Placental Abruption in Term and Preterm

Gestations
Evidence for Heterogeneity in Clinical Pathways
Cande V. Ananth, PhD, MPH, Darios Getahun,
and John C. Smulian, MD, MPH

MD, MPH,

OBJECTIVE: To estimate the magnitude of associations

of acute and chronic processes with abruption in preterm
and term gestations.
METHODS: A retrospective cohort study was performed
using data on women that delivered singleton live births
and stillbirths at 20 or more weeks of gestation in the
United States, 19952002 (n 30,378,902). Rates of 1)
acute-inflammationassociated clinical conditions (premature rupture of membranes and intrauterine infection); 2) chronic processes associated with vascular dysfunction or chronic inflammation (chronic and
pregnancy-induced hypertension, preexisting or gestational diabetes, small for gestational age, and maternal
smoking); and 3) both acute and chronic processes, were
examined among women with and without abruption.
Rates were examined separately among preterm (< 37
weeks) and term births, with adjustment for confounders.
Relative risk (RR) for aforementioned groups in relation
to abruption was derived from multivariate logistic regression models after adjusting for potential confounders.
RESULTS: At preterm gestation, the rates of acute-inflammationassociated conditions were higher among
women with than without abruption (12.0% compared
with 10.2%; RR 1.38, 95% confidence interval [CI] 1.34
1.42). At term, acute-inflammationassociated conditions
were present in 4.2% and 3.3% of births with and without
From the Division of Epidemiology and Biostatistics and Division of MaternalFetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson
Medical School/Robert Wood Johnson University Hospital, New Brunswick,
New Jersey.
Drs. Ananth, Getahun, and Smulian are partially supported through a grant
(HD038902) from the National Institutes of Health awarded to Dr. Ananth.
Corresponding author: Cande V. Ananth, PhD, MPH, Division of Epidemiology
and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive
Sciences, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street,
New Brunswick, NJ 08901-1977; e-mail: cande.ananth@umdnj.edu.
2006 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/06

VOL. 107, NO. 4, APRIL 2006

Morgan R. Peltier,

PhD,

abruption, respectively (RR 1.39, 95% CI 1.331.45). At

preterm gestation, the rates of chronic processes were
43.9% and 30.0% among women with and without abruption, respectively (RR 1.87, 95% CI 1.851.90). At term,
the corresponding rates of chronic processes were 41.0%
and 22.7%, respectively (RR 2.37, 95% CI 2.34 2.41).
Association between both acute and chronic processes
and abruption are similar to those of acute-inflammationassociated conditions.
CONCLUSION: Among women with placental abruption, conditions associated with acute inflammation are
more prevalent at preterm than term gestations, whereas
chronic processes are present throughout gestation.
(Obstet Gynecol 2006;107:785792)

LEVEL OF EVIDENCE: II-2

lacental abruption, defined as the premature separation of the placenta before the delivery of the
fetus, is among the most devastating complications of
pregnancy for both the fetus and, to a lesser extent,
the mother. The condition occurs in approximately 1
in 100 pregnancies,12 but is associated with up to one
third of all perinatal deaths.35 Although the cause of
placental abruption remains elusive, epidemiologic
studies suggest that advanced maternal age, multiparity, smoking, cocaine use, hypertensive disorders,
intrauterine infection, preterm (prolonged) premature
rupture of membranes, and prior abruption are associated with increased risk.111
Evidence from previous studies collectively suggests that placental abruption is the manifestation of
clinical events that likely have at least 2 distinct
causative pathways7,10,12,13: 1) acute-inflammationassociated conditions, and 2) chronic processes (vascular dysfunction and chronic inflammation). If true,
then clues to these pathways may be found in associated clinical risk factors identified throughout pregnancy. Similarly, profiles of these so-called causative

