1 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
2 Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
3 Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
4 Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Received for publication June 26, 2003; accepted for publication February 6, 2004.
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ABSTRACT |
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hemorrhage; labor, premature; pregnancy
Abbreviations: Abbreviations: CI, confidence interval; PIN, Pregnancy, Infection, and Nutrition; PPROM, preterm premature rupture of the membranes; RR, risk ratio.
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INTRODUCTION |
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About half of the bleeding episodes during pregnancy have unknown causes (1012) and, thus, the reason that vaginal bleeding predicts preterm birth is unclear. Vaginal bleeding and consequent thrombin generation lead to a proteolytic cascade capable of damaging the fetal membranes, which could result in preterm premature rupture of the membranes (PPROM) (13, 14). Thrombin also stimulates uterine contractions, which may promote preterm labor (13, 15). In addition to the direct effects of the blood itself, bleeding could be a manifestation of subclinical or occult infection or inflammation in the uterus, which in turn is hypothesized to cause spontaneous preterm birth presenting as PPROM and preterm labor (13). Few studies of vaginal bleeding have attempted to separate spontaneous preterm birth due to PPROM and preterm labor (16).
We used data from the Pregnancy, Infection, and Nutrition (PIN) Study, a prospective study of pregnant women, to examine the occurrence of vaginal bleeding in relation to preterm birth. We evaluated detailed bleeding characteristics, including trimester of occurrence, heaviness, number of episodes, duration, and estimated total blood loss, in relation to preterm birth and considered preterm subgroups defined by gestational age (34 weeks, 3536 weeks) and clinical presentation (PPROM, preterm labor, and medically indicated).
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MATERIALS AND METHODS |
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This study included 2,829 women whose pregnancy started between January 1995 and August 2000, with 27 excluded because of missing data on details of vaginal bleeding, leaving a final sample size of 2,802 women. Gestational age was estimated from the last menstrual period if it agreed with an ultrasound estimation within 14 days; otherwise, the ultrasound estimation was used. The overall participation rate of the study cohort was 62 percent, with pregnant women who were White, who were married, and who had less than a college education slightly more likely to enroll. The cumulative incidence of preterm birth was 12.4 percent among participants, which was similar to that of nonparticipants (11.8 percent) (17).
In the telephone interview, vaginal bleeding was defined as "any bleeding or spotting with blood." If bleeding was reported, the calendar month and year of occurrence, duration, and heaviness were then queried for each bleeding episode up to the first three. The number of episodes beyond the third was noted, but no further information on bleeding characteristics was collected. We categorized the bleeding episodes as "single" or "multiple" in the analysis.
The PIN Study collected the calendar month and year of bleeding occurrence but did not attempt to identify the calendar day, given expected limitations in recall. We imputed the midday of the bleeding month as the day of bleeding and determined the gestational month of bleeding using the imputed bleeding date and the estimated conception date. We classified bleeding as "first trimester only," "second trimester only," or "both trimesters," defining the first trimester as gestational months 03 and the second trimester as gestational months 47.
"Light spotting" was assigned when women reported detection of bleeding by wiping but did not require use of sanitary protection, and "heavy bleeding" was bleeding that soaked underwear or required a pad. If there were multiple episodes, we assigned the womans heaviest bleeding experience.
Bleeding duration was measured in days for each episode and summed across episodes to determine the total number of bleeding days during pregnancy. Bleeding days were subcategorized as "1 day" and "multiple days" in the analysis.
We constructed a total blood loss index by combining information on bleeding heaviness and bleeding duration to create an ordinal scale of estimated total blood loss during pregnancy. Light spotting and heavy bleeding were assigned values of "1" and "2," respectively, multiplied by the number of bleeding days of each episode, and summed across episodes. The median score of the total blood loss index was 2. We divided women into a "less total blood loss" group if the index value was 2 or less and a "more total blood loss" group if it was greater than 2.
Preterm birth (livebirth before 37 completed weeks gestation) was subdivided into less than or equal to 34 weeks and 3536 weeks in the analysis. It was also divided into subtypes of PPROM if membrane rupture occurred 4 hours or more before the onset of labor, preterm labor if labor started spontaneously or within 4 hours of membrane rupture, and medically indicated if delivery was induced in the absence of PPROM or preterm labor. Two study obstetricians reviewed medical charts to assign preterm birth subtypes.
