Original Research

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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

BACKGROUND: Placental abruption traditionally is defined as the

premature separation of the implanted placenta before 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 abruption cases are accompanied by fetal or neonatal complications, including preterm delivery. A clinically meaningful classification for abruption therefore should include not only maternal complications but also adverse fetal and neonatal outcomes that include intrauterine growth restriction and preterm delivery. OBJECTIVES: The purpose of this study was to define severe placental abruption and to compare serious maternal morbidity profiles of such cases with all other cases of abruption (ie, mild abruption) and nonabruption cases. STUDY DESIGN: We performed a retrospective cohort analysis using the Premier database of hospitalizations that resulted in singleton births in the United States between 2006 and 2012 (n ¼ 27,796,465). Severe abruption was defined as abruption accompanied by at least 1 of the following events: maternal (disseminated intravascular coagulation, hypovolemic shock, blood transfusion, hysterectomy, renal failure, or inhospital death), fetal (nonreassuring fetal status, intrauterine growth restriction, or fetal death), or neonatal (neonatal death, preterm delivery or small for gestational age) complications. Abruption cases that did not qualify as being severe were classified as mild abruption cases. The morbidity profile included amniotic fluid embolism, pulmonary edema, acute respiratory or heart failure, acute myocardial infarction, cardiomyopathy, puerperal cerebrovascular disorders, or coma. Associations were expressed as rate ratios with 95% confidence intervals that were derived from fitting log-linear Poisson regression models. RESULTS: The overall prevalence rate of abruption was 9.6 per 1000, of which two-thirds of cases were classified as being severe

P

lacental abruption traditionally is defined as the premature separation of the implanted placenta before the delivery of the fetus. The existing clinical criteria of severity rely exclusively on fetal (fetal distress or fetal death)

Cite this article as: Ananth CV, Lavery JA, Vintzileos AM, et al. Severe placental abruption: clinical definition and associations with maternal complications. Am J Obstet Gynecol 2016;214:272.e1-9. 0002-9378/$36.00 ª 2016 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajog.2015.09.069

(6.5 per 1000). Serious maternal complications occurred in 15.4, 33.3, and 141.7 per 10,000 among nonabruption cases and mild and severe abruption cases, respectively. In comparison with no abruption, the rate ratio for serious maternal complications were 1.52 (95% confidence interval, 1.35e1.72) and 4.29 (95% confidence interval, 4.11e4.47) in women with mild and severe placental abruption, respectively. Rate ratios for the individual complications were 2- to 7-fold higher among severe abruption cases. Furthermore, the rate ratios for serious maternal complications among severe abruption cases compared with mild abruption cases was 3.47 (95% confidence interval, 3.05e3.95). This association was considerably stronger for virtually all maternal complications among cases with severe abruption compared with mild abruption. Annual rates of mild and severe abruption were fairly constant during the study period. Although the maternal complication rate among non-abruption births was stable from 2006-2012, the rate of complications among mild abruption cases dropped from 2006-2008 and then leveled off thereafter. In contrast, the rate of serious complications among severe abruption cases remained fairly stable from 2006-2010 and increased sharply thereafter. CONCLUSIONS: Severe abruption was associated with a distinctively higher morbidity risk profile compared with the other 2 groups. The clinical characteristics and morbidity profile of mild abruption were 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 clinically relevant and may facilitate epidemiologic and genetic research. Key words: blood transfusion, disseminated intravascular coagulation,

fetal death, intrauterine growth restriction, maternal complication, placental abruption, preterm delivery

and maternal complications without consideration of neonatal or preterm delivery-related complications.1 However, two-thirds of abruption cases are accompanied by fetal or neonatal complications, which includes preterm delivery. A clinically meaningful classification for abruption therefore should include not only maternal complications but also adverse fetal and neonatal outcomes that include intrauterine growth restriction and preterm delivery. We hypothesized that the criteria that were needed to define placental abruption as “severe” should be clinically

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meaningful and should include at least 1 of maternal (disseminated intravascular coagulation, hypovolemic shock, blood transfusion, hysterectomy, renal failure, or in-hospital death), fetal (nonreassuring fetal status, intrauterine growth restriction, or fetal death), or neonatal (neonatal death, preterm delivery, or small for gestational age) complications. The intrinsic motivation for this hypothesis was that abruption cases with 1 of the aforementioned criteria will identify a distinct subset of women with very high risks of serious maternal complications, in comparison

ajog.org with women with mild abruption or no abruption. We tested this hypothesis in a large cohort of almost 28 million singleton pregnancies in the United States.