OBSTETRICS & GYNECOLOGY

785

determinants would be expected to vary between

placental abruptions that occur at term and those at
preterm gestations.14,15 There is a growing body of
evidence to suggest that placental abruption is a
pathologic condition, chiefly associated with longstanding chronic vascular lesions, and to a lesser
extent, acute inflammatory processes (Ananth CV,
Oyelese Y, Getahun D, Smulian JC. Evidence of
placental abruption as a chronic process: associations
with vaginal bleeding early in pregnancy and placental lesions. Eur J Obstet Gynecol Reprod Biol 2006. In
press).7,12,13
Acute and chronic inflammatory processes are
mediated by cytokines such as interleukin (IL)-1 and
tumor necrosis factor (TNF)-.16,17 These cytokines
are known to upregulate the production and activity
of matrix metalloproteinases in a number of tissues,
including the trophoblast.18 Increased production of
matrix metalloproteinases may result in destruction of
the extracellular matrices and cell cell interactions
that secure the placenta and lead to premature detachment. Matrix metalloproteinases seem to play an
important role in normal placental detachment, because reduced matrix metalloproteinase activity is
known to be associated with retained placentas in
cattle.19 Our proposed model for placental abruption
that involves acute inflammation and chronic process
pathways is described in Figure 1.
The relative contributions of acute and chronic
inflammatory processes associated with placental abruption at preterm and term gestations remain unclear. Therefore, we tested the hypothesis that the
clinical pathways for placental abruption (ie, acuteinflammationassociation conditions and chronic
processes) are heterogeneous among pregnancies delivered at preterm and term gestations.

MATERIALS AND METHODS

We used the National Center for Health Statistics
(NCHS) linked birth/infant death data files for the
years 1995 through 2002. The NCHS routinely links
birth and infant death records that are provided by
individual states under the Vital Statistics Cooperative Program.20 The linked data included information
on maternal characteristics, medical and obstetric
history, complications of pregnancy, as well as fetal
and infant outcomes.21 Natality and stillbirth data are
routinely recorded on the live birth and death certificates, respectively, by attendants at the time of
delivery.21
Gestational age on these data files was derived
from the last menstrual period for more than 95% of
the pregnancies. When the estimated gestational age

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Ananth et al

Fig. 1. Proposed model for placental abruption with acute

inflammation and chronic clinical processes as potential
causative pathways. Like many complications of pregnancy, inflammation seems to play a key role in placental
abruption. Infections and tissue injury cause a rapid release
of bacterial (lipopolysaccharide) or cellular (heat shock
protein 60) activators of macrophages and other cells at the
maternalfetal interface. Oxidative stress and products of
vascular activation and coagulation such as thrombin may
have similar effects. Increased production of proinflammatory cytokines such as tumor necrosis factor and interleukin can function at the maternalfetal interface to
stimulate the production of matrix metalloproteinases by
trophoblasts and other cell types. Matrix metalloproteinases
digest extracellular matrix and can lead to necrosis. Tumor
necrosis factor and interleukin1 are known to induce
pro-apoptotic pathways. This combination of necrosis, apoptosis, and destruction of the extracellular matrix at the
maternalfetal interface lowers the threshold for placental
detachment and favors the development of placental abruption. SGA, small for gestational age; PROM, premature
rupture of membranes; LPS, lipopolysaccharide; Hsp, heat
shock protein; PAF, platelet activation factor; MMP, matrix
metalloproteinase; IL, interleukin; TNF, tumor necrosis
factor.
Ananth. Acute and Chronic Processes in Abruption. Obstet
Gynecol 2006.

based on menstrual dates was contradictory to the

reported birth weight, a clinical estimate of gestational
age (also contained on the vital statistics data) was