We applied multiple log-linear models to estimate the adjusted risk ratio and the adjusted risk difference using the SAS procedure GENMOD (18). Separate log-linear models were fit for each subgroup of preterm birth as defined above. The trimester of bleeding occurrence, bleeding heaviness, number of episodes, duration, and total blood loss index were evaluated individually. We stratified the analysis by maternal race to examine the pattern of bleeding and preterm birth among African-American women and White women. The potential confounding variables included maternal age, education, parity, marital status, household income, cigarette smoking, alcohol drinking, illegal drug use, exercise during pregnancy, genital tract infection during pregnancy, and prior adverse pregnancy outcomes. Covariates that changed any crude risk ratios between vaginal bleeding and a subset of preterm birth by 5 percent or more were retained in the model. The identified confounders were maternal age, illegal drug use during pregnancy, regular exercise since 3 months before pregnancy, self-reported genital tract infection during pregnancy (vaginal warts, genital herpes, chlamydia, trichomoniasis, gonorrhea, syphilis, or bacterial vaginosis), and prior adverse pregnancy outcome (spontaneous abortion, induced abortion, or preterm birth). Information on all confounders was obtained in the telephone interview.
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RESULTS |
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Vaginal bleeding during pregnancy was associated with a modest increased risk of preterm birth (risk ratio (RR) = 1.3, 95 percent confidence interval (CI): 1.1, 1.6) (table 3), with greater effects for bleeding in both trimesters (RR = 2.4, 95 percent CI: 1.6, 3.6) and bleeding with multiple episodes (RR = 1.7, 95 percent CI: 1.2, 2.3) but to a lesser extent with heaviness, duration of bleeding, and total blood loss. Bleeding in a single trimester, in a single episode, on a single day, and with less total blood loss was virtually unrelated to risk of preterm birth. About 30 percent of all preterm births, 3.8 percent (95 percent CI: 0.8, 6.8) of the overall incidence of 12.4 percent, was attributable to vaginal bleeding.
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DISCUSSION |
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We found that bleeding in both trimesters was more strongly associated with preterm birth, which was similar to results from previous studies (3, 5, 19). However, we did not find an association between bleeding initiated in the second trimester and preterm birth as previous studies did (3, 19, 20). Bleeding heaviness was slightly associated with preterm birth in the aggregate, consistent with some previous findings (3) but not all (4, 9). Recurrent bleeding predicted preterm birth more strongly than did single episodes, consistent with previous studies (5, 20). Bleeding of multiple days duration or more total blood loss, which had not been examined in the literature, was associated with a greater risk of preterm birth. Bleeding characteristics are associated with each other in our study, in some cases by definition or more generally because more intense bleeding on one dimension is associated with more intense bleeding on other dimensions. For example, bleeding for a single day had to be a single episode and had to result in less total blood loss by our definition; bleeding in both trimesters must be bleeding of multiple episodes and bleeding on multiple days; and bleeding with the initial episode in the second trimester was more likely to be characterized by light spotting, single episode, single day, and less total blood loss than bleeding with the initial episode in the first trimester. The correlation among bleeding characteristics would account to some extent for their similar associations with preterm birth. However, because of limited sample size, we were unable to analyze the combined bleeding characteristics in relation to preterm birth or to adjust the characteristics for one another.
Overall, analysis by bleeding characteristics confirmed previous findings that more intense bleeding predicted preterm birth. Conversely, we found that light spotting, bleeding on one day, a single episode, or lesser total blood loss was not associated with any type of preterm birth. If the absence of association for such minor episodes were confirmed, many women with similar bleeding experiences during pregnancy could be reassured that the health of their pregnancy is not likely to be threatened.
Generally, vaginal bleeding was associated with earlier (34 weeks) preterm birth, but not later (3536 weeks gestation) preterm birth, consistent with a previous study based on national survey data (6). Previous studies (2, 6) suggested that very early vaginal bleeding could be mistakenly reported as the last menstrual period, leading to a spuriously lower gestational age and an inflation of the association between vaginal bleeding and earlier preterm birth. However, the study by Harville et al (21), which collected bleeding data based on daily dairies, indicated that early bleeding was light and unlikely to be misinterpreted as a menstrual period. Since we were able to correct last menstrual period dates using early ultrasound information in our study, the finding that vaginal bleeding was related to earlier but not later preterm birth is not likely to be a product of misclassified gestational age.
