Abstract
While there is consistent evidence that episodes of physical exertion are associated with an immediately higher risk of acute ischemic vascular events, the risk of placental abruption immediately following episodes of physical exertion has not been studied. In a multicenter case-crossover study, we interviewed 663 women with placental abruption at 7 Peruvian hospitals between January 2013 and August 2015. We asked women about physical exertion in the hour before symptom onset and compared this with their frequency of physical exertion over the prior week. Compared with times with light or no exertion, the risk of placental abruption was 7.8 (95% confidence interval (CI): 5.5, 11.0) times greater in the hour following moderate or heavy physical exertion. The instantaneous incidence rate ratio of placental abruption within an hour of moderate or heavy physical exertion was lower for women who habitually engaged in moderate or heavy physical activity more than 3 times per week in the year before pregnancy (rate ratio (RR) = 3.0, 95% CI: 1.6, 5.9) compared with more sedentary women (RR = 17.3, 95% CI: 11.3, 26.7; P for homogeneity < 0.001), and the rate ratio was higher among women with preeclampsia/eclampsia (RR = 13.6, 95% CI: 7.0, 26.2) than among women without (RR = 6.7, 95% CI: 4.4, 10.0; P for homogeneity = 0.07).
Keywords: abruptio placentae, case-crossover, exercise, physical exertion, placental abruption
Editor’s note: An invited commentary on this article appears on page 2080, and the authors’ response appears on page 2083.
Placental abruption—the premature separation of the implanted placenta—is an obstetrical complication that affects roughly 1%–2% of all pregnancies (1). Potential sequelae of placental abruption include hemorrhagic shock, coagulopathy, disseminated intravascular coagulation, uterine rupture, and renal failure. In more and less developed countries alike, placental abruption, along with infection and hypertensive disorders, continues to appear among the top 3 causes of maternal mortality. In addition to its impact on women, placental abruption is also a significant cause of infant morbidity and mortality (2–4).
Despite its acute clinical presentation, placental abruption is characterized by both acute and chronic pathophysiologic features. The specific etiology of placental abruption is still unknown, but its underlying mechanisms include uteroplacental underperfusion (5, 6), ischemia (7, 8), and chronic hypoxemia (9). While there is a substantial body of evidence showing an acutely heightened risk of ischemic cardiovascular events immediately following physical exertion (10), the association between physical exertion and the acute risk of placental abruption—“an ischemic placental disorder” (7, 11–13)—has not yet been investigated. Similar to cardiovascular disorders, habitual physical activity among pregnant women is associated with several health benefits over the long-term, including a lower baseline risk of several maternal (14–17) and fetal (18) outcomes.
We used a case-crossover design to compare each woman’s risk of placental abruption in the hour following episodes of physical exertion with that same woman’s risk at other times. We examined whether moderate or heavy physical exertion was associated with an immediately higher risk of placental abruption and whether the risk was different for moderate versus heavy physical exertion. We also evaluated whether the association varied according to habitual physical activity or with comorbid hypertensive disorders of pregnancy (i.e., preeclampsia or eclampsia).
