08)
0.73 (0.62, 0.86)
Anemia
1.59 (1.56, 1.63)
Premature rupture of membranes
1.27 (1.23, 1.32)
Intrapartum fever
2.13 (1.76, 2.57)
4.21 (4.13, 4.29)
1.35 (1.26, 1.45)
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Chronic renal disease
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1.00 (Reference)
Polyhydramnios Oligohydramnios Chorioamnionitis
2.45 (2.42, 2.47)
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Normotensive
2.52 (2.48, 2.56) 1.34 (1.16, 1.55)
1.15 (1.07, 1.23)
1.39 (1.33, 1.45)
0.96 (0.91, 1.00)
1.45 (1.42, 1.49)
1.50 (1.43, 1.58)
2.42 (2.36, 2.48)
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Rate ratios for mild and severe abruption are each compared to the non-abruption group Associations were adjusted for all factors listed in the table 1 through log-linear Poisson regression model
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Non-abruption (n=27,528,415) Rate
Severe placental abruption (n=181,133) Adjusted Rate Rate Ratio (95% CI)
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Mild placental abruption (n=86,917) Adjusted Rate Rate Ratio (95% CI)
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Table 3 Rate and rate ratio (95% confidence interval) of serious maternal complications in relation to mild and severe placental abruption Severe versus mild abruption Adjusted Rate Ratio (95% CI)
1.52 (1.35, 1.72) 1.60 (1.24, 2.08) 2.46 (1.97, 3.08)
141.7 23.4
0.93 (0.69, 1.25)
1.62 (1.33, 1.96)
27.5 2.7 15.2 88.9
̶
5.1
10.31 (8.21, 12.94) ̶
1.9
7.04 (4.83, 10.25)
̶
15.4 2.8
33.3 7.2
2.9
9.8
4.1 0.2 3.4 5.7
5.7 ̶ 7.4 13.0
̶ 1.48 (1.13, 1.92)
Amniotic fluid embolism
0.4
̶
Coma
0.1
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Composite maternal outcome Pulmonary edema Puerperal cerebrovascular disorders Acute heart failure Acute myocardial infarction Cardiomyopathy Acute respiratory failure
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̶
̶
16.5
4.29 (4.11, 4.47) 2.97 (2.68, 3.29) 2.72 (2.41, 3.07)
3.47 (3.05, 3.95) 2.40 (1.82, 3.17)
3.05 (2.78, 3.36) 7.56 (5.51, 10.38)
4.20 (3.08, 5.74) ̶ 1.68 (1.26, 2.26) 5.47 (4.48, 6.68)
2.12 (1.87, 2.41) 7.00 (6.62, 7.39)
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Rates are expressed per 10,000 Associations were adjusted for factors listed in table 1 through log-linear Poisson regression model
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1.20 (0.92, 1.55)
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Figure 1
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Supplemental Table 1 ICD-9 clinical modification codes for variables in this study ICD-9-CM code
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Condition
V27.0-V27.9 Multiple births (V272-V277, 654.x) were excluded
Placental abruption
641.2
Infant outcomes Stillbirth Neonatal death Preterm delivery Fetal growth restriction Nonreassuring fetal status
656.4x, V27.1x 768.x, 798.x 644.2x 656.5x, 764x 656.3x, 659.7x
Covariates Hypertensive disorders Chronic hypertension Gestational hypertension Mild preeclampsia Severe preeclampsia Superimposed preeclampsia
642.00-642.24 642.30-642.34 642.40-642.49 642.50-642.54 642.70-642.74
Chronic renal disease Asthma
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Tobacco use Alcohol use Drug abuse
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Delivery Singleton birth
305.1.x, 649.0x 291.xx, 303.xx, 305.0x 304.x, 305.2x-305.9x, 648.3x 646.2x, 581.x, 582.x, 583.x, 585.x, 587, 588.x 493, 493.0, 493.00, 493.02, 493.1, 493.10, 493.12, 493.2, 493.20, 493.22, 493.81, 493.82, 30
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Pulmonary edema Amniotic fluid embolism DIC Acute renal failure Acute heart failure Acute myocardial infarction Cardiomyopathy Acute liver failure Acute respiratory failure Blood transfusion Hysterectomy Coma Shock
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Puerperal cerebrovascular disorders
761.6 671.5, 671.50, 671.51, 671.52, 671.53, 671.54, 674.0, 674.00, 674.01, 674.02, 674.03, 674.04, 430, 431, 432, 432.0, 432.1, 432.9, 436, 997.01, 997.02, 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91, 325, 348.1, 348.3, 348.30, 348.31, 348.39, 348.5, 437.1, 437.2, 437.6, 346.6, 346.60, 346.61, 346.62, 346.63 514, 518.4, 428.1 673.1x 666.3x, 286.6, 286.7, 286.9, 287.4, 287.41, 287.49 584, 584.5, 584.6, 584.7, 584.8, 584.9, 669.3, 669.30, 669.32, 669.34 415, 415.0, 427.5, 428.0, 428.1, 428.21, 428.31, 428.41, 997.1, 428.23, 428.33, 428.43, 428.9 410.x 674.5x, 425x 570, 646.7, 646.70, 646.71, 646.73 518.81, 518.82, 518.84, 518.5, 518.51, 518.52, 518.53, 799.1, 518.7 V58.2, 99.0, 99.01-99.07 68.3, 68.31, 68.39, 68.4, 68.41, 68.49, 68.6, 68.69, 68.9 780.01, 780.03, 572.2, 250.2x, 250.3x, 251.0x 669.1x, 785.5x, 998.0x, 995.4, 995.0, 995.94, 99.4x
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Outcomes/procedures Maternal death
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Preexisting diabetes Gestational diabetes
493.9, 493.90, 493.92 250.x, 648.0x 648.8x (without pre-existing diabetes)