Bleeding of multiple episodes and on multiple days was associated with both types of spontaneous preterm birth (PPROM or preterm labor), consistent with the study by French et al. (7). We also found some indication that bleeding in the first trimester predicted only PPROM and that bleeding in both trimesters was associated only with preterm labor, suggesting that there may be different pathways to these two forms of spontaneous preterm birth. Both a previous study (6) and the present study found a stronger effect of bleeding among Whites than among African Americans. The observed racial difference cannot be attributed to differences in bleeding intensity that was similar for Whites and African Americans. The overall incidences were 25.5 percent and 23.1 percent for Whites and African Americans, respectively. More intense bleeding, defined as bleeding in both trimesters, heavy bleeding, multiple episodes, multiple days, or more total blood loss, was reported by 68.3 percent and 65.4 percent of White women and African-American women, respectively. Since vaginal bleeding has different underlying causes (22, 23) with different consequences for preterm birth (13), racial differences in bleeding etiology may help to explain the weaker association for African-American women, but the reasons for this disparity warrant further study.
Our study had limitations regarding the information collected on vaginal bleeding. The PIN Study did not attempt to identify the cause of the bleeding episodes, to explicitly define "episode" in the telephone interview, to collect bleeding characteristics for the fourth episode or higher, or to query heaviness change across days within a bleeding episode. Therefore, some bleeding characteristics might have been misclassified in the analysis relative to a more refined measure. Bleeding information in the third trimester was not available because the interview was conducted at the end of the second trimester or early third trimester.
Some forms of placental dysfunction cause vaginal bleeding in late pregnancy (24) and are well established as causes of preterm birth (25). Including pregnancies complicated by placental abnormalities could account in part for the reported association between vaginal bleeding in the aggregate and preterm birth. Medical charts were reviewed for a randomly selected subcohort of participants (n = 958), among whom we identified 18 placenta previas, eight placental abruptions, and seven combined placenta previa and abruption. The risk ratio for vaginal bleeding and preterm birth was 1.2 (95 percent CI: 1.0, 1.5) for the subcohort with medical charts reviewed and was 1.1 (95 percent CI: 0.8, 1.4) with the 33 affected pregnancies excluded, indicating that some of the association reported is due to bleeding associated with known placental abnormalities.
Recall errors of bleeding characteristics, particularly underreporting of early light bleeding, could have occurred given that bleeding information was collected late in pregnancy. Nondifferential misclassification introduced by recall inaccuracy, assuming it is unrelated to outcome, would underestimate the association with preterm birth, with possibly more serious underestimation among less educated women who often are found to recall events less completely (26, 27). A stratified analysis by maternal education suggested that the effect of vaginal bleeding on preterm birth was greater among women with a college education (RR = 1.6, 95 percent CI: 1.2, 2.3) than among women without a college education (RR = 1.1, 95 percent CI: 0.8, 1.5), consistent with this hypothesis. In addition, women who were known to be at higher risk of preterm birth, for example, those who had a history of preterm birth, might have had more complete reporting of vaginal bleeding because of increased anxiety during the current pregnancy and might have inflated the association between bleeding and preterm birth. As part of the psychosocial assessment, women were asked whether they were "worried about bleeding or spotting or pain with this pregnancy." Women who reported that they were worried showed a slightly weaker association between bleeding and preterm birth (RR = 1.2, 95 percent CI: 0.9, 1.8) than did women who indicated that they were not worried (RR = 1.6, 95 percent CI: 1.0, 2.7), counter to the hypothesized direction of the reporting bias.
Further insights regarding the association between vaginal bleeding and preterm birth are likely to come only from more detailed understanding of the underlying causes of the bleeding or more refined and complete assessment of bleeding characteristics. Beyond statistical prediction of preterm birth, the biologic and clinical meaning of this common pregnancy complication remains to be fully elucidated.
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ACKNOWLEDGMENTS |
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Appreciation goes to Jude Williams, project manager, and Barbara Eucker and Anne Carter, clinic site coordinators.
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NOTES |
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REFERENCES |
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