Acute and Chronic Processes in Abruption

OBSTETRICS & GYNECOLOGY

instead substituted. When the day of the menstrual

period was missing (but month and year were available), the missing gestational age was statistically
imputed.22 The replacement of clinically estimated
gestational age and the imputation were both performed by the NCHS consistently for all years examined in this study.21,22
We restricted the analysis to women who delivered a singleton live birth or stillbirth at 22 or more
weeks and fetus weighing at least 500 g. These
restrictions help avoid errors in these early gestational
ages23 and minimize interstate differences in reporting
births at the borderline of viability.24
The clinical pathways for placental abruption
examined were chosen based on previous published
literature,7,10 13 and grouped as 1) acute-inflammationassociated clinical conditions only; 2) chronic
clinical processes only, which included either vascular
dysfunction or chronic inflammation; and 3) both
acute inflammation and chronic clinical processes.
Acute-inflammationassociated clinical conditions included premature rupture of the membranes (rupture
more than 12 hours before the onset of labor) with or
without suspected intrauterine infections (defined as
intrapartum fever of 100F or 38C) and intrauterine infections in the absence of premature rupture
of membranes.
Chronic clinical processes included chronic hypertension (blood pressure at least 140/90 mm Hg
before pregnancy or within the first 20 weeks of
gestation), pregnancy-induced hypertension (blood
pressure increase of 30 mm Hg systolic, or 15 mm
Hg diastolic, on 2 occasions recorded 6 hours apart at
20 weeks), pregestational or gestational diabetes
(types I and II, or gestational diabetes), small for
gestational age (SGA), and smoking during pregnancy
(yes or no). Small for gestational age was defined as
sex-specific birth weight less than 10th centile for
gestational age. The norms for defining SGA births
were based on all United States 1995 singleton births
(internal standard). Maternal smoking during pregnancy was based on self-report, and details on smoking status by trimester or quit patterns were unavailable.
We estimated the rates of acute-inflammation
associated conditions and chronic processes among
women with and without a diagnosis of abruption.
Placental abruption-specific rates of causative factors
were compared across various gestational age categories of preterm (37 weeks) and term births, as well as
each week of gestation.
Logistic regression analyses were carried out to
examine associations between the 2 clinical pathways

VOL. 107, NO. 4, APRIL 2006

(dependent variables) and placental abruption (independent variable) before and after adjustment for
potential confounders. Odds ratios with 95% confidence intervals were derived from these models to
quantify the association between the causative determinant and abruption. Because the incidences of the
outcomes were fairly low, odds ratios derived from
the regression models were interpreted as relative
risks (RRs). The RR was based on comparing the rate
of a determinant (eg, acute-inflammationassociated
conditions) among women with and without abruption. Confounders considered for adjustment in the
regression models included birth year (1995,
1996,. . ., 2002), maternal age (less than 20 years,
20 24 years, 2529 years, 30 34 years, and 35
years), parity (parity 1 or parity 2), maternal race
(white, African American, and other races, irrespective of their Hispanic ethnicity), maternal education
(less than 9 years, 9 11 years, 12 years, 1315 years,
and 16 years of completed schooling), and marital
status (married or single).
We calculated population attributable fractions
(PAF) for acute-inflammationassociated conditions
and chronic processes among pregnancies complicated by abruption. The PAF was derived using the
relation Pd[(RR-1)/RR], where Pd refers to the incidence rate of the determinant among women with
abruption, and RR is the adjusted RR.25 The PAF is
interpreted as the proportion of the outcome that can
be attributed to abruption. Because none of these
determinants are the result of abruption, we underscore the need for caution in the interpretation of
PAFs. More importantly, the PAF should be used
only for relative comparisons between acute-inflammationassociated conditions and chronic clinical
processes associated with placental abruption.
The study was approved by the Institutional
Review Board of the UMDNJ-Robert Wood Johnson
Medical School, New Jersey. Statistical analyses were
performed using SAS 9.1 (SAS Institute, Cary, NC).

RESULTS
During the period 1995 through 2002, there were
30,378,902 singleton live births and stillbirths at 22 or
more weeks of gestation among fetuses that weighed
500 g or more. Placental abruption was recorded in
0.6% (n 179,204) of these births, with the rate at
preterm and term births being 2.8% and 0.3%, respectively (Table 1). The distribution of maternal characteristics by placental abruption status at preterm and
term gestations is shown in Table 1. Rates of abruption were higher with increasing maternal age and

Ananth et al

Acute and Chronic Processes in Abruption

787

Table 1. Maternal and Infant Characteristics of Women With and Without Placental Abruption: U.S.
Singleton Births, 19952002
Preterm Gestations (2236 wk)

Term Gestations (3744 wk)

Nonabruption

Abruption

Nonabruption

Abruption

3,151,895

89,151

27,227,007

90,053

Total pregnancies (n)

Maternal age (y) (%)
20
2024
2529
3034
35
Primiparity (%)
Race/ethnicity (%)
White
African American
Other
Maternal education (y) (%)
8
911
12
1315

Maternal smoking (%)