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S0002-9378(15)01120-5
DOI:
10.1016/j.ajog.2015.09.069
Reference:
YMOB 10657
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 31 August 2015 Accepted Date: 14 September 2015
Please cite this article as: Ananth CV, Lavery JA, Vintzileos AM, Skupski DW, Varner M, Saade G, Biggio J, Williams MA, Wapner RJ, Wright JD, Severe Placental Abruption: Clinical Definition and Associations with Maternal Complications, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.09.069. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Severe Placental Abruption: Clinical Definition and Associations with Maternal Complications
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Cande V. ANANTH, PhD, MPH,1,2,3 Jessica A. LAVERY, MS,1,2 Anthony M. VINTZILEOS, MD,4 Daniel W. SKUPSKI, MD,5 Michael VARNER, MD,6 George SAADE, MD,7
Joseph BIGGIO, MD,8 Michelle A. WILLIAMS, ScD,9
Author affiliations
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Ronald J. WAPNER, MD,1 Jason D. WRIGHT, MD1
1. Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY
2. Biostatistics Coordinating Center, Department of Obstetrics and Gynecology, College of
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Physicians and Surgeons, Columbia University, New York, NY
3. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
4. Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, NY
New York, NY
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5. Department of Obstetrics and Gynecology, Weill Medical College of Cornell University,
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6. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT 7. Department of Obstetrics and Gynecology, University of Texas, Galveston, TX 8. Department of Obstetrics and Gynecology, University of Alabama, Birmingham, AL 9. Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA
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Correspondence Cande V. Ananth Department of Obstetrics and Gynecology
Columbia University
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College of Physicians and Surgeons
622 West 168th Street, New York NY 10032
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Email: [email protected]
Abstract 499; Text 2,819; Tables 3; Figures 1; Online tables 1
Running head
Mild versus severe placental abruption
Funding
None
Conflicts
None declared
Print version
Please use figure 1
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Word count
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Condensation Severe placental abruption is clinically more homogeneous and is associated with substantially
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increased risks of serious maternal complications compared to mild abruptions.
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Abstract Background: Placental abruption is traditionally defined as the premature separation of the
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implanted placenta prior to the delivery of the fetus. The existing clinical criteria of severity rely exclusively on fetal (fetal distress or fetal death) and maternal complications without
consideration of neonatal or preterm delivery-related complications. However, two-thirds of
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abruption cases are accompanied by fetal or neonatal complications, including preterm
delivery. A clinically meaningful classification for abruption should therefore include not only
growth restriction and preterm delivery.
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maternal complications, but also adverse fetal and neonatal outcomes including intrauterine
Objectives: To define severe placental abruption and to compare serious maternal morbidity
abruptions.
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profiles of such cases to all other cases of abruption (i.e., mild abruption) as well as non-
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Study design: We performed a retrospective cohort analysis using the Premier database of hospitalizations resulting in singleton births in the US between 2006 and 2012 (n=27,796,465).
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Severe abruption was defined as abruption accompanied by at least one of the following: maternal (DIC, hypovolemic shock, blood transfusion, hysterectomy, renal failure or in-hospital death), fetal (non-reassuring fetal status, intrauterine growth restriction or fetal death) or neonatal (preterm delivery or small for gestational age) complications. Abruption cases that did not qualify as being severe were classified as mild abruptions. Morbidity profile included amniotic fluid embolism, pulmonary edema, acute respiratory or heart failure, acute myocardial
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infarction, cardiomyopathy, puerperal cerebrovascular disorders or coma. Associations were expressed as rate ratio (RR) with 95% confidence interval (CI) derived from fitting log-linear
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Poisson regression models.
