Background: Placenta previa (PP) can cause repeated and
catastrophic bleeding that may lead to increased maternal and neonatal mortality
and morbidity. The purposes of this study were to determine the relationship
between antepartum hemorrhage (APH) and gestational week, the frequency of APH,
the risk factors for APH, and whether patients with APH developed more severe
adverse perinatal outcomes. Methods: This was a multi-center,
retrospective study in which we enrolled all placenta previa patients between
October 2015 and September 2018 within the Partners Healthcare System.
Results: The mean APH frequency was 2.2
Placenta previa is a serious obstetric complication that may lead to increased maternal and neonatal mortality and morbidity [1], with an incidence that varies between 0.15% and 0.91% [2, 3, 4, 5, 6]. Clinically, placenta previa presents as recurrent painless vaginal bleeding in the antenatal period and massive hemorrhage during cesarean delivery (CD) and postoperatively. However, not all patients with placenta previa encounter antepartum hemorrhage (APH), and some may not experience any bleeding during the entire prenatal period. It is thus currently unclear as to which risk factors contribute to APH or at which gestational week bleeding occurs. To our knowledge, there are no extant studies in the literature that describe the relationship between APH and gestational week.
Given the importance of this condition as well as the paucity of the existing literature on this topic, the aims of the current study were to identify the following in placenta previa patients: (1) the relationship between APH and gestational week, (2) the frequency of APH, (3) the risk factors for APH, and (4) whether patients with APH developed more severe adverse perinatal outcomes. This knowledge will assist in improving the antenatal management of placenta previa and optimize prophylactic measures to ameliorate outcomes.
The present investigation was a multi-center, retrospective study approved by the Institutional Review Board at Partners Healthcare System (PHS) (Protocol#2019P000028). We collected all patient delivery data between October 2015 and September 2018 within the PHS, which includes 7 different hospitals, 2 of which are large, tertiary, academic medical centers.
The total number of deliveries during this period was 39945, including 12884 cesarean deliveries (32.3%) and 27061 vaginal deliveries (67.7%). We sought patients in the PHS using the indication of placenta previa for “cesarean section” or “cesarean delivery”, and found 268 cases diagnosed with placenta previa by ultrasonography; 9 cases were excluded as inconsistent at intraoperative diagnosis. To avoid data bias in maternal and newborn outcomes, we excluded patients with multiple pregnancies (n = 8), stillbirths (n = 1), or delivery at less than 24 weeks of gestational age (n = 3). A total of 247 patients were ultimately included in our study.
Demographic data were collected from electronic medical records (EMR) and
included maternal age, gravidity, parity, body mass index (BMI), smoking history,
in vitro fertilization (IVF) history, prior number of CDs, history of
CDs, and duration of the CD interval. The interval duration depicted the interval
between the most recent CD and the current delivery. Gestational week was either
calculated using the date of the last menstrual period or estimated from the
first-trimester ultrasonographic measurements. Antepartum hemorrhage was defined
as bleeding from or into the genital tract that occurred from 24
All vaginal bleeding was recorded in our data, including the number of bleeding episodes and specific gestational week when bleeding occurred. Persistent bleeding was recorded once at the beginning of bleeding; however, if the patient experienced an interval without bleeding for more than 1 week, then the next bleeding was considered a second bleeding incident. Repeated bleeding was recorded several times according to the number of bleeding episodes. All hemorrhages were recorded, including those that occurred during inpatient and outpatient visits; however, bleeding caused by labor was not included. We observed no bleeding caused by neoplasm, infection, trauma, or iatrogenesis in any of our cases. There was also no bleeding due to vasa previa or placental abruption. The amount of bleeding was not included in our data because the amount was not quantified; here, some cases describe the amount of bleeding as spotting, or baseball- or golf-ball sized. As such, to avoid any data bias, we did not analyze the specific amount of vaginal bleeding.
All included cases met the recommendations and guidelines for data collection and analysis for APH in placenta previa [9].
We conducted our statistical analysis using the Statistical Package for Social
Sciences (SPSS) software, version 23.0 (International Business Machines
Corporation, Armonk, NY, USA). Continuous variables were presented as means
The prevalence of placenta previa in our study was 0.65% (259/39945). We identified 247 patients who underwent CD for placenta previa: 17 of these underwent a hysterectomy (6.9%, 17/247), 7 were treated with a uterine balloon (2.8%, 7/247), 3 underwent bilateral uterine artery embolization (1.2%, 3/247), and 7 patients received ureteral stents (2.8%, 7/247).