METHODS
Source population
The Placental Abruption Genetic Epidemiology and Triggers (PAGE) study was conducted in Lima, Peru, in South America, in the following hospitals: Instituto Nacional Materno Perinatal, Hospital Rebagliati, Hospital San Bartolome, Hospital Hipolito, Hospital Loayza, Hospital Dos de Mayo, and Hospital Maria Auxiliadrosa. During the study period, there were 218,420 deliveries in the participating hospitals. Between January 2013 and August 2015, 883 women were identified as eligible for interview during the in-patient labor and delivery period, 663 (75%) of whom elected to participate. Research staff identified eligible women by reviewing admission logbooks for the emergency room, labor and delivery, and surgery. Study participants were recruited during their hospital stay. Placental abruption cases were identified using daily monitoring of all new admissions to antepartum wards, emergency room wards (intensive care unit), and labor and delivery wards of the study hospitals. Study personnel made periodic visits to specific wards in a fixed order for the purposes of identifying potential placental abruption cases for the present study. Hospital medical records were reviewed to ensure that cases met the definition of placental abruption based on preestablished diagnostic criteria (19), by fulfilling one or more of the following 4 eligibility criteria noted in the women’s medical records: 1) antepartum hemorrhage after 20 weeks of gestation; 2) uterine pain or tenderness (localized or diffuse); 3) fetal distress or death; and 4) retroplacental blood clot. The data-collection protocol also included ascertainment of differential diagnoses for placental abruption, including all causes of abdominal pain and bleeding, such as placenta previa, appendicitis, urinary tract infection, preterm labor, fibroid degeneration, ovarian pathology, and muscular pain. We excluded women who had a multifetal pregnancy, who were not residents of Lima (i.e., women transferred from remote areas of Peru), or whose medical records were insufficient to determine the presence or absence of placental abruption. If a woman met the criteria, she was invited to participate in a 30-minute in-person interview, and she signed a consent form if she agreed. Interviews occurred a median of 2 days (interquartile range, 1–3 days) after placental abruption. The study procedures used in this study were in agreement with the protocols approved by the institutional review board at each participating institution.
Case-crossover design
Instead of selecting a separate control group, we employed a case-crossover design whereby the cases serve as their own controls. The method was developed to estimate the transient effect of an intermittent exposure on events with an identifiable, abrupt onset (20). Because the approach involves a comparison of the same person at different times, there is no confounding by fixed or slowly varying characteristics such as age, prepregnancy body mass index, socioeconomic level, or history of previous placental abruption. This design involves collecting information on exposure (e.g., participation in moderate or heavy physical exertion) immediately preceding the event (e.g., placental abruption) and comparing this with the expected frequency of exposure based on women’s exposure patterns during similar control time periods. A priori, based on the presumed pathophysiologic process, we defined the case window as the hour before onset of placental abruption and the control window as the rest of the week before onset of placental abruption.
Interview
Interviews were completed in Spanish by trained, female interviewers using a standardized, structured questionnaire that covered a variety of potential triggers as well as sociodemographic, medical, reproductive, and lifestyle information. We also conducted a physical exam to obtain anthropometric measurements. To help standardize reporting of the intensity of physical exertion, women were shown a 15-point visual analogue Borg Scale (21) (scores ranging from 6 to 20). Then we provided examples of physical exertion at each level of intensity to help women classify episodes as light (e.g., mopping), moderate (e.g., dancing), or heavy (e.g., sprinting). We started by asking each woman her usual frequency of exertion during 3 periods: the year before pregnancy, the first 3–6 months of pregnancy, and months 6–9 of pregnancy. Then we asked about her frequency of light exertion during the week before placental abruption onset, and asked when she last engaged in light exertion before placental abruption onset (e.g., abdominal/back pain with or without vaginal bleeding). Her responses to the latter question were classified as: never, at the time of event onset, 1/2 hour before, 1 hour before, 2 hours before, 3–6 hours before, 6–24 hours before, 1–2 days before, 3–4 days before, or ≥5 days before. Then we asked about her frequency of moderate exertion in the week before, and asked when she last engaged in moderate exertion before placental abruption onset. Last, we asked about her frequency and last time of heavy exertion.
Statistical analysis
In a case-crossover analysis, data are stratified by individual persons (20, 22). In the analysis of this self-matched design, each woman forms her own stratum. She is considered an exposed case if she was exposed to moderate or heavy physical exertion in the hour before symptom onset and unexposed otherwise. For each woman, the number of exposed person-hours in the week prior to placental abruption was calculated by multiplying the number of self-reported episodes of moderate or heavy physical exertion by the hypothesized duration of its physiologic effect (1 hour). Her unexposed person-time was calculated by subtracting the number of exposed person-hours from the 168 hours in a week. Using methods for sparse data analysis, we calculated the Mantel-Haenszel incidence rate ratio for person-time and 95% confidence intervals (23).