Results: The overall prevalence rate of abruption was 9.6 per 1000, of which two-thirds were
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classified as being severe (6.5 per 1000). Serious maternal complications occurred in 15.4, 33.3 and 141.7 per 10,000 among non-abruption, and mild and severe abruption, respectively. In
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comparison to no abruptions, the RR for serious maternal complications were 1.51 (95% CI 1.34, 1.71) and 3.93 (95% CI 3.77, 4.10) in women with mild and severe placental abruption, respectively. RRs for the individual complications were 2 to 7-fold higher among severe abruptions. Furthermore, the RR’s for serious maternal complications among severe abruption
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compared to mild abruption was 3.47 (95% CI 3.05, 3.95). This association was considerably stronger for virtually all maternal complications among severe abruption compared to mild
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abruption.
Annual rates of mild and severe abruption were fairly constant during the study period (figure).
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While the maternal complication rate among non-abruption births was stable between 2006 and 2012, the rate of complications among mild abruption dropped between 2006 and 2008 and then leveled off thereafter. In contrast, the rate of serious complications among severe abruption remained fairly stable between 2006 and 2010, and increased sharply thereafter.
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Conclusions: Severe abruption was associated with a distinctively higher morbidity risk profile as compared to the other two groups. The clinical characteristics and morbidity profile of mild
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abruption was more similar to those of women without an abruption. These findings suggest that the definition of severe placental abruption based on the proposed specific criteria is
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clinically relevant and may facilitate epidemiological and genetic research.
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Key words
Placental abruption; maternal complications; ischemic placental disease; IUGR; preterm
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delivery; fetal death; DIC; blood transfusion
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Introduction Placental abruption is traditionally defined as the premature separation of the implanted
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placenta prior to the delivery of the fetus. The existing clinical criteria of severity rely exclusively on fetal (fetal distress or fetal death) and maternal complications without
consideration of neonatal or preterm delivery-related complications.1 However, two-thirds of
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abruption cases are accompanied by fetal or neonatal complications, including preterm
delivery. A clinically meaningful classification for abruption should therefore include not only
growth restriction and preterm delivery.
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maternal complications, but also adverse fetal and neonatal outcomes including intrauterine
We hypothesized that the criteria to define placental abruption as “severe” should be clinically
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meaningful and should include at least one of maternal (disseminated intravascular coagulation, hypovolemic shock, blood transfusion, hysterectomy, renal failure or in-hospital death), fetal (non-reassuring fetal status, intrauterine growth restriction or fetal death) or
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neonatal (preterm delivery or fetal growth restriction [FGR]) complications. The intrinsic motivation for this hypothesis was that abruption cases with one or more of the above criteria
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will identify a distinct subset of women with very high risks of serious maternal complications, in comparison to women with mild abruption or no abruption. We test this hypothesis in a large cohort of almost 28 million singleton pregnancies in the United States.
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Methods Premier data
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We performed a retrospective cohort analysis of data from the Premier database (www.premierinc.com) to obtain all maternal hospital records for deliveries that occurred from 2006 to 2012. The data includes hospitalizations from in-patient, ambulatory and emergency
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admissions in about 500 hospitals each year in the US. These hospitals are chosen to provide representation of hospitalizations across the US. The Premier data can be purchased from
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Premier, Inc. All diagnosis and procedure codes in the Premier data were coded based on the International Classification of Disease, 9th version (ICD-9), and the codes used for conditions in this study are listed in the supplemental table 1. We sought and obtained approval from the
Placental abruption
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Institutional Review Board as an exempt protocol from Columbia University Medical Center, NY.
A diagnosis of placental abruption was based on clinical symptoms that include vaginal bleeding
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accompanied with severe abdominal pain, uterine tenderness, or tetanic contractions. Severe placental abruption was defined as a delivery with an abruption accompanied by one or more
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of the following maternal, fetal or neonatal complications. Maternal complications included disseminated intravascular coagulation, hypovolemic shock, blood transfusion, hysterectomy, and renal failure and in-hospital death. Fetal complications included non-reassuring fetal status, fetal growth restriction or fetal death, and neonatal complications included neonatal death, preterm delivery and small for gestational age (SGA) births. Although the risk of some of the severe maternal morbidity, such as pulmonary edema or cardiomyopathy, are expected to be
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higher among pregnancies complicated by abruption, these conditions are not the typical complications following abruption; therefore we do not consider these variables in the
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definition of severe abruption.2-4 Abruption cases that did not qualify as being severe were classified as mild abruptions.
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Maternal morbidity profile
The primary endpoint was a composite morbidity outcome comprised of serious maternal
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complications including pulmonary edema, acute respiratory failure, acute heart failure, acute myocardial infarction, cardiomyopathy, puerperal cerebrovascular disorder, and coma and amniotic fluid embolism. In addition, we also examined the associations between abruption and
Clinical characteristics
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each of these serious maternal complications.