Stillbirth (%)
Preterm birth* (wk) (%)
35
32
Birth weight* (g) (%)
2,500
1,500

16.1
25.9
24.3
20.2
13.5
33.8

14.8
25.2
24.3
21.0
14.8
28.8

11.9
24.9
27.4
23.1
12.6
33.6

10.2
23.0
25.8
24.2
16.9
28.9

70.4
10.0
19.5

71.3
9.2
19.5

80.1
7.7
12.2

79.0
8.0
13.0

6.9
20.7
34.5
20.4
17.4
13.3
2.0

5.1
21.4
36.3
20.5
16.7
22.5
9.8

5.9
15.6
32.3
22.0
24.1
10.3
0.1

4.9
16.6
34.4
21.9
22.2
17.8
3.4

40.7
16.0

70.1
41.9

37.7
11.0

77.5
36.1

2.6
0.1

12.0
0.7

* Preterm birth and birth weight analysis were restricted to liveborn infants.

Table 2. Distributions of Acute-InflammationAssociated Conditions and Chronic Clinical Processes at

Preterm and Term Gestations: U.S. Singleton Births, 19952002
Preterm Gestations
(2236 wk) [n (%)]

Term Gestations
(3744 wk) [n (%)]

1,971,280 (62.5)
1,180,615 (37.5)
323,215 (10.3)
273,148 (8.7)
37,171 (1.2)
12,896 (0.4)
958,900 (30.4)
49,029 (1.6)
247,124 (7.9)
303,960 (9.6)
122,123 (3.9)
426,881 (13.5)
101,500 (3.2)

20,353,483 (74.7)
6,873,524 (25.3)
887,207 (3.3)
455,977 (1.7)
393,620 (1.5)
37,610 (0.1)
6,203,611 (22.8)
166,873 (0.6)
908,424 (3.4)
2,497,214 (9.2)
723,639 (2.7)
2,820,681 (10.4)
217,294 (0.8)

Absence of all conditions

Any cause
Acute inflammation (any)
PROM without fever
Fever without PROM
PROM with fever
Chronic clinical processes (any)
Chronic hypertension
Pregnancy-induced hypertension
Small for gestational age
Diabetes (all types)
Smoking during pregnancy
Both acute and chronic processes
PROM, premature rupture of membranes.

parity, as well as among smokers in both preterm and

term birth categories.
An acute-inflammationassociated condition or a
chronic clinical process was present in 37.5% of preterm

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Ananth et al

and 25.3% of term births (Table 2). Rates of acuteinflammationassociated conditions and chronic clinical
processes were, in general, higher at preterm than at
term births.

Acute and Chronic Processes in Abruption

OBSTETRICS & GYNECOLOGY

In cases of placental abruption, more than one

half of preterm births (51.3%) had either an acuteinflammationassociated condition or chronic clinical
process, in comparison with 43.5% at term (Table 3).
Within preterm births, acute-inflammationassociated conditions occurred 1.38-fold (95% confidence
interval [CI] 1.34 1.42), and chronic clinical processes 1.87-fold (95% CI 1.851.90) more frequently
in the presence, than absence, of abruption (Table 4).
At term, both acute-inflammationassociated conditions and chronic clinical processes were more frequent among abruption, compared with nonabruption births. The PAF for acute-inflammation
associated pregnancies in relation to abruption was
small, both at preterm (2.4%) and term (0.7%). In
contrast, more than one fifth of all chronic clinical
processes were associated with abruption, both at
preterm (PAF 20.4%) and term (PAF 22.7%) births.
Figure 2 shows gestational agespecific incidence
rates of acute-inflammationassociated conditions,
chronic clinical processes, and both acute and chronic
clinical processes among women with and without
abruption. The rate of acute-inflammationassociated
conditions showed a steady decline with advancing
gestation among abruption and nonabruption births
(Fig. 2A). Among women with abruption, the rate of
chronic clinical processes increased with advancing
gestational age up through 36 weeks, whereas among
women without abruption, the rate began to decline
earlier around 28 weeks (Fig. 2B). The difference in
the rates of chronic clinical processes between abruption and nonabruption births therefore progressively
widened at 28 weeks and beyond. The rate of both

acute-inflammationassociated
conditions
and
chronic clinical processes showed a steady decline
with advancing gestation among abruption and nonabruption births (Fig.2C), similar to those seen for
acute-inflammationassociated conditions.