Methods Premier data We performed a retrospective cohort analysis of data from the Premier database (www.premierinc.com; Premier, Inc, Charlotte, NC) to obtain all maternal hospital records for deliveries that occurred from 2006-2012. The data include hospitalizations from in-patient, ambulatory, and emergency admissions in approximately 500 hospitals each year in the United States. These hospitals are chosen to provide a representation of hospitalizations across the United States. The Premier data can be purchased from Premier, Inc. All diagnosis and procedure codes in the Premier data were coded based on the International Classification of Disease, 9th version; the codes used for conditions in this study are listed in the Supplemental Table. We sought and obtained approval from the Institutional Review Board as an exempt protocol from Columbia University Medical Center, NY.

Placental abruption A diagnosis of placental abruption was based on clinical symptoms that include vaginal bleeding accompanied with severe abdominal pain, uterine tenderness, or tetanic contractions. Severe placental abruption was defined as a delivery with an abruption accompanied by 1 of the following maternal, fetal, or neonatal complications. Maternal complications included disseminated intravascular coagulation, hypovolemic shock, blood transfusion, hysterectomy, renal failure, and in-hospital death. Fetal complications included nonreassuring fetal status, intrauterine growth restriction, or fetal death. Neonatal complications included neonatal death, preterm delivery, and small-for-gestational-age (SGA) births. Although the risk of some of the severe maternal morbidities, such as pulmonary edema or cardiomyopathy, are expected to be higher among pregnancies that are complicated by abruption, these

OBSTETRICS

conditions are not the typical complications after abruption; therefore, we do not consider these variables in the definition of severe abruption.2-4 Abruption cases that did not qualify as being severe were classified as mild abruptions.

Maternal morbidity profile The primary endpoint was a composite morbidity outcome comprised of serious maternal complications that included pulmonary edema, acute respiratory failure, acute heart failure, acute myocardial infarction, cardiomyopathy, puerperal cerebrovascular disorder, coma, and amniotic fluid embolism. In addition, we also examined the associations between abruption and each of these serious maternal complications.

Clinical characteristics We examined the rates of mild and severe abruption across patient characteristics. Maternal sociodemographic and behavioral characteristics included year of delivery (2006-2012), maternal age, single marital status, insurance status, and tobacco, drug, or alcohol use. Maternal comorbidities included hypertensive diseases (chronic hypertension, gestational hypertension, or preeclampsia/eclampsia), 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.

Statistical analysis Two sets of log-linear regression models (with a Poisson distribution and a loglink function) were fit: the first model was to evaluate the maternal characteristics that are associated with mild and severe placental abruption; the second model was to estimate the association of serious maternal complications (morbidity profile) that are associated with births with mild and severe abruptions compared with births with no abruption and to compare serious maternal complications between severe

Original Research

vs mild (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 >1.2 or <0.8 for mild and severe abruption; risk factors that met this criterion were entered in the final multivariable log linear Poisson regression models from which we evaluated the associations. RRs and 95% CIs were calculated for the composite serious maternal morbidity profile and for each severe maternal outcome individually. In this analysis, we adjusted for all maternal characteristics as potential confounding factors. All analyses were weighted based on the weights provided in Premier to generate national estimates.

Cohort composition From 28,504,661 (weighted) singleton deliveries that were identified in the Perspectives database, records identified as male (n ¼ 1308; unweighted, 236), twins and higher-order multiple births (n ¼ 530,065; unweighted, 79,594) and women <15 or >59 years old were sequentially excluded (n ¼ 32,688; unweighted, 5187). We additionally excluded women who received a diagnosis of placenta previa (n ¼ 144,135; unweighted, 21,241). After all exclusions, the analysis cohort was composed of 27,796,465 (3,961,031 unweighted) women.