We examined the rates of mild and severe abruption across patient characteristics. Maternal
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sociodemographic and behavioral characteristics included year of delivery (2006-2012), maternal age, single marital status, and insurance status, as well as tobacco, drug or alcohol
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use. Maternal comorbidities included hypertensive diseases (chronic hypertension, gestational hypertension, or preeclampsia/eclampsia), pregestational diabetes, gestational diabetes, chronic renal disease, asthma, and congenital cardiac disease. Intrapartum and labor characteristics included premature rupture of membranes (at preterm or term gestations), anemia, intrapartum fever, polyhydramnios, oligohydramnios, and chorioamnionitis. SGA was used as a proxy for intrauterine growth restriction.
9
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Statistical analysis
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Two sets of log-linear regression models (with a Poisson distribution and a log-link function) were fit: the first was to evaluate the maternal characteristics associated with mild and severe placental abruption; and second, to estimate the association of serious maternal complications
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(morbidity profile) associated with mild and severe abruptions compared to non-abruption births, as well as a comparison of serious maternal complications between severe versus mild
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(reference) abruptions. For evaluating risk factors for mild and severe abruptions, we first estimated the unadjusted rate ratio (RR) and 95% confidence interval (CI). From this analysis, we chose risk factors that had RRs either above 1.2 or below 0.8 for mild and severe abruption; risk factors that met this criterion were entered in the final multivariable log linear Poisson
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regression models from which we evaluated the associations.
Rate ratios (RR) and 95% confidence intervals (CI) were calculated for the composite serious
EP
maternal morbidity profile, as well as for each severe maternal outcome individually. In this analysis, we adjusted for all maternal characteristics as potential confounding factors. All
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analyses were weighted based on the weights provided in Premier in order to generate national estimates.
Cohort composition From 28,504,661 (weighted) singleton deliveries identified in the Perspectives database, twins and higher-order multiple births (n=530,091; unweighted 79,594) and women younger than 15
10
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or older than 59 years were excluded (n=30,940; unweighted 5,187). We additionally excluded women diagnosed with placenta previa (n=141,135; unweighted 22,241). After all exclusions,
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the analysis cohort was composed of 27,796,465 (3,961,031 unweighted) women.
Results
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In this cohort of 27,796,465 singleton births, the prevalence rates of mild and severe abruption were 3.1 and 6.5 per 1000, respectively (overall prevalence rate of 9.6 per 1000). The
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distribution of clinical characteristics among the three groups of non-abruption, mild abruption and severe abruption is shown in table 1. Maternal age 40 years or older, black race, cigarette smoking status and use of drugs or alcohol were associated with increased rates of abruption, with a stark contrast in rates observed for mild versus severe abruption cases. Compared to
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non-abruption births, the prevalence rates of hypertensive disorders were increased among women with mild abruption but were substantially higher among women with severe abruption. Similarly, rates of premature rupture of membranes, polyhydramnios and
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oligohydramnios were also relatively higher among severe abruption.
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The associations between the clinical characteristics and mild and severe placental abruption are shown in Table 2. Several differences were found between mild versus severe abruption. For instance, compared to women 25-29 years (reference), maternal age up to 45 years showed stronger associations with mild abruption, whereas the risk among women ≥45 years higher among severe abruption. Rate ratios were higher for severe than mild abruption for black race, single marital status, tobacco use. The risk of severe abruption was substantially higher than
11
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mild abruption in relation to chronic hypertension (RRs 1.64 versus 1.35), mild preeclampsia (2.06 versus 1.69) and severe preeclampsia (4.21 versus 2.00). In contrast, the RRs of mild
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abruption were higher compared to severe abruption among gestational hypertensive women (1.47 versus 1.21). The RRs for severe abruption were higher than mild abruption in relation to premature rupture of membranes, anemia, polyhydramnios, oligohydramnios, and
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chorioamnionitis.
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The morbidity profile and the rates of individual maternal complications in mild and severe abruption, as well as the adjusted RR for these complications are shown in Table 3. Serious maternal complications occurred in 15.4 per 10,000 among non-abruption births, and in 33.3 and 141.7 per 10,000 in women with mild and severe abruption. After adjusting for
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confounders, compared to women without abruption, the RR for maternal complications was 2.14 (95% CI 1.89, 2.41) in women with mild abruption and 4.29 (95% CI 4.11, 4.47) in women with severe abruption. RRs for many of the individual complications were moderately increased
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in women with mild abruption, but were 2 to 7-fold higher among severe abruptions. In fact, the RR of the composite serious maternal complications in relation to severe abruption was
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3.47 (95% CI 3.05, 3.95) (Table 3). Similarly, the RRs for pulmonary edema (RR 2.40, 95% CI 1.82, 3.17), acute heart failure (RR 4.20, 95% CI 3.08, 5.74), and acute respiratory failure (RR 5.47, 95% CI 4.48, 6.68) were all considerably higher in women with severe abruptions.