DISCUSSION
Despite years of research, there has been surprisingly
little progress toward an understanding of the causes
of placental abruption. Our population-based study
offers a number of important insights in this direction.
Placental abruption seems to be a multifactorial disease process with different causative patterns at preterm and at term gestations. At preterm gestations,
acute inflammation, notably preterm premature rupture of membranes, seems to be more frequently
associated with abruption, suggestive of an acute
infectious process compared with those that occur at
term gestations. On the contrary, chronic clinical
processes seem to be associated with increased risk,
both at preterm and term births. More importantly,
the increased rates of chronic clinical processes associated with abruption births are largely accounted for
by hypertensive diseases and small for gestational age
births, suggesting that such high-risk pregnancies may
reflect long-standing pathologic processes. Finally,
pregnancies with both acute and chronic clinical
processes combined are relatively rare, but their
association with abruption largely resembles those of
acute-inflammationassociated conditions.
The incidence of chronic clinical processes increases with advancing gestational age, with a peak
close to term, and begins to decline thereafter (Fig. 2).

Table 3. Rates of Acute InflammationAssociated-Conditions and Chronic Clinical Processes Among

Women With and Without Placental Abruption: U.S. Singleton Births, 19952002
Preterm Gestations (2236 wk)

Term Gestations (3744 wk)

Underlying Causes of Placental Abruption

Nonabruption
[n (%)]

Abruption
[n (%)]

Nonabruption
[n (%)]

Abruption
[n (%)]

Absence of all conditions

Any cause
Acute inflammation (any)
PROM without fever
Fever without PROM
PROM with fever
Chronic clinical processes (any)
Chronic hypertension
Pregnancy-induced hypertension
Small for gestational age
Diabetes (all types)
Smoking during pregnancy
Both acute and chronic processes

1,927,841 (62.9)
1,134903 (37.1)
312,543 (10.2)
264,340 (8.6)
35,838 (1.2)
12,365 (0.4)
919,770 (30.0)
47,004 (1.5)
237,964 (7.8)
289,274 (9.4)
119,160 (3.9)
406,846 (13.8)
97,410 (3.2)

43,439 (48.7)
45,712 (51.3)
10,672 (12.0)
8,808 (9.9)
1,333 (1.5)
531 (0.6)
39,130 (43.9)
2,025 (2.3)
9,160 (10.4)
14,686 (16.5)
2,963 (3.3)
20,035 (23.5)
4,090 (4.6)

20,302,574 (74.8)
6,834,380 (25.2)
883,450 (3.3)
435,924 (1.7)
392,053 (1.4)
37,473 (0.1)
6,166,693 (22.7)
165,714 (0.6)
901,956 (3.3)
2,477,065 (9.2)
720,325 (2.7)
2,804,624 (10.6)
215,763 (0.8)

50,909 (56.5)
39,144 (43.5)
3,757 (4.2)
2,053 (2.3)
1,567 (1.7)
137 (0.2)
36,918 (41.0)
1,159 (1.3)
6,468 (7.2)
20,149 (22.5)
3,314 (3.7)
16,057 (18.6)
1,531 (1.7)

PROM, premature rupture of membranes.

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Ananth et al

Acute and Chronic Processes in Abruption

789

Table 4. Adjusted Relative Risk and Population Attributable Fraction for the Causative Determinants of
Placental Abruption at Preterm and Term Gestations: U.S. Singleton Births, 19952002
Preterm Gestations (2236 wk)
Underlying Causes of Placental Abruption
Absence of all conditions
Any cause
Acute inflammation (any)
PROM without fever
Fever without PROM
PROM with fever
Chronic clinical processes (any)
Chronic hypertension
Pregnancy-induced hypertension
Small for gestational age birth
Diabetes (all types)
Smoking during pregnancy
Both acute and chronic processes

Term Gestations (3744 wk)

RR (95% CI)

PAF

RR (95% CI)

PAF

1.00 (Reference)
1.78 (1.761.80)
1.38 (1.341.42)
1.49 (1.461.53)
1.68 (1.591.78)
1.92 (1.762.10)
1.87 (1.851.90)
1.84 (1.761.93)
1.72 (1.681.76)
1.93 (1.901.97)
0.83 (0.800.86)
1.87 (1.841.90)
1.86 (1.791.92)