Results 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, 9.6 per 1000). The distribution of clinical characteristics among the 3 groups of nonabruption, mild abruption, and severe abruption is shown in Table 1. Maternal age 35 years old, black race, cigarette smoking status, and the use of drugs or alcohol were associated with increased rates of abruption. Compared with nonabruption births, the prevalence rates of hypertensive disorders were increased among women with mild abruption but were

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TABLE 1

Distribution of clinical characteristics based on mild and severe placental abruptiona Variable

No abruption, %

Mild abruption, %

Severe abruption, %

Maternal age, yb <20

9.0

7.1

10.6

20-24

23.5

22.5

24.3

25-29

28.6

28.1

26.3

30-34

24.3

25.0

22.4

35-39

12.9

14.8

14.0

40-44

1.5

2.3

2.0

45

0.1

0.2

0.3

White

51.3

53.0

47.1

Black

12.6

13.0

19.7

Maternal race

Hispanic

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

Other Marital status

Unknown

12.7

12.1

12.1

Tobacco use

4.7

7.6

10.2

Alcohol use

0.1

0.3

0.4

Drug use

0.2

0.7

1.0

52.1

48.7

43.7

Medicare

0.6

0.7

0.8

Medicaid

41.2

43.6

47.8

Insurance Commercial

Uninsured

2.5

3.1

3.4

Unknown

3.6

3.9

4.2

91.4

86.7

82.2

Hypertension status Normotensive Chronic hypertension

1.8

2.5

3.2

Gestational hypertension

3.2

4.5

3.5

Mild preeclampsia

1.8

2.9

3.5

Severe preeclampsia

1.8

3.4

7.6

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

Ananth et al. Severe placental abruption. Am J Obstet Gynecol 2016.

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(continued)

substantially higher among women with severe abruption. Similarly, rates of premature rupture of membranes, polyhydramnios, and oligohydramnios were also relatively higher among severe abruption. The associations between the clinical characteristics and mild and severe placental abruption are shown in Table 2. Several differences were found between mild vs severe abruption. For instance, compared with women 25-29 years (reference), maternal age 45 years showed stronger associations with mild abruption, whereas the risk among women 45 years old was higher among women with severe abruption. RRs were higher for severe rather than mild abruption for black race, single marital status, and tobacco use. The risk of severe abruption was substantially higher than mild abruption in relation to chronic hypertension (RR, 1.64 vs 1.35), mild preeclampsia (RR, 2.06 vs 1.69), and severe preeclampsia (RR, 4.21 vs 2.00). In contrast, the RRs of mild abruption were higher compared with severe abruption among women with gestational hypertension (RR, 1.47 vs 1.21). The RRs for severe abruption were higher than mild abruption in relation to premature rupture of membranes, anemia, polyhydramnios, oligohydramnios, and chorioamnionitis. The morbidity profile and the rates of individual maternal complications in mild and severe abruption and the adjusted RRs for these complications are shown in Table 3. Serious maternal complications occurred in 15.4 per 10,000 for nonabruption and in 33.3 and 141.7 per 10,000 in women for mild and severe abruption. After adjustment for confounders, compared with women without abruption, the RRs for maternal complications were 1.52 (95% CI, 1.35e1.72) in women with mild abruption and 4.29 (95% CI, 4.11e4.47) in women with severe abruption. RRs for many of the individual complications were increased moderately 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 4.29 (95% CI,

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TABLE 1

Distribution of clinical characteristics based on mild and severe placental abruptiona (continued) Variable

No abruption, %

Mild abruption, %

Severe abruption, %

Chorioamnionitis

1.4

2.2

4.1

Polyhydramnios

0.8

1.0

1.2

Oligohydramnios

2.6

2.5

3.9

a

Number (abruption rate per 1000): no abruption, 27,528,415; mild abruption, 86,917 (3.1); severe abruption, 181,133 (6.5); b Mean  standard deviation: no abruption, 27.7  6.0; mild abruption, 28.3  6.1; severe abruption, 27.7  6.4. Ananth et al. Severe placental abruption. Am J Obstet Gynecol 2016.