We conducted analyses to assess whether the association between physical exertion and placental abruption differed according to the intensity of physical exertion (heavy vs. moderate). In addition, we conducted subgroup analyses to assess whether the association varied according to self-reported history of habitual physical activity (≤3 vs. >3 times per week in the year before pregnancy) and preeclampsia/eclampsia (yes vs. no) by means of a Wald χ2 test of homogeneity (23). To evaluate whether other potential triggers could account for the observed association, we conducted a sensitivity analysis excluding women who engaged in other potentially triggering activities in the hour before placental abruption (sexual intercourse; cigarette smoking; consumption of alcohol, coffee, tea, or cola; or use of cocaine, marijuana, or terokal (an adhesive that is inhaled recreationally)). To explore the extent to which results might vary due to circadian rhythm, we conducted an ad hoc analysis in which we compared the proportion of exertion- and non-exertion-associated placental abruptions that occurred between 6 pm and 12 am. All reported P values are 2-sided.
RESULTS
The characteristics of women who experienced placental abruption are described in Table 1. Among 663 women who had placental abruption, 7 provided no information on usual physical exertion so they were excluded from the analyses. Of the 656 included, 352 (54%) reported that they engaged in moderate or heavy physical exertion in the week before placental abruption. Among the 352 who engaged in moderate or heavy physical exertion, 263 (75%) reported engaging in such exertion once that week, and 42 (12%) reported more than 3 times that week. The mean frequency of habitual physical activity decreased after conception and over the course of pregnancy, from 3.8 times/week in the year before pregnancy, to 2.7 times/week in the first 3–6 months of pregnancy, to 1.6 times/week in months 6–9 of pregnancy, to 0.9 times/week in the week prior to placental abruption (Figure 1).
Table 1.
Characteristics of Women With Placental Abruption (n = 656) in Peru, 2013–2015
| Characteristic | Moderate or Heavy Physical Exertion in Prior Week | |||
|---|---|---|---|---|
| Yes (n = 352) | No (n = 304) | |||
| No.a | % | No.a | % | |
| Maternal age, years | ||||
| <20 | 19 | 5.4 | 22 | 7.4 |
| 20–24 | 89 | 25.5 | 82 | 27.4 |
| 25–29 | 92 | 26.4 | 66 | 22.1 |
| 30–34 | 64 | 18.3 | 68 | 22.7 |
| 35–39 | 66 | 18.9 | 42 | 14.0 |
| ≥40 | 19 | 5.4 | 19 | 6.4 |
| Prepregnancy BMIb | ||||
| Underweight (<18.5) | 9 | 3.2 | 5 | 2.2 |
| Normal (18.5–24.9) | 142 | 51.1 | 123 | 54.4 |
| Overweight (25.0–29.9) | 101 | 36.3 | 82 | 36.3 |
| Obese (≥30.0) | 26 | 9.4 | 16 | 7.1 |
| Education | ||||
| Less than high school | 36 | 10.4 | 18 | 6.0 |
| High school | 205 | 59.2 | 174 | 58.0 |
| More than high school | 105 | 30.3 | 108 | 36.0 |
| Gravidac | ||||
| ≤1 | 109 | 31.5 | 100 | 33.3 |
| 2 | 102 | 29.5 | 86 | 28.7 |
| ≥3 | 135 | 39.0 | 114 | 38.0 |
| Parityc | ||||
| 0 | 19 | 5.5 | 16 | 5.3 |
| 1 | 135 | 39.1 | 127 | 42.3 |
| ≥2 | 191 | 55.4 | 157 | 52.3 |
| Substance use during pregnancy | ||||
| Cigarette | 14 | 4.0 | 8 | 2.6 |
| Alcohol | 88 | 25.0 | 41 | 13.5 |
| Cocaine | 3 | 0.9 | 5 | 1.7 |
| Marijuana | 3 | 0.9 | 2 | 0.7 |
| Terokal | 4 | 1.1 | 1 | 0.3 |
| Employed during pregnancy | 192 | 55.0 | 165 | 54.6 |
| Preeclampsia/eclampsia | 72 | 20.5 | 73 | 24.6 |
| Chorioamnionitis | 14 | 4.0 | 14 | 4.7 |
| Premature rupture of membranes | 54 | 15.4 | 44 | 14.8 |
| Prior placental abruption | 14 | 4.0 | 12 | 4.0 |
| Chronic hypertension | 8 | 2.3 | 0 | 0.0 |
| Anemiad | 146 | 44.9 | 111 | 41.6 |
| Prenatal care | 329 | 94.3 | 286 | 94.1 |
| Prenatal vitamin use | 293 | 84.4 | 262 | 86.8 |
| Gestational age, weekse,f | 35.1 (4.1) | 34.1 (4.4) | ||
Abbreviation: BMI, body mass index.