22.5
2.4
3.3
0.6
0.3
20.4
1.1
4.4
8.0

10.9
2.1

1.00 (Reference)
2.30 (2.272.33)
1.39 (1.331.45)
1.85 (1.771.94)
1.69 (1.601.77)
1.55 (1.311.84)
2.37 (2.342.41)
2.64 (2.492.81)
2.92 (2.842.99)
2.95 (2.913.00)
1.34 (1.301.39)
1.91 (1.881.95)
2.92 (2.773.07)

24.6
0.7
1.1
0.7
0.7
22.7
0.8
4.7
14.9
0.9
8.9
1.1

RR, relative risk; CI, confidence interval; PAF, population attributable fraction (percent); PROM, premature rupture of membranes.
Relative risks were adjusted for the confounding effects of birth year, maternal age, parity, maternal race, maternal education, and marital
status.

Fig. 2. Rates (per 100 births) of acute-inflammationassociated conditions (A), chronic clinical processes (B), and
acute-inflammationassociated conditions and chronic clinical processes combined (C) among women with and without
placental abruption.
Ananth. Acute and Chronic Processes in Abruption. Obstet Gynecol 2006.

Impaired placentation, placental insufficiency, intrauterine hypoxia, and uteroplacental underperfusion are the
chief mechanisms that have been suggested to be associated with the occurrence of abruption.6,7,14,26,27 We believe
that our study supports our initial hypothesis that the
causative patterns of abruption differ substantially be-

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Ananth et al

tween those that occur at term compared with those that

occur preterm. However, the presence of different patterns in rates of acute-inflammationassociated conditions
and chronic clinical processes throughout gestation in the
presenceand absenceof placental abruption adds a
new dimension toward understanding its cause.

Acute and Chronic Processes in Abruption

OBSTETRICS & GYNECOLOGY

Premature rupture of membranes, preterm labor,

and placental abruption may have similar causes and
probably have similar biochemical pathways. How
inflammation leads to 3 separate conditions (ie, premature rupture of membranes, preterm labor, and
abruption) may have to do with the spatiotemporal
patterns by which the inflammation occurs. Chronic
processes and acute inflammation may cause placental abruption through various chemical triggers that
regulate the inflammatory processes at the maternal
fetal interface (Fig. 1). Neutrophils and macrophages
are increased in placentas harvested from women
with abruption compared with controls (Ananth CV,
Oyelese Y, Getahun D, Smulian JC. Evidence of
placental abruption as a chronic process: Associations
with vaginal bleeding early in pregnancy and placental lesions. Eur J Obstet Gynecol Reprod Biol 2006. In
press). When activated, these cells secrete matrix
metalloproteinases. Increased production of matrix
metalloproteinase-9 at the maternalfetal interface is
probably a normal process during labor,18,28 where it
may serve to facilitate the detachment of the placenta
after the delivery of the fetus by breaking down local
extracellular matrix. It is possible that premature
production of these enzymes as a part of an inflammatory response could be one mechanism by which
abruption occurs in vivo.
Similarly, acute inflammation of the maternal
fetal interface will activate these same pathways,
leading to fever and ruptured membranes as well as
abruption. Using fever in labor as a surrogate marker
for acute intrauterine infection has limitations. Not all
patients with fever in labor have evidence of acute
infection.29,30 Nevertheless, at least at term, women
who develop fever even without demonstrable infection have higher circulating levels of inflammatory
cytokines.31 This suggests that fever, even in the
absence of confirmed intrauterine infection, is a
marker for an inflammatory environment. In the
context of placental abruption, fever may represent
the inflammatory status that is the contributor to
abruption, or be a marker for the abruption process
itself, because blood components themselves are inflammatory stimuli. The association between fever
and abruption, particularly at preterm gestations,
supports this idea because preterm births are known
to have a strong link to infection and inflammation.16,17
The 2 causative determinants combined accounted for only one half of placental abruption cases,
both among preterm and term births. This suggests
that causes of the majority of abruption cases, both at
preterm and at term, remain largely unknown and