4.11e4.47; Table 3). Similarly, the RRs for pulmonary edema (RR, 2.97; 95% CI, 2.68e3.29), acute heart failure (RR, 3.05; 95% CI, 2.78e3.36), and acute respiratory failure (RR, 7.00; 95% CI, 6.62e7.39) were all considerably higher in women with severe abruptions. The RRs for serious maternal complications among severe abruption compared with mild abruption was 3.47 (95% CI, 3.05e3.95). The associations were considerably stronger for virtually all maternal complications for severe abruption rather than for mild abruption. Rates of mild and severe abruption between 2006 and 2012 and the corresponding rates of serious maternal complications in relations to abruption are shown in the Figure. Rates of mild and severe abruption were fairly constant during the study period. Although the maternal complication rate among births with no abruption was stable between 2006 and 2012, the rate of complications for mild abruption dropped between 2006 and 2008 and then leveled off thereafter. In contrast, the rate of serious complications for severe abruption remained fairly stable between 2006 and 2010, and increased sharply thereafter.

Comment Placental abruption is a serious and often a life-threatening condition to the fetus and, to a 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 associations. The choices of maternal

conditions that constitute a diagnosis of severe abruption were not different than those previously reported in the obstetrics literature. The maternal morbidity profile that we chose includes extreme maternal conditions that typically are not seen with abruption and typically are not included in the definition of abruption. Under maternal morbidity profile, we included cardiomyopathy, myocardial infarction, and respiratory failure, which are conditions that are associated with severe, prolonged hypoxia. Amniotic fluid embolism was also included in the maternal morbidity profile because it is not typical for the diagnosis, but its association with abruption has been well-documented.2-4,14 These conditions are extremely serious but not typical of abruption; for this reason, we included them in the maternal morbidity profile rather than in the definition of severe abruption. The morbidity profile and rates of serious maternal complications are profoundly different between mild and severe abruptions, with the rates being substantially higher between severe (141.7 per 10,000) rather 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 symptoms. Taken together, these findings suggest that severe abruptions are the distinct group of really ill patients and that combining mild and severe forms of the disease may introduce substantial heterogeneity in clinical research.

Original Research

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 may not be necessary for 3 reasons: (1) epidemiologic databases very rarely, if ever, have data regarding pathology reports; (2) there are very few experts in placental diseases, so any definition that use reliable placental pathology information may affect generalizability; and (3) the prevalence rate of abruption of 9.6 per 1000 in this study is within the range that has been reported in other populationbased studies.5,15-17 This suggests that we have not missed a significant number of cases because of a lack of placental pathology data. However, the data allowed for distinguishing 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. Primarily, the Premier data includes data on a large number of deliveries, but data on few socioeconomic and behavioral characteristics (such as maternal education, prepregnancy body 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 the really ill patients with >1 serious complication, and it is very unlikely that abruption status would be misclassified in this group.

Strengths of the study The strengths of the study include the large study size with data from hospitalizations that are associated with over 27 million singleton deliveries from 441 hospitals over a 7-year period (20062012) in the United States. All analyses were weighted by the sampling weights of deliveries, which permitted generalizability of the findings. The associations

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that we report were adjusted for a variety of confounding factors.

TABLE 2

Association between clinical characteristics and risks of mild and severe placental abruptiona

Interpretation of findings

Adjusted rate ratio (95% confidence interval)b Risk factors

Mild abruption

Severe abruption

<20

0.70 (0.68, 0.72)

0.97 (0.95, 0.99)

20-24

0.89 (0.87, 0.91)

0.95 (0.94, 0.97)

25-29

1.00 (Reference)

1.00 (Reference)

30-34

1.10 (1.08, 1.13)

1.11 (1.09, 1.12)

35-39

1.23 (1.21, 1.26)

1.28 (1.26, 1.30)

40-44

1.58 (1.51, 1.65)

1.47 (1.42, 1.52)

45

0.70 (0.68, 0.72)

0.97 (0.95, 0.99)

White

1.00 (Reference)

1.00 (Reference)