a Frequencies in subgroups may not sum to column total due to missing data.
b Weight (kg)/height (m)2.
c Including current pregnancy.
d Hemoglobin value of <11 g/dL in second or third trimester.
e Estimated from last menstrual period.
f Values are expressed as mean (standard deviation).
Figure 1.
Mean frequency (standard deviation (SD)) of self-reported habitual physical activity per week according period relative to pregnancy among women with placental abruption in Peru (n = 656), 2013–2015. The mean frequency of habitual physical activity decreased from before conception and over the course of pregnancy: 3.8 (SD, 4.9) times/week in the year before pregnancy, 2.7 (SD, 4.5) times/week in the first 3–6 months of pregnancy, 1.6 (SD, 3.3) times/week in months 6–9 of pregnancy, and 0.9 (SD, 2.9) times/week in the week prior to placental abruption.
Among 352 women who engaged in moderate or heavy physical exertion in the week before placental abruption, 34 women reported having engaged in moderate or heavy physical exertion in the hour before the onset of placental abruption. The immediate risk of placental abruption was 7.8-fold higher (95% confidence interval (CI): 5.5, 11.0) within an hour of moderate or heavy physical exertion compared with periods of lower exertion or rest. The rate ratio of placental abruption within an hour of physical exertion was higher following heavy-intensity physical exertion (rate ratio (RR) = 13.7, 95% CI: 7.0, 26.5) than after moderate physical exertion (RR = 6.0, 95% CI: 4.0, 9.0; P for homogeneity = 0.04; Figure 2).
Figure 2.
Rate ratio (RR) of placental abruption within an hour of heavy-intensity physical exertion and moderate-intensity physical exertion, among women with placental abruption in Peru (n = 656), 2013–2015. The RR of placental abruption within an hour of physical exertion was higher following heavy physical exertion (RR = 13.7, 95% CI: 7.0, 26.5; n = 10 women exposed in the hour before placental abruption) than after moderate physical exertion (RR = 6.0, 95% CI: 4.0, 6.0; n = 24 women exposed in the hour before placental abruption; P for homogeneity = 0.04). The y-axis is in log scale. The error bars indicate 95% confidence intervals.
The rate ratio of placental abruption was lower for women who habitually engaged in physical activity more than 3 times per week in the year before pregnancy (RR = 3.0, 95% CI: 1.6, 5.9) compared with women who engaged in such activity 3 or fewer times per week (RR = 17.3, 95% CI: 11.3, 26.7; P for homogeneity < 0.001; Figure 3A). Additionally, the rate ratio of placental abruption appeared to be higher among women with preeclampsia/eclampsia (RR = 13.6, 95% CI: 7.0, 26.2) than among normotensive women (RR = 6.7, 95% CI: 4.4, 10.0; P for homogeneity = 0.07) (Figure 3B).
Figure 3.