The incidence of APH in placenta previa was 49.0% (121/247). The mean number of
bleeding episodes was 2.2
The mean proportion of patients with APH at each gestational age.
Although we did not observe any statistical differences in the demographic
characteristics between patients with or without APH (Table 1) (p
Without APH | With APH | p value | ||
(n = 126) | (n = 121) | |||
Age (years), mean |
34.7 |
34.9 |
0.893 | |
Gravidity, median (range) | 2 (2–4) | 3 (2–4) | 0.172 | |
Parity, median (range) | 1 (0–2) | 1 (1–2) | 0.116 | |
BMI (kg/m |
29.7 |
29.1 |
0.182 | |
Smoking, n (%) | 24 (19.0) | 19 (15.7) | 0.488 | |
IVF, n (%) | 31 (24.8) | 33 (27.3) | 0.659 | |
Prior CD number, median (range) | 0 (0–1) | 0 (0–0) | 0.217 | |
CD history, n (%) | 34 (27.0) | 25 (20.7) | 0.244 | |
CD interval (year), median (range) | 2.7 |
2.9 |
0.239 | |
Fetal presentation, n (%) | 0.590 | |||
Vertex | 110 (87.3) | 100 (82.6) | ||
Breech | 9 (7.1) | 12 (9.9) | ||
Transverse | 7 (5.6) | 9 (7.4) | ||
GBS infection, n (%) | 99 (88.4) | 102 (87.9) | 0.914 | |
APH, antepartum hemorrhage; BMI, body mass index; IVF, in vitro fertilization; CD, cesarean delivery; GBS, group B streptococcus. |
Without APH | With APH | p value | ||
(n = 126) | (n = 121) | |||
ASA status, n (%) | 0.049 | |||
1 | 13 (10.3) | 6 (5.0) | ||
2 | 95 (75.4) | 85 (70.2) | ||
3–4 | 18 (14.3) | 30 (24.8) | ||
Placental location, n (%) | 1.000 | |||
Anterior | 31 (26.7) | 30 (25.9) | ||
Posterior | 66 (56.9) | 67 (57.8) | ||
Lateral | 5 (4.3) | 5 (4.3) | ||
Anterior + posterior | 14 (12.1) | 14 (12.1) | ||
Placental classification, n (%) | 0.000 | |||
Complete | 55 (47.4) | 86 (72.9) | ||
Incomplete | 37 (31.9) | 23 (19.0) | ||
Low lying | 24 (20.7) | 9 (7.6) | ||
Placenta accreta, n (%) | 14 (11.1) | 16 (13.2) | 0.611 | |
Emergent CD, n (%) | 15 (11.9) | 66 (54.5) | 0.000 | |
Duration of procedure (min), mean |
63.6 |
66.8 |
0.801 | |
Anesthetic type, n (%) | 0.024 | |||
General anesthesia (GA) | 1 (0.8) | 9 (7.4) | ||
Neuraxial anesthesia (NA) | 121 (96.0) | 108 (89.3) | ||
NA converted to GA | 4 (3.2) | 4 (3.3) | ||
Anesthesia time (min), mean |
123.8 |
136.9 |
0.114 | |
EBL (mL), median (range) | 800 (775–1000) | 900 (800–1215) | 0.109 | |
PRBC product (mL), mean |
1112.7 |
863.0 |
0.269 | |
All blood products (mL), mean |
238.3 |
297.5 |
0.045 | |
Blood transfusion, n (%) | 12 (9.5) | 23 (19.0) | 0.033 | |
Total fluid infusion (mL), median (range) | 1600 (1000–2000) | 1500 (1100–2225) | 0.395 | |
HGB (g/dL), mean | ||||
First trimester | 12.4 |
12.0 |
0.022 | |
Pre-operation | 11.8 |
11.2 |
0.000 | |
Post-operation | 9.9 |
9.5 |
0.207 | |
HCT (%), mean | ||||
First trimester | 36.8 |
35.6 |
0.012 | |
Pre-operation | 35.0 |
33.3 |
0.001 | |
Post-operation | 28.9 |
28.4 |
0.245 | |
PPH, n (%) | 46 (36.5) | 56 (46.3) | 0.119 | |
Hysterectomy, n (%) | 9 (7.1) | 8 (6.6) | 0.869 | |
ICU admission, n (%) | 3 (2.4) | 1 (0.8) | 0.643 | |
Inpatient days (day), mean |
4.6 |
7.2 |
0.000 | |
APH, antepartum hemorrhage; ASA, the American Sociological Association; CD, cesarean delivery; EBL, estimated blood loss; PRBC, packed red blood cells; HGB, hemoglobin; HCT, hematocrit; PPH, postpartum hemorrhage; ICU, intensive care unit. |
The gestational week in which delivery occurred for patients without APH was
much later than for patients with APH (37.1
Time to delivery for women with placenta previa with or without APH.