Black

0.92 (0.90, 0.94)

1.31 (1.29, 1.33)

Hispanic

0.83 (0.81, 0.86)

0.89 (0.88, 0.91)

Other

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)

Drug use

2.08 (1.91, 2.26)

2.32 (2.21, 2.44)

Commercial

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)

1.00 (Reference)

1.00 (Reference)

Maternal age, y

Maternal race

Insurance

Hypertension status Normotensive 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)

4.21 (4.13, 4.29)

Chronic renal disease

0.73 (0.62, 0.86)

1.35 (1.26, 1.45)

Asthma

1.13 (1.09, 1.17)

1.04 (1.02, 1.07)

Anemia

1.59 (1.56, 1.63)

2.45 (2.42, 2.47)

Premature rupture of membranes

1.27 (1.23, 1.32)

2.52 (2.48, 2.56)

Intrapartum fever

2.13 (1.76, 2.57)

1.34 (1.16, 1.55)

Polyhydramnios

1.15 (1.07, 1.23)

1.39 (1.33, 1.45)

Oligohydramnios

0.96 (0.91, 1.00)

1.45 (1.42, 1.49)

Chorioamnionitis

1.50 (1.43, 1.58)

2.42 (2.36, 2.48)

a

Associations for all factors listed in the Table 1 were adjusted with the use of the log-linear Poisson regression model; b Rate ratios for mild and severe abruption are each compared with the nonabruption group. Ananth et al. Severe placental abruption. Am J Obstet Gynecol 2016.

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More than 4 decades ago, Pritchard et al18 proposed that severe abruptions are those that are accompanied by 1 of short umbilical cord, external trauma, sudden uterine 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 that ranges from 0-3, with 0 indicating asymptomatic women with evidence of small retroplacental clots on the placental surface on pathologic examination after delivery, 1 denoting those women with bleeding and uterine tenderness 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, maternal shock, and fetal death.19 The classification for severe placental abruption that we propose is broad and encompasses more objective criteria of clinically meaningful abruption. In fact, the conditions that were used to define severe abruption were based on serious co-occurring maternal, fetal, and neonatal clinical complications. The grading system to classify abruption severity19 is restrictive, because even the grade 0 abruption that results in preterm delivery will be deemed as being “severe” based on 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 which 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 serious morbidity but also acknowledges that women with severe

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Original Research

TABLE 3

Ratea and rate ratio of serious maternal complications in relation to mild and severe placental abruptionb Nonabruption (n ¼ 27,528,415)

Mild placental abruption (n ¼ 86,917)

Severe placental abruption (n ¼ 181,133)

Severe vs mild abruption Adjusted rate ratio (95% confidence interval)

Variable

Rate

Rate

Adjusted rate ratio (95% confidence interval)

Rate

Adjusted rate ratio (95% confidence interval)

Composite maternal outcome

15.4

33.3

1.52 (1.35e1.72)

141.7

4.29 (4.11e4.47)

3.47 (3.05e3.95)

Pulmonary edema

2.8

7.2

1.60 (1.24e2.08)

23.4

2.97 (2.68e3.29)

2.40 (1.82e3.17)

Puerperal cerebrovascular disorders

2.9

9.8

2.46 (1.97e3.08)

16.5

2.72 (2.41e3.07)

1.20 (0.92e1.55)

0.93 (0.69e1.25)

27.5

3.05 (2.78e3.36)

4.20 (3.08e5.74)

2.7

7.56 (5.51e10.38)

—

Acute heart failure

4.1

Acute myocardial infarction

0.2

5.7

Cardiomyopathy

3.4

7.4

1.48 (1.13e1.92)

15.2

2.12 (1.87e2.41)

1.68 (1.26e2.26)

Acute respiratory failure

5.7

13.0

1.62 (1.33e1.96)

88.9

7.00 (6.62e7.39)

5.47 (4.48e6.68)

Amniotic fluid embolism

0.4

—

—

5.1

10.56 (8.42e13.24)

—

Coma

0.1

—

—

1.9

7.04 (4.83e10.25)

—

—

—

a

Rates are expressed per 10,000; b Associations were adjusted for the factors listed in Table 1 with the use of the log-linear Poisson regression model. Ananth et al. Severe placental abruption. Am J Obstet Gynecol 2016.