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The rate ratio for serious maternal complications among severe abruption compared to mild abruption was 3.47 (95% CI 3.05, 3.95). The associations were considerably stronger for
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virtually all maternal complications among severe abruption than among mild abruption.
Rates of mild and severe abruption between 2006 and 2012 and the corresponding rates of
SC
serious maternal complications in relations to abruption are shown in Figure 1. Rates of mild and severe abruption were fairly constant during the study period. While the maternal
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complication rate among non-abruption births was stable between 2006 and 2012, the rate of complications among mild abruption dropped between 2006 and 2008 and then leveled off thereafter. In contrast, the rate of serious complications among severe abruption remained
Comment
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fairly stable between 2006 and 2010, and increased sharply thereafter.
Placental abruption is a serious and often a life threatening condition to the fetus and, to a
EP
lesser extent, to the woman.5-13 We show that the clinical characteristics for abruption differ substantially between mild and severe forms of the condition and with varying strengths of
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associations. The choices of maternal conditions that constitute a diagnosis of severe abruption were not different than those previously reported in the obstetrical literature. The maternal morbidity profile that we chose includes extreme maternal conditions that are not typically seen with abruption and are not typically included in the definition of abruption. Under maternal morbidity profile we included cardiomyopathy, myocardial infarction and respiratory failure, which are conditions, associated with severe, prolonged hypoxia. Amniotic fluid
13
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embolism was also included in the maternal morbidity profile since it is not typical for the diagnosis but its association with abruption has been well documented.2-4, 14 These conditions
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are extremely serious but not typical of abruption and this was the reason that we included them in the maternal morbidity profile rather than in the definition of severe abruption.
SC
The morbidity profile and rates of serious maternal complications are profoundly different between mild and severe abruptions, with the rates being substantially higher among severe
M AN U
(141.7 per 10,000) than mild (33.3 per 10,000) abruptions. Importantly, severe abruptions comprise two-thirds of all abruptions mainly because preterm delivery and SGA were included in the definition of severe abruption even in the absence of severe maternal symptomatology. Taken together, these findings suggest that severe abruptions are the distinct group of really
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sick patients and that combining mild and severe forms of the disease may introduce substantial heterogeneity in clinical research.
EP
In this study the diagnosis of placental abruption was based on clinical criteria rather than placental pathology reports (which were unavailable). However, in our view, pathology reports
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may not be necessary for three reasons: (i) epidemiologic database very rarely, if ever, have data regarding pathology reports; (ii) there are very few experts in placental pathology, so any definition using reliable placental pathology information may affect generalizability; and (iii) the prevalence rate of abruption of 9.6 per 1000 in this study is within the range reported in other population-based studies.5, 15-17 This suggests that we have not missed a significant number of
14
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cases due to lack of placental pathology data. However, the data allowed for distinguishing
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preterm from term births despite the lack of data on the individual gestational age.
Limitations of the data
Despite the interesting observations, the findings must be interpreted with some caution.
SC
Primarily, the Premier data includes data on large number of deliveries, but data on few
socioeconomic and behavioral characteristics (such as maternal education, prepregnancy body-
M AN U
mass index, and weight gain during pregnancy) are lacking, so the possibility of the associations being affected by unmeasured confounders remain. There is also some possibility of misclassification of abruption cases. However, we believe that such misclassification, if present, is likely more common for the milder forms of the condition. Women with severe abruption are
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the really sick patients with more than one serious complication and it is very unlikely that abruption status will be misclassified in this group.
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Strengths of the study
The strengths of the study include the large study size with data from hospitalizations
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associated with over 27 million singleton deliveries from 441 hospitals over a seven-year period (2006-2012) in the US. All analyses were weighted by the sampling weights of deliveries permitting generalizability of the findings. The associations we report are adjusted for a variety of confounding factors.
Interpretation of findings
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Over four decades ago, Pritchard and colleagues18 proposed that severe abruptions are those that are accompanied by one or more of short umbilical cord, external trauma, sudden uterine
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decomposition, uterine anomaly or tumor, occlusion of the inferior vena cava, maternal folate deficiency, maternal vascular disease, high parity, and previous abruption. A second
classification was based on a system that assigns a score ranging from 0 to 3, with 0 indicating
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asymptomatic women with evidence of small retroplacental clots on the placental surface on pathologic examination after delivery, 1 denoting those with bleeding and uterine tenderness
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or tetanic contractions, 2 denoting bleeding with fetal distress (but no signs of maternal shock) and 3 denoting bleeding with uterine tetany, persistent abdominal pain, and maternal shock and fetal demise.19
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The classification for severe placental abruption that we propose is broad and encompasses more objective criteria of clinically meaningful abruption. In fact, the conditions used to define severe abruption are based on serious co-occurring maternal, fetal and neonatal clinical
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complications. The grading system to classify abruption severity19 is restrictive since even the grade 0 abruption that results in preterm delivery will be deemed as being “severe” based on
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this classification system. Based on this definition, two-thirds of all clinically diagnosed abruption cases were classified as being severe. Furthermore, fetal growth restriction and abruption are both largely a chronic process that share strong similarities and are driven by uteroplacental ischemia,20, 21 and this provides further support that both preterm delivery and fetal growth restriction should be considered in the definition of severe abruptions. This classification not only identifies women with severe abruption with substantially higher risk of
16
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serious morbidity, but also acknowledges that women with severe abruption are distinctly
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different than those with milder forms of the complication.