VOL. 107, NO. 4, APRIL 2006

that abruption is a disease process that often occurs

independently of the more common traditional medical and obstetric risk factors. We believe that the
majority of women who develop placental abruption
in the absence of any complication may bear a genetic
predisposition.32 Further research to identify the specific genes and polymorphisms, as well as their interactions with other environmental risk factors for
placental abruption are needed.
The limitations of our study are typical to those of
large, population-based studies. Most notably, errors
in the estimation of gestational age are likely to shift
the gestational age distribution toward lower gestational ages,23 thereby classifying a fraction of term
births as preterm. Moreover, there is some possibility
of delayed bleeding early in pregnancy often mistaken for late menses.33 Second, because inconsistent
gestational age birth weight were replaced by a clinical estimate of gestation, the proportion of SGA birth
may have been affected. However, because the replacement of inconsistent gestational age was done
only in a small fraction of births, the effect of this
replacement is likely small. Misclassification of some
of the determinants of placental abruption may have
also affected our results to some extent.34,35 Some of
the obstetric complications are underreported on the
natality and fetal mortality data files, but given the
nondifferential nature of the misclassification, this
may have resulted in effect measures (ie, RR) being
driven more toward the null. Equally, a small proportion of abruption cases would also have been misclassified,34 with this misclassification being more at preterm than at term gestations. The possibility of some
residual confounding due to drug use, maternal anthropometry, and nutritional factors is possible because these data were unavailable. Finally, although
small differences in the frequency of acute lesions
between abruption and nonabruption births at preterm (12.0% and 10.2%) and term (4.2% and 3.3%)
gestations were statistically significant, these differences may be of less clinical importance.
The population-based nature of this study offers
generalizability of findings. More importantly, the
findings have large and varied clinical implications.
Placental abruption seems to represent a final common clinical event that arises from a variety of
different causative pathways. By better understanding
these pathways, it is likely that intervention points can
be identified that will be amenable to targeted prevention strategies. Thinking of placental abruption in
terms of the causative heterogeneity and clinical
pathways identified in this study (acute compared
with chronic) is perhaps the first step in that direction.

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REFERENCES
1. Ananth CV, Smulian JC, Demissie K, Vintzileos AM, Knuppel
RA. Placental abruption among singleton and twin births in the
United States: risk factor profiles. Am J Epidemiol 2001;153:
7718.
2. Salihu HM, Bekan B, Aliyu MH, Rouse DJ, Kirby RS,
Alexander GR. Perinatal mortality associated with abruptio
placenta in singletons and multiples. Am J Obstet Gynecol
2005;193:198203.
3. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. Placental
abruption and adverse perinatal outcomes. JAMA 1999;282:
164651.
4. Rasmussen S, Irgens LM, Dalaker K. Outcome of pregnancies
subsequent to placental abruption: a risk assessment. Acta
Obstet Gynecol Scand 2000;79:496501.
5. Ananth CV, Wilcox AJ. Placental abruption and perinatal
mortality in the United States. Am J Epidemiol 2001;153:
3327.
6. Kramer MS, Usher RH, Pollack R, Boyd M, Usher S. Etiologic
determinants of abruptio placentae. Obstet Gynecol 1997;89:
2216.

19.

20.

21.

22.

23.

24.

25.

7. Rasmussen S, Irgens LM, Dalaker K. A history of placental

dysfunction and risk of placental abruption. Paediatr Perinat
Epidemiol 1999;13:921.

26.

8. Voigt LF, Hollenbach KA, Krohn MA, Daling JR, Hickok DE.
The relationship of abruptio placentae with maternal smoking
and small for gestational age infants. Obstet Gynecol 1990;75:
7714.

27.

9. Williams MA, Lieberman E, Mittendorf R, Monson RR,

Schoenbaum SC. Risk factors for abruptio placentae. Am J
Epidemiol 1991;134:96572.
10. 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;104:717.

28.

11. Raymond EG, Mills JL. Placental abruption: maternal risk

factors and associated fetal conditions. Acta Obstet Gynecol
Scand 1993;72:6339.

29.

12. Sherer DM, Salafia CM. Chronic intrauterine bleeding and

fetal growth at less than 32 weeks of gestation. Gynecol Obstet
Invest 2000;50:925.
13. Salafia CM, Lopez-Zeno JA, Sherer DM, Whittington SS,
Minior VK, Vintzileos AM. Histologic evidence of old intrauterine bleeding is more frequent in prematurity. Am J Obstet
Gynecol 1995;173:106570.
14. Sheiner E, Shoham-Vardi I, Hallak M, Hadar A, GortzakUzan L, Katz M, et al. Placental abruption in term pregnancies:
clinical significance and obstetric risk factors. J Matern Fetal
Neonatal Med 2003;13:459.
15. Spinillo A, Capuzzo E, Colonna L, Solerte L, Nicola S,
Guaschino S. Factors associated with abruptio placentae in
preterm deliveries. Acta Obstet Gynecol Scand 1994;73:
30712.