FIGURE

Changes in the rates of mild and severe placental abruption between 2006 and 2012 and that of composite outcome among women with mild and severe abruption

Although the maternal complication rate among births with no abruption was stable between 2006 and 2012, the rate of complications for mild abruption dropped between 2006 and 2008 and then leveled off thereafter. In contrast, the rate of serious complications for severe abruption remained fairly stable between 2006 and 2010, and increased sharply thereafter. Ananth et al. Severe placental abruption. Am J Obstet Gynecol 2016.

abruption are distinctly 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 evaluations of maternal risks that are associated with this 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 (preterm delivery and SGA) in the definition of severe abruption results in two-thirds of all abruptions being classified as severe. Risk factors for severe abruption appear driven largely by inflammation and, to a lesser extent, infection-related pathways.27 That tobacco and drug use are stronger risk factors for severe, rather than mild, abruptions suggest that chronic hypoxia that leads to uteroplacental under-perfusion as a result of tobacco smoke11,28-30 appears to shape the risk of severe abruption. Other pathologic chronic conditions that include chronic hypertension,12,31-33 preeclampsia,34,35 premature rupture

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Original Research

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of membranes,36 anemia,37 oligohydramnios,38 and infection-related conditions such as chorioamnionitis38,39 are stronger risk factors for severe, rather than mild, abruptions. Interestingly, asthma and intrapartum fever showed stronger associations with mild than with severe abruptions. The long-term risk of death and morbidity from premature cardiovascular disease are approximately 2- to 6-fold higher among women with abruption compared with otherwise normal pregnancies.40-43 In addition, this study suggests that the risks of serious maternal cardiovascular complications also remain substantially higher among women with severe, rather than mild, abruptions. Acute complications such as myocardial infarction and respiratory failure are approximately 7-fold higher among women with severe abruption. These findings provide support to available data that show that ischemic conditions during pregnancy such as preeclampsia,44,45 fetal growth restriction,46,47 preterm delivery48,49 and placental abruption40,41,43 may be linked to future cardiovascular disease in women later in life. One of the intriguing and unexpected findings is the temporal increase in the rate of serious maternal complications among women with severe abruption since 2010 (Figure), but this increase remains clinically insignificant.

Conclusion This large population-based study suggests that the frequency of maternal clinical risk factors is different with mild vs severe abruptions. Furthermore, the associated serious morbidity profile of women who receive a diagnosis of severe abruption is considerably worse than in 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 that we propose is based on objective data that include 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. Research to unravel the causes may also benefit from separating mild from severe placental abruption. n References 1. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol 2006;108:1005-16. 2. Abenhaim HA, Azoulay L, Kramer MS, Leduc L. Incidence and risk factors of amniotic fluid embolisms: a population-based study on 3 million births in the United States. Am J Obstet Gynecol 2008;199:49.e1-8. 3. Conde-Agudelo A, Romero R. Amniotic fluid embolism: an evidence-based review. Am J Obstet Gynecol 2009;201:445.e1-13. 4. Spiliopoulos M, Puri I, Jain NJ, Kruse L, Mastrogiannis D, Dandolu V. Amniotic fluid embolism-risk factors, maternal and neonatal outcomes. J Matern Fetal Neonatal Med 2009;22:439-44. 5. Parker SE, Werler MM, Gissler M, Tikkanen M, Ananth CV. Placental abruption and subsequent risk of pre-eclampsia: a population-based casecontrol study. Paediatr Perinat Epidemiol 2015;29:211-9. 6. Ananth CV, Kinzler WL. Placental abruption: clinical features and diagnosis. In: Lockwood CJ, ed. UpToDate. Philadelphia: Wolters Kluwer Health; 2014. 7. Sanchez SE, Pacora PN, Farfan JH, et al. Risk factors of abruptio placentae among Peruvian women. Am J Obstet Gynecol 2006;194: 225-30. 8. Broers T, King WD, Arbuckle TE, Liu S. The occurrence of abruptio placentae in Canada: 1990 to 1997. Chronic Dis Can 2004;25:16-20. 9. Sheiner E, Shoham-Vardi I, Hadar A, Hallak M, Hackmon R, Mazor M. Incidence, obstetric risk factors and pregnancy outcome of preterm placental abruption: a retrospective analysis. J Matern Fetal Neonatal Med 2002;11: 34-9. 10. Rasmussen S, Irgens LM, Dalaker K. A history of placental dysfunction and risk of placental abruption. Paediatr Perinat Epidemiol 1999;13:9-21. 11. Kramer MS, Usher RH, Pollack R, Boyd M, Usher S. Etiologic determinants of abruptio placentae. Obstet Gynecol 1997;89:221-6. 12. Williams MA, Lieberman E, Mittendorf R, Monson RR, Schoenbaum SC. Risk factors for abruptio placentae. Am J Epidemiol 1991;134: 965-72. 13. Ananth CV, Oyelese Y, Yeo L, Pradhan A, Vintzileos AM. Placental abruption in the United States, 1979 through 2001: temporal trends and potential determinants. Am J Obstet Gynecol 2005;192:191-8.