Rate ratio (RR) of placental abruption within an hour of moderate or heavy physical exertion, stratified by habitual physical activity in the year before pregnancy or preeclampsia/eclampsia, among women with placental abruption in Peru (n = 656), 2013–2015. A) Among women who habitually engaged in physical activity more than 3 times per week before pregnancy, the RR of placental abruption was lower (RR = 3.0, 95% confidence interval (CI): 1.6, 5.9; n = 25 women exposed in the hour before placental abruption) compared with women who engaged in physical activity 3 or fewer times per week (RR = 17.3, 95% CI: 11.3, 26.7; n = 9 women exposed in the hour before placental abruption; P for homogeneity < 0.001. B) Among women with preeclampsia/eclampsia, the RR of placental abruption appeared to be higher (RR = 13.6, 95% CI: 7.0, 26.2; n = 10 women exposed in the hour before placental abruption) than among normotensive women (RR = 6.7, 95% CI: 4.4, 10.0; n = 24 women exposed in the hour before placental abruption; P for homogeneity = 0.07). The y-axis is in log scale. The error bars indicate 95% confidence intervals.
In a sensitivity analysis excluding women who were exposed to other potential triggers (sexual intercourse, cigarette smoking, illicit drugs, or caffeinated or alcoholic beverages), the rate ratio of placental abruption associated with moderate or heavy physical exertion was marginally attenuated but remained strong (RR = 7.0, 95% CI: 4.9, 10.2). Between 6 pm and 12 am, there were 10 (31%) exertion-related placental abruptions and 160 (27%) non-exertion-related abruptions.
DISCUSSION
In this study, episodes of moderate or heavy physical exertion were associated with an immediately heightened risk of placental abruption that was 7.8-fold higher in the subsequent hour compared with periods of lower exertion or rest. The risk of placental abruption within an hour of physical exertion was higher for exertion at heavy intensity than it was for moderate levels of exertion. The risk of placental abruption within an hour of moderate or heavy physical exertion was lower among women who habitually engaged in physical activity more than 3 times a week prior to pregnancy than for those who were more sedentary, and it appeared to be higher for women with preeclampsia or eclampsia than it was for normotensive women, although the association among women with preeclampsia or eclampsia was statistically imprecise.
To our knowledge, no prior study has assessed the association between episodes of physical exertion and the acute risk of placental abruption. While considerable progress has been made in understanding traditional chronic risk factors of placental abruption, acute triggers have been the subject of much less inquiry. More than two decades ago, placental abruption was linked to acute sympathetic activation in a case report (24), and it was linked to labor-intensive employment in a case-control study (25). Change in the risk of acute placental abruption was recently described in a different context; Michikawa et al. (26) used a case-crossover approach to demonstrate an increased risk of placental abruption within 3 days of heightened nitrogen dioxide air pollution in Japan, an isolated finding that parallels the association between pollutants and acute myocardial infarction (27) and ischemic stroke (28). Moreover, effect modification from habitual physical activity in this study of placental abruption and in other studies of acute ischemic cardiovascular events (29–31) was similar, providing support for the possibility that the short-term effect of physical exertion might contribute to the pathophysiology of both types of disorders through similar mechanisms.
Our finding that habitual physical activity decreases after conception and over the course of pregnancy is also consistent with prior work on activity trends during pregnancy in the United States (32). Given that physical activity during pregnancy is also associated with a lower risk of gestational diabetes (15, 17), preeclampsia (16), and cesarean delivery (14) and that sedentary behavior is associated with a higher risk of venous thromboembolism (33), it is nonetheless important for women who are pregnant to remain active at levels that are safe for them. Further, because habitual physical activity before pregnancy may mitigate the acute risk of placental abruption associated with each episode of moderate or heavy physical activity, the period before conception may represent the ideal time for enrollment into a graduated exercise program for those at highest risk of placental abruption.
In the case of physical exertion and acute myocardial infarction, the transient effect of strenuous exertion is more than offset by the cumulative protective effect of regular moderate exertion. It is possible that the same is true for physical exertion and placental abruption. However, without comparison with a traditional control group, we cannot assess whether there is an overall protective effect of regular physical exertion on occurrence of placental abruption. However, based on the lower rate ratio for women who were more physically active, we believe it is plausible that regular moderate exertion provides a protective effect that more than offsets the very transient hazardous association between moderate and heavy exertion and placental abruption risk.