Virtually all studies on placental abruption have focused exclusively on assessing risks in the perinatal period and during infancy,22-26 and evaluation of maternal risks associated with this
SC
condition are sparse. Furthermore, we are unaware of any study that has attempted to
separate mild from severe forms of abruption. In fact, the inclusion of neonatal complications
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(preterm delivery and SGA) in the definition of severe abruption results in two-thirds of all abruptions being classified as being severe.
Risk factors for severe abruption appear largely driven by inflammation and, to a lesser extent,
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infection-related pathways.27 That tobacco and drug use are stronger risk factors for severe than mild abruptions suggest that chronic hypoxia leading to uteroplacental underperfusion as a result of tobacco smoke11, 28-30 appears to shape the risk of severe abruption. Other
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pathological chronic conditions including chronic hypertension,12, 31-33 preeclampsia,34, 35 premature rupture of membranes,36 anemia,37 oligohydramnios38 and infection-related
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conditions such as chorioamnionitis38, 39 are stronger risk factors for severe than mild abruptions. Interestingly, asthma and intrapartum fever showed stronger associations with mild than with severe abruptions.
The long-term risk of mortality and morbidity from premature cardiovascular disease are about 2 to 6-fold higher among women with abruption compared to otherwise normal pregnancies.40-
17
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43
In addition, this study suggests that the risks of serious maternal cardiovascular complications
also remain substantially higher among women with severe than mild abruptions. Acute
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complications such as myocardial infarction and respiratory failure are about 7-fold higher among women with severe abruption. These findings provide support to available data showing that ischemic conditions during pregnancy such as preeclampsia,44, 45 fetal growth restriction,46, preterm delivery48, 49 and placental abruption40, 41, 43 may be linked to future cardiovascular
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47
disease in women later in life. One of the intriguing and unexpected finding is the temporal
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increase in the rate of serious maternal complications among women with severe abruption since 2010 (Figure 1), but this increase remains clinically insignificant.
Conclusions
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This large population-based study suggests that the frequency of maternal clinical risk factors is different between mild versus severe abruptions. Furthermore, the associated serious morbidity profile of women diagnosed with severe abruption is considerably worse than in
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those with mild abruption. These findings underscore a substantial heterogeneity in both risk factor profile and serious adverse maternal complications. Importantly, the definition of severe
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that we propose is based on objective data that includes maternal, fetal and neonatal complications. Although this proposed definition is not one that can be used prospectively because it includes outcome data in the definition of severe abruption, these observations underscore that future studies on placental abruption should attempt to separate mild from severe forms, when feasible. This recommendation will be particularly helpful for studies that seek to understand the genetic imprints and gene-environment interactions on abruption risk.
18
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Research to unravel the etiology may also benefit from separating mild from severe placental
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abruption.