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ajog.org 14. Hogberg U, Joelsson I. Amniotic fluid embolism in Sweden, 1951-1980. Gynecol Obstet Invest 1985;20:130-7. 15. Ananth CV, Keyes KM, Hamilton A, et al. An international contrast of rates of placental abruption: an age-period-cohort analysis. PLoS One 2015;10:e0125246. 16. Pariente G, Wiznitzer A, Sergienko R, Mazor M, Holcberg G, Sheiner E. Placental abruption: critical analysis of risk factors and perinatal outcomes. J Matern Fetal Neonatal Med 2011;24:698-702. 17. Ruiter L, Ravelli AC, de Graaf IM, Mol BW, Pajkrt E. Incidence and recurrence rate of placental abruption: a longitudinal linked national cohort study in the Netherlands. Am J Obstet Gynecol 2015;213:573.e1-8. 18. Pritchard JA, Mason R, Corley M, Pritchard S. Genesis of severe placental abruption. Am J Obstet Gynecol 1970;108:22-7. 19. Sher G, Statland BE. Abruptio placentae with coagulopathy: a rational basis for management. Clin Obstet Gynecol 1985;28: 15-23. 20. Ananth CV, Vintzileos AM. Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth. Am J Obstet Gynecol 2006;195:1557-63. 21. Ananth CV, Vintzileos AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006;19:773-82. 22. Kyrklund-Blomberg NB, Gennser G, Cnattingius S. Placental abruption and perinatal death. Paediatr Perinat Epidemiol 2001;15: 290-7. 23. 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. 24. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. Placental abruption and adverse perinatal outcomes. JAMA 1999;282:1646-51. 25. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001;153:332-7. 26. Tikkanen M, Luukkaala T, Gissler M, et al. Decreasing perinatal mortality in placental abruption. Acta Obstet Gynecol Scand 2013;92:298-305. 27. 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. 28. Christianson RE. Gross differences observed in the placentas of smokers and nonsmokers. Am J Epidemiol 1979;110:178-87. 29. 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. 30. 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.

ajog.org 31. Williams MA, Mittendorf R, Monson RR. Chronic hypertension, cigarette smoking, and abruptio placentae. Epidemiology 1991;2: 450-3. 32. 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. 33. Misra DP, Ananth CV. Risk factor profiles of placental abruption in first and second pregnancies: heterogeneous etiologies. J Clin Epidemiol 1999;52:453-61. 34. Ananth CV, Peltier MR, Chavez MR, Kirby RS, Getahun D, Vintzileos AM. Recurrence of ischemic placental disease. Obstet Gynecol 2007;110:128-33. 35. 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. 36. 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. 37. 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. 38. 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.