In addition to gestational week, we observed significant differences between the
2 groups regarding maternal outcomes including length of hospital stay, first
trimester and pre-operative levels of HGB and HCT, emergent CD, blood transfusion
rate, total blood product, general anesthesia (GA), and American Society of
Anesthesiologists (ASA) physical status classification (p
Neonatal outcomes were also significantly different between the 2 groups. The
APH group manifested a higher rate of preterm delivery and a lower birth weight
(p
Without APH | With APH | p value | ||
(n = 126) | (n = 121) | |||
Gestational age (weeks), mean |
37.1 |
35.6 |
0.000 | |
Newborn birth weight (grams), mean |
2920 |
2686 |
0.000 | |
Apgar score at 1 min, n (%) | 0.003 | |||
23 (18.3) | 42 (34.7) | |||
103 (81.7) | 79 (65.3) | |||
Apgar score at 5 min, n (%) | 0.090 | |||
7 (5.6) | 14 (11.6) | |||
119 (94.4) | 107 (88.4) | |||
Preterm delivery, n (%) | 41 (32.5) | 90 (74.4) | 0.000 | |
Endotracheal intubation of newborns, n (%) | 40 (31.7) | 52 (43.3) | 0.060 | |
NICU admission, n (%) | 47 (37.3) | 68 (56.7) | 0.002 | |
Antenatal corticosteroids, n (%) | 12 (9.5) | 67 (55.3) | 0.000 | |
APH, antepartum hemorrhage; NICU, neonatal intensive care unit. |
We found that the incidence of APH was different for each gestational week, and the number of APH events varied between 1 and 7 episodes, with nearly half of the patients experiencing 2 to 3 incidents throughout their pregnancies. The 32nd gestational week appearing to be the most precarious and possessing the highest incidence of APH. We evaluated the incidence of APH in placenta previa patients as it was first described and during the gestational week in which it occurred, and to the best of our knowledge, there are no other extant reports on this specific topic. In general, the 32nd week marked a turning point in that prior to 32 weeks, bleeding gradually increased commensurate with increasing gestational week. However, after 32 weeks, the bleeding began to diminish. This pattern appears to be consistent with data demonstrating that as the numbers of CDs gradually increase commensurately with the increase in gestational weeks, the resulting incidence of vaginal bleeding is markedly reduced [10]. It is possible that augmented uterine contractions (particularly after 32 weeks) may lead to a shortened cervical length and further separation of the placenta from the uterine wall, thus allowing hemorrhaging to occur more readily. Previous investigators have postulated that the etiology of APH in placenta previa comprises a poor blood supply that induces atrophy of thin portions of the placenta implanted over the cervix; this subsequently leads to placental migration as gestation continues, ensuring an improved blood supply from a more richly vascularized area (a process known as trophotropism) [11]. Oppenheimer et al. [12] reported that the placenta did not overlap the cervical orifice consistently; rather, placental migration occurred at an average rate of +5.4 mm/week, while the rate was only +0.3 mm/week in placenta previa. Uterine contractions, cervical effacement, and dilatation during the third trimester can also cause separation of the placenta, which leads to small amounts of bleeding; this bleeding may subsequently stimulate further placental separation and unavoidable hemorrhage [13].