19
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Table 1 Distribution of clinical characteristics based on mild and severe placental abruption Severe Abruption %
27,528,415
86,917 (3.1)
181,133 (6.5)
<20
9.0
20-24
23.5
25-29
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Maternal age (years)
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Mild Abruption %
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Number (abruption rate per 1000)
Non Abruption %
7.1
10.6
22.5
24.3
28.6
28.1
26.3
24.3
25.0
22.4
12.9
14.8
14.0
1.5
2.3
2.0
0.1
0.2
0.3
27.7 (6.0)
28.3 (6.1)
27.7 (6.4)
51.3
53.0
47.1
12.6
13.0
19.7
9.9
8.6
8.3
26.2
25.4
24.8
Married
49.7
48.7
41.3
Single
37.6
39.3
46.6
Unknown
12.7
12.1
12.1
Tobacco use
4.7
7.6
10.2
Alcohol use
0.1
0.3
0.4
30-34 35-39 40-44 ≥45
White Black Hispanic
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Other
EP
Maternal race
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Mean (standard deviation)
Marital status
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Mild Abruption %
Severe Abruption %
0.2
0.7
1.0
Insurance 52.1
Medicare
0.6
Medicaid
41.2
Uninsured
2.5
Unknown
3.6
48.7
43.7
0.7
0.8
43.6
47.8 3.4
3.9
4.2
91.4
86.7
82.2
1.8
2.5
3.2
3.2
4.5
3.5
1.8
2.9
3.5
1.8
3.4
7.6
0.8
0.7
1.2
5.5
5.3
5.1
Chronic renal disease
0.2
0.2
0.5
Asthma
2.9
3.5
3.9
Anemia
9.8
15.1
23.9
Congenital cardiac disease
0.1
0.0
0.1
Premature rupture of membranes
3.5
4.5
8.8
Intrapartum fever
0.1
0.1
0.1
Chorioamnionitis
1.4
2.2
4.1
Polyhydramnios
0.8
1.0
1.2
Hypertension status Normotensive Chronic hypertension Gestational hypertension
Severe preeclampsia
Pregestational diabetes
EP
Gestational diabetes
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Mild preeclampsia
M AN U
3.1
AC C
Commercial
SC
Drug use
RI PT
Non Abruption %
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Non Abruption %
Mild Abruption %
Severe Abruption %
2.6
2.5
3.9
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EP
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M AN U
SC
RI PT
Oligohydramnios
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Table 2 Association between clinical characteristics and risks of mild and severe placental abruption Adjusted Risk Ratio (95% Confidence Interval)
Maternal age (years) 0.70 (0.68, 0.72)
20-24
0.89 (0.87, 0.91)
25-29
1.00 (Reference)
30-34
1.10 (1.08, 1.13)
35-39
1.23 (1.21, 1.26)
0.97 (0.95, 0.99) 0.95 (0.94, 0.97)
1.00 (Reference) 1.11 (1.09, 1.12) 1.28 (1.26, 1.30)
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<20
Severe abruption
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Mild abruption
SC
Risk Factors
1.58 (1.51, 1.65)
1.47 (1.42, 1.52)
0.70 (0.68, 0.72)
0.97 (0.95, 0.99)
1.00 (Reference)
1.00 (Reference)
0.92 (0.90, 0.94)
1.31 (1.29, 1.33)
0.83 (0.81, 0.86)
0.89 (0.88, 0.91)
0.94 (0.92, 0.96)
1.01 (1.00, 1.02)
Single marital status
1.06 (1.04, 1.08)
1.20 (1.19, 1.22)
Tobacco use
1.49 (1.45, 1.53)
1.90 (1.87, 1.93)
Alcohol use
1.86 (1.63, 2.13)
1.78 (1.65, 1.92)
2.08 (1.91, 2.26)
2.32 (2.21, 2.44)
1.00 (Reference)
1.00 (Reference)
Medicare
1.14 (1.05, 1.24)
1.10 (1.04, 1.16)
Medicaid
1.21 (1.19, 1.23)
1.19 (1.18, 1.21)
Uninsured
1.43 (1.37, 1.49)
1.56 (1.52, 1.60)
40-44 ≥45
Maternal race White
TE D
Black Hispanic
AC C
EP
Other
Drug use
Insurance
Commercial
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ACCEPTED MANUSCRIPT
Hypertension status 1.00 (Reference)
Chronic hypertension
1.35 (1.29, 1.41)
1.64 (1.60, 1.69)
Gestational hypertension
1.47 (1.42, 1.52)
1.21 (1.18, 1.24)
Mild preeclampsia
1.69 (1.63, 1.77)
2.06 (2.01, 2.12)
Severe preeclampsia
2.00 (1.92, 2.08)
0.73 (0.62, 0.86)
Anemia
1.59 (1.56, 1.63)
Premature rupture of membranes
1.27 (1.23, 1.32)
Intrapartum fever
2.13 (1.76, 2.57)
4.21 (4.13, 4.29)
1.35 (1.26, 1.45)
M AN U
Chronic renal disease
RI PT
1.00 (Reference)
Polyhydramnios Oligohydramnios Chorioamnionitis
2.45 (2.42, 2.47)
SC
Normotensive
2.52 (2.48, 2.56) 1.34 (1.16, 1.55)