Most cases of placental abruption are caused by both acute and chronic pathophysiological processes (1). Studies of its acute etiology report factors such as shear stress, often a result of trauma and/or sudden uterine decompression from hydramnios or delivery of a first twin (1). Other acute factors include vasoconstriction secondary to cocaine use and endothelial dysfunction secondary to intense inflammatory responses at the placental-decidual interface (34). Suggested pathophysiologic triggers that may be involved in the acute effect of episodes of physical exertion include hypoxia-induced changes in the maternal-fetal circulation, uteroplacental vascular insufficiency and ischemia, infarctions, and heightened sympathetic activity, which provide support for the concept that placental abruption is in part an ischemic placental disorder (7, 11, 13).
There are some limitations to our study. By using each patient as her own control, the case-crossover design eliminates between-person confounding by all fixed and slow-varying characteristics. However, within-person confounding by factors that change over time can occur. Therefore, we conducted a sensitivity analysis excluding individuals exposed to other potential triggering exposures in the hour before placental abruption; the results were not materially different. In an effort to minimize recall bias, women were not informed of the duration of the hypothesized hazard period and were presented with many options for the time period in which they were last exposed, including the entire control period in the week preceding the placental abruption. In this study, we had limited statistical power to test whether risk associated with physical exertion varied according to vaginal bleeding during pregnancy, hypertensive disorders of pregnancy, and prior placental abruption, due to the small number of exposed cases in these categories. A larger study that also collects information on the type of physical exertion performed before placental abruption would help inform physical activity recommendations among women at highest risk. Also, we did not collect information on the timing of typical physical exertion in the reference period, but future research to examine the association according to time of day might provide insight into whether there are times when women are particularly susceptible.
In conclusion, within an hour of moderate or heavy physical exertion, there is an elevated risk of placental abruption compared with periods of lower exertion or rest. The rate ratio of placental abruption within an hour of physical exertion was higher following heavy exertion than moderate exertion. The association between moderate or heavy physical exertion and placental abruption is lower among women who engaged in higher levels of habitual physical activity before pregnancy, and it was higher among women who had preeclampsia or eclampsia. Further research is necessary to design activity recommendations for women at high risk of placental abruption that can maximize the benefits of habitual physical activity while minimizing the risk of placental abruption associated with each episode of exertion.
ACKNOWLEDGMENTS
Author affiliations: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Harpreet S. Chahal, Bizu Gelaye, Elizabeth Mostofsky, Murray A. Mittleman, Michelle A. Williams); Mississauga Academy of Medicine, University of Toronto Mississauga, Mississauga, Canada (Harpreet S. Chahal); Cardiovascular Epidemiology Research Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Elizabeth Mostofsky, Murray A. Mittleman); Universidad Peruana de Ciencias Aplicadas, Lima, Peru (Sixto E. Sanchez); Asociación Civil Proyectos en Salud , Lima, Peru (Sixto E. Sanchez); Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada (Malcolm Maclure); Department of Obstetrics and Gynecology, San Marcos University, Hospital Madre-Nino San Bartolome, Lima, Peru (Percy Pacora, Jose A. Torres); Department of Obstetrics and Gynecology, San Marcos University, Hospital Nacional Hipólito Unanue, Lima, Peru (Jose A. Torres); Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Roberto Romero); Department of Obstetrics and Gynecology, University of Michigan Health System, University of Michigan, Ann Arbor, Michigan (Roberto Romero); Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan (Roberto Romero); Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (Roberto Romero); Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, New York (Cande V. Ananth); and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York (Cande V. Ananth).
H.S.C. and B.G. contributed equally to this work.
This work was funded by the National Institutes of Health (grants R01 HD059827 and T37 MD001449). This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services, and, in part, with Federal funds from the National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services, under contract HHSN275201300006C. R.R. has contributed to this work as part of his official duties as an employee of the US Federal Government.
We thank the participating hospitals. We also thank Elena Sanchez and the dedicated staff members of Asociacion Civil Proyectos en Salud (PROESA), Peru, for their expert technical assistance with this research.
Conflict of interest: none declared.
Abbreviations
- CI
confidence interval
- RR
rate ratio
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