30.

31.

32.

33.

34.

16. Romero R, Erez O, Espinoza J. Intrauterine infection, preterm

labor, and cytokines. J Soc Gynecol Investig 2005;12:4635.
17. Peltier MR. Immunology of term and preterm labor. Reprod
Biol Endocrinol 2003;1:122.

35.

18. Meisser A, Chardonnens D, Campana A, Bischof P. Effects of

tumour necrosis factor-alpha, interleukin-1 alpha, macrophage
colony stimulating factor and transforming growth factor beta

792

Ananth et al

Acute and Chronic Processes in Abruption

on trophoblastic matrix metalloproteinases. Mol Hum Reprod

1999;5:25260.
Maj JG, Kankofer M. Activity of 72-kDa and 92-kDa matrix
metalloproteinases in placental tissues of cows with and without retained fetal membranes. Placenta 1997;18:6837.
National Center for Health Statistics. 19952002 linked birth/
infant death data set. NCHS CD-ROM series 20, No 16-23.
Hyattsville, MD: United States Department of Health and
Human Services, Centers for Disease Control and Prevention.
Taffel SM, Ventura SJ, Gay GA. Revised U.S. certificate of
birthnew opportunities for research on birth outcome. Birth
1989;16:18893.
Taffel S, Johnson D, Heuser R. A method of imputing length of
gestation on birth certificates. Vital Health Stat 2 1982;93:
111.
Kramer MS, McLean FH, Boyd ME, Usher RH. The validity
of gestational age estimation by menstrual dating in term,
preterm, and postterm gestations. JAMA 1988;260:33068.
Kramer MS, Platt RW, Yang H, Haglund B, Cnattingius S,
Bergsjo P. Registration artifacts in international comparisons of
infant mortality. Paediatr Perinat Epidemiol 2002;16:1622.
Rockhill B, Newman B, Weinberg C. Use and misuse of
population attributable fractions. Am J Public Health 1998;88:
159.
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;11:349.
Ananth CV, Savitz DA, Bowes WA Jr, Luther ER. Influence of
hypertensive disorders and cigarette smoking on placental
abruption and uterine bleeding during pregnancy. Br J Obstet
Gynaecol 1997;104:5728.
Xu P, Alfaidy N, Challis JR. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in human placenta and fetal
membranes in relation to preterm and term labor. J Clin
Endocrinol Metab 2002;87:135361.
Smulian JC, Bhandari V, Vintzileos AM, Shen-Schwarz S,
Quashie C, Lai-Lin YL, et al. Intrapartum fever at term: serum
and histologic markers of inflammation. Am J Obstet Gynecol
2003;188:26974.
Lieberman E, Odonoghue C. Unintended effects of epidural
analgesia during labor: a systematic review. Am J Obstet
Gynecol. 2002;186:S3168.
Steinborn A, Seidl C, Sayehli C, Sohn C, Seifried E, Kaufmann
M, et al. Anti-fetal immune response mechanisms may be
involved in the pathogenesis of placental abruption. Clin
Immunol 2004;110:4554.
Lockwood CJ. Inherited thrombophilias in pregnant patients:
detection and treatment paradigm. Obstet Gynecol 2002;99:
33341.
Gjessing HK, Skjaerven R, Wilcox AJ. Errors in gestational
age: evidence of bleeding early in pregnancy. Am J Public
Health 1999;89:2138.
Lydon-Rochelle MT, Holt VL, Cardenas V, Nelson JC, Easterling TR, Gardella C, et al. The reporting of pre-existing
maternal medical conditions and complications of pregnancy
on birth certificates and in hospital discharge data. Am J Obstet
Gynecol 2005;193:12534.
DiGiuseppe DL, Aron DC, Ranbom L, Harper DL, Rosenthal
GE. Reliability of birth certificate data: a multi-hospital comparison to medical records information. Matern Child Health
J 2002;6:16979.

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