1.15 (1.07, 1.23)
1.39 (1.33, 1.45)
0.96 (0.91, 1.00)
1.45 (1.42, 1.49)
1.50 (1.43, 1.58)
2.42 (2.36, 2.48)
AC C
EP
TE D
Rate ratios for mild and severe abruption are each compared to the non-abruption group Associations were adjusted for all factors listed in the table 1 through log-linear Poisson regression model
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ACCEPTED MANUSCRIPT
Non-abruption (n=27,528,415) Rate
Severe placental abruption (n=181,133) Adjusted Rate Rate Ratio (95% CI)
SC
Mild placental abruption (n=86,917) Adjusted Rate Rate Ratio (95% CI)
RI PT
Table 3 Rate and rate ratio (95% confidence interval) of serious maternal complications in relation to mild and severe placental abruption Severe versus mild abruption Adjusted Rate Ratio (95% CI)
1.52 (1.35, 1.72) 1.60 (1.24, 2.08) 2.46 (1.97, 3.08)
141.7 23.4
0.93 (0.69, 1.25)
1.62 (1.33, 1.96)
27.5 2.7 15.2 88.9
̶
5.1
10.31 (8.21, 12.94) ̶
1.9
7.04 (4.83, 10.25)
̶
15.4 2.8
33.3 7.2
2.9
9.8
4.1 0.2 3.4 5.7
5.7 ̶ 7.4 13.0
̶ 1.48 (1.13, 1.92)
Amniotic fluid embolism
0.4
̶
Coma
0.1
TE D
M AN U
Composite maternal outcome Pulmonary edema Puerperal cerebrovascular disorders Acute heart failure Acute myocardial infarction Cardiomyopathy Acute respiratory failure
EP
̶
̶
16.5
4.29 (4.11, 4.47) 2.97 (2.68, 3.29) 2.72 (2.41, 3.07)
3.47 (3.05, 3.95) 2.40 (1.82, 3.17)
3.05 (2.78, 3.36) 7.56 (5.51, 10.38)
4.20 (3.08, 5.74) ̶ 1.68 (1.26, 2.26) 5.47 (4.48, 6.68)
2.12 (1.87, 2.41) 7.00 (6.62, 7.39)
AC C
Rates are expressed per 10,000 Associations were adjusted for factors listed in table 1 through log-linear Poisson regression model
28
1.20 (0.92, 1.55)
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 1
29
ACCEPTED MANUSCRIPT
Supplemental Table 1 ICD-9 clinical modification codes for variables in this study ICD-9-CM code
RI PT
Condition
V27.0-V27.9 Multiple births (V272-V277, 654.x) were excluded
Placental abruption
641.2
Infant outcomes Stillbirth Neonatal death Preterm delivery Fetal growth restriction Nonreassuring fetal status
656.4x, V27.1x 768.x, 798.x 644.2x 656.5x, 764x 656.3x, 659.7x
Covariates Hypertensive disorders Chronic hypertension Gestational hypertension Mild preeclampsia Severe preeclampsia Superimposed preeclampsia
642.00-642.24 642.30-642.34 642.40-642.49 642.50-642.54 642.70-642.74
Chronic renal disease Asthma
M AN U TE D
EP
AC C
Tobacco use Alcohol use Drug abuse
SC
Delivery Singleton birth
305.1.x, 649.0x 291.xx, 303.xx, 305.0x 304.x, 305.2x-305.9x, 648.3x 646.2x, 581.x, 582.x, 583.x, 585.x, 587, 588.x 493, 493.0, 493.00, 493.02, 493.1, 493.10, 493.12, 493.2, 493.20, 493.22, 493.81, 493.82, 30
ACCEPTED MANUSCRIPT
RI PT
SC
M AN U
Pulmonary edema Amniotic fluid embolism DIC Acute renal failure Acute heart failure Acute myocardial infarction Cardiomyopathy Acute liver failure Acute respiratory failure Blood transfusion Hysterectomy Coma Shock
TE D
Puerperal cerebrovascular disorders
761.6 671.5, 671.50, 671.51, 671.52, 671.53, 671.54, 674.0, 674.00, 674.01, 674.02, 674.03, 674.04, 430, 431, 432, 432.0, 432.1, 432.9, 436, 997.01, 997.02, 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91, 325, 348.1, 348.3, 348.30, 348.31, 348.39, 348.5, 437.1, 437.2, 437.6, 346.6, 346.60, 346.61, 346.62, 346.63 514, 518.4, 428.1 673.1x 666.3x, 286.6, 286.7, 286.9, 287.4, 287.41, 287.49 584, 584.5, 584.6, 584.7, 584.8, 584.9, 669.3, 669.30, 669.32, 669.34 415, 415.0, 427.5, 428.0, 428.1, 428.21, 428.31, 428.41, 997.1, 428.23, 428.33, 428.43, 428.9 410.x 674.5x, 425x 570, 646.7, 646.70, 646.71, 646.73 518.81, 518.82, 518.84, 518.5, 518.51, 518.52, 518.53, 799.1, 518.7 V58.2, 99.0, 99.01-99.07 68.3, 68.31, 68.39, 68.4, 68.41, 68.49, 68.6, 68.69, 68.9 780.01, 780.03, 572.2, 250.2x, 250.3x, 251.0x 669.1x, 785.5x, 998.0x, 995.4, 995.0, 995.94, 99.4x
EP
Outcomes/procedures Maternal death
AC C
Preexisting diabetes Gestational diabetes
493.9, 493.90, 493.92 250.x, 648.0x 648.8x (without pre-existing diabetes)
31