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39. Darby MJ, Caritis SN, Shen-Schwarz S. Placental abruption in the preterm gestation: an association with chorioamnionitis. Obstet Gynecol 1989;74:88-92. 40. 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. 41. 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. 42. Veerbeek JH, Smit JG, Koster MP, et al. Maternal cardiovascular risk profile after placental abruption. Hypertension 2013;61: 1297-301. 43. 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. Epub ahead of print. 44. 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. 45. 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. 46. Lykke JA, Paidas MJ, Triche EW, LanghoffRoos J. Fetal growth and later maternal death, cardiovascular disease and diabetes. Acta Obstet Gynecol Scand 2012;91:503-10.

Original Research

47. Smith GD, Whitley E, Gissler M, Hemminki E. Birth dimensions of offspring, premature birth, and the mortality of mothers. Lancet 2000;356: 2066-7. 48. 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. 49. 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.

Author and article information From the Department of Obstetrics and Gynecology (Drs Ananth, Wapner, and Wright and Ms Lavery) and the Biostatistics Coordinating Center (Dr Ananth and Ms Lavery), College of Physicians and Surgeons, and the Department of Epidemiology, Joseph L. Mailman School of Public Health (Dr Ananth), Columbia University, New York, NY; the Department of Obstetrics and Gynecology, Winthrop-University Hospital, Mineola, NY (Dr Vintzileos); the Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY (Dr Skupski); the Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT (Dr Varner); the Department of Obstetrics and Gynecology, University of Texas, Galveston, TX (Dr Saade); the Department of Obstetrics and Gynecology, University of Alabama, Birmingham, AL (Dr Biggio); the Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA (Dr Williams). Received Aug. 31, 2015; accepted Sept. 14, 2015. The authors report no conflict of interest. Corresponding author: Cande V. Ananth, PhD, MPH. [email protected]

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SUPPLEMENTAL TABLE

International Classification of Diseases, 9th edition, clinical modification codes for variables in this study Condition

International Classification of Diseases, 9th edition, clinical modification code

Delivery

V27.0-V27.9

Singleton birth

Multiple births (V272-V277, 654.x) excluded

Placental abruption

641.2

Infant outcomes Stillbirth

656.4x, V27.1x

Neonatal death

768.x, 798.x

Preterm delivery

644.2x

Fetal growth restriction

656.5x, 764x

Nonreassuring fetal status

656.3x, 659.7x

Covariates Hypertensive disorders Chronic hypertension

642.00-642.24

Gestational hypertension

642.30-642.34

Mild preeclampsia

642.40-642.49

Severe preeclampsia

642.50-642.54

Superimposed preeclampsia

642.70-642.74

Tobacco use

305.1.x, 649.0x

Alcohol use

291.xx, 303.xx, 305.0x

Drug abuse

304.x, 305.2x-305.9x, 648.3x

Chronic renal disease

646.2x, 581.x, 582.x, 583.x, 585.x, 587, 588.x

Asthma

493, 493.0, 493.00, 493.02, 493.1, 493.10, 493.12, 493.2, 493.20, 493.22, 493.81, 493.82, 493.9, 493.90, 493.92

Outcomes/procedures Maternal death

761.6

Puerperal cerebrovascular disorders

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

Pulmonary edema

514, 518.4, 428.1

Amniotic fluid embolism

673.1x

Disseminated intravascular coagulation

666.3x, 286.6, 286.7, 286.9, 287.4, 287.41, 287.49

Acute renal failure

584, 584.5, 584.6, 584.7, 584.8, 584.9, 669.3, 669.30, 669.32, 669.34

Acute heart failure

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

Acute myocardial infarction

410.x

Cardiomyopathy

674.5x, 425x

Acute liver failure

570, 646.7, 646.70, 646.71, 646.73

Acute respiratory failure

518.81, 518.82, 518.84, 518.5, 518.51, 518.52, 518.53, 799.1, 518.7

Blood transfusion

V58.2, 99.0, 99.01-99.07

Hysterectomy

68.3, 68.31, 68.39, 68.4, 68.41, 68.49, 68.6, 68.69, 68.9

Coma

780.01, 780.03, 572.2, 250.2x, 250.3x, 251.0x

Shock

669.1x, 785.5x, 998.0x, 995.4, 995.0, 995.94, 99.4x

Ananth et al. Severe placental abruption. Am J Obstet Gynecol 2016.

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