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Obstetrics & Gynecology 2006;107:785-792
© 2006 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Placental Abruption in Term and Preterm Gestations

Evidence for Heterogeneity in Clinical Pathways

Cande V. Ananth, PhD, MPH1, Darios Getahun, MD, MPH1, Morgan R. Peltier, PhD2 and John C. Smulian, MD, MPH2

From the 1Division of Epidemiology and Biostatistics and 2Division of Maternal-Fetal 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.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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, 1995–2002 (n = 30,378,902). Rates of 1) acute-inflammation–associated 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-inflammation–associated 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-inflammation–associated conditions were present in 4.2% and 3.3% of births with and without abruption, respectively (RR 1.39, 95% CI 1.33–1.45). 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 1.85–1.90). 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-inflammation–associated 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.

LEVEL OF EVIDENCE: II-2

Placental 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, but is associated with up to one third of all perinatal deaths. 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.

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-inflammation–associated 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 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 long-standing 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)-{alpha}.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.


Figure 18
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  		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 maternal–fetal 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–{alpha} and interleukin–ß can function at the maternal–fetal 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–{alpha} and interleukin–1ß are known to induce pro-apoptotic pathways. This combination of necrosis, apoptosis, and destruction of the extracellular matrix at the maternal–fetal 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.

 

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, acute-inflammation–association conditions and chronic processes) are heterogeneous among pregnancies delivered at preterm and term gestations.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
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 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 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-inflammation–associated 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-inflammation–associated 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 ≥ 100°F or ≥ 38°C) 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 (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-inflammation–associated 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, 25–29 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, 13–15 years, and ≥ 16 years of completed schooling), and marital status (married or single).

We calculated population attributable fractions (PAF) for acute-inflammation–associated 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-inflammation–associated 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
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
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 parity, as well as among smokers in both preterm and term birth categories.


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  		Table 1. Maternal and Infant Characteristics of Women With and Without Placental Abruption: U.S. Singleton Births, 1995–2002

 

An acute-inflammation–associated condition or a chronic clinical process was present in 37.5% of preterm and 25.3% of term births (Table 2). Rates of acute-inflammation–associated conditions and chronic clinical processes were, in general, higher at preterm than at term births.


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  		Table 2. Distributions of Acute-Inflammation–Associated Conditions and Chronic Clinical Processes at Preterm and Term Gestations: U.S. Singleton Births, 1995–2002

 

In cases of placental abruption, more than one half of preterm births (51.3%) had either an acute-inflammation–associated condition or chronic clinical process, in comparison with 43.5% at term (Table 3). Within preterm births, acute-inflammation–associated conditions occurred 1.38-fold (95% confidence interval [CI] 1.34–1.42), and chronic clinical processes 1.87-fold (95% CI 1.85–1.90) more frequently in the presence, than absence, of abruption (Table 4). At term, both acute-inflammation–associated 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.


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  		Table 3. Rates of Acute Inflammation–Associated-Conditions and Chronic Clinical Processes Among Women With and Without Placental Abruption: U.S. Singleton Births, 1995–2002

 

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  		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, 1995–2002

 

Figure 2 shows gestational age–specific incidence rates of acute-inflammation–associated conditions, chronic clinical processes, and both acute and chronic clinical processes among women with and without abruption. The rate of acute-inflammation–associated 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-inflammation–associated 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-inflammation–associated conditions.


Figure 28
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  		Fig. 2. Rates (per 100 births) of acute-inflammation–associated conditions (A), chronic clinical processes (B), and acute-inflammation–associated conditions and chronic clinical processes combined (C) among women with and without placental abruption.

Ananth. Acute and Chronic Processes in Abruption. Obstet Gynecol 2006.

 


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
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-inflammation–associated 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). 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 between those that occur at term compared with those that occur preterm. However, the presence of different patterns in rates of acute-inflammation–associated conditions and chronic clinical processes throughout gestation in the presence—and absence—of placental abruption adds a new dimension toward understanding its cause.

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 maternal–fetal 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 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.


   Footnotes
 
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{at}umdnj.edu.

doi:10.1097/01.AOG.0000207560.41604.19


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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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;193:198–203.[Medline]

3. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. Placental abruption and adverse perinatal outcomes. JAMA 1999;282:1646–51.[Abstract/Free Full Text]

4. Rasmussen S, Irgens LM, Dalaker K. Outcome of pregnancies subsequent to placental abruption: a risk assessment. Acta Obstet Gynecol Scand 2000;79:496–501.[Medline]

5. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001;153:332–7.[Abstract/Free Full Text]

6. Kramer MS, Usher RH, Pollack R, Boyd M, Usher S. Etiologic determinants of abruptio placentae. Obstet Gynecol 1997;89:221–6.[Abstract]

7. Rasmussen S, Irgens LM, Dalaker K. A history of placental dysfunction and risk of placental abruption. Paediatr Perinat Epidemiol 1999;13:9–21.[Medline]

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29. 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;188:269–74.[Medline]

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