Our finding of complete placenta previa as a risk factor for APH is consistent with prior studies. Bahar et al. [3] for example, reported that women with major (complete or partial) placenta previa manifested a significantly higher incidence of APH (OR, 3.18; 95% CI, 1.58–6.4; p = 0.001). Similarly, Atsuko et al. [14] reported that APH was more prevalent in women with complete placenta previa compared to those with incomplete previa (59.1% vs. 17.6%: OR, 6.79; 95% CI, 3.31–13.92). Yang et al. [15] also reported a higher frequency of APH in complete previa compared to marginal previa. From these studies, it appears that complete previa is likely to be an independent risk factor in predicting APH in these patients. Some authors have also used ultrasonography to identify short uterine cervical length (observed in the third trimester) and the sinus venosus at the margin of the placenta as risk factors for APH in placenta previa [16]. Regarding complete placenta previa, there may exist other risk factors for APH caused by placenta previa. Stafford et al. [17] demonstrated that in the third trimester, a cervical length of 30 mm or less was associated with an increased risk for hemorrhage (79% vs 28%) in placenta previa patients, whereas Saitoh et al. [18] reported that the risk of massive antenatal hemorrhage was higher (83.3%) in placenta previa patients with an echo-free space in the placental edge overlying the cervical orifice compared to other locations (7.7–10%). We must, however, admit that the evidence remains controversial, with other investigators showing contrasting results. Hasegawa et al. [19] maintained that the use of ultrasonography could not predict bleeding episodes, and according to the 2011 RCOG Green-top guidelines No.63, APH possesses a heterogeneous pathophysiology and thereby cannot be predicted reliably. Intriguingly, the location of the placenta was not reported to influence APH [14], and the anterior placenta may only increase hemorrhage during and after CD [20]. Contradicting our original hypothesis, placenta accreta did not serve as a protective factor in ameliorating APH.
With regard to maternal outcomes, we also demonstrated that recurrent or major APH enhanced hospitalizations, led to maternal anemia, and increased emergent CDs, blood transfusion rate, and total blood-product infusion; these findings were also confirmed by Takayama [21] and Crane et al. [22]. Although these authors also reported that APH elevated rates of hysterectomy [21] and PPH [22, 23], we did not find an increase in bleeding with hysterectomy or PPH in our study. In placenta previa, abundant blood flow enters the uterus not only from the internal iliac artery but also via anastomoses of the external iliac artery, interior mesenteric artery, lumbar artery, and median sacral artery. Therefore, it is difficult to control bleeding [24].
We additionally treated our hysterectomy or PPH patients with various hemostatic
methods including uterine balloons, B-Lynch sutures, arterial ligation, or
bilateral uterine artery embolization. To avoid repeated or massive bleeding,
scheduled CDs for placenta previa are performed at 36–37 weeks of gestation, and
preterm CD is performed only when massive, uncontrollable hemorrhage or fetal
distress occurs. The American Society for Maternal-Fetal Medicine (SMFM) and the
RCOG guidelines both recommend delivery dates for placenta previa to be between
36
In our study, 79 pregnant women received antenatal corticosteroids to prevent RDS because of irregular contractions or vaginal bleeding and were admitted 34 weeks ago. Antenatal corticosteroids are an essential component in the management of women at risk for preterm labor; they promote lung maturation and reduce the risk of other preterm neonatal complications [26].
Our research has shown that recurrent APH caused higher rates of NICU admission, preterm delivery, respiratory distress and other adverse neonatal outcomes, all of which are consistent with previous results [27, 28, 29]. Jing et al. [5] also reported that such adverse outcomes may be due to recurrent antenatal vaginal bleeding that affects the placental blood supply, which subsequently leads to insufficient fetal blood supply. The guidelines for the diagnosis and management of placenta previa also mention that recurrent hemorrhage, local infection, and production of inflammatory factors in pregnant women with placenta previa stimulate uterine contractions, which can easily lead to premature birth [1]. In contrast, however, some investigators have not found that severe bleeding leads to increased adverse maternal or neonatal outcomes [30]. The discrepancies among these aforementioned studies may reflect differences in maternal background and patient management, and suggest that additional large, multicenter studies are needed to confirm the effects of APH on both maternal and neonatal outcomes.
To our knowledge, this is the first study to identify an association between APH in placenta previa patients and gestational week. Our work adds to the important literature regarding risk factors for APH and its significant implications for maternal and neonatal outcomes. Although it is difficult to reliably predict APH among women, we identified the third trimester—especially around 32 weeks—as a potential turning point with respect to bleeding risk. We also found complete placenta previa to be an independent risk factor for APH in this specific patient population.
Several limitations to this study should be noted. First, this was a relatively small study limited to one healthcare system, which may result in informational and regional biases that require increased case numbers and an expanded research area. Second, because of the retrospective nature of the study design, we were unable to collect and report on data regarding other important information, including the amount of APH, cervical length, neonatal arterial pH data, and long-term neonatal complications. In the future, large prospective studies are needed to assist clinicians and researchers in better understanding the risks and implications of APH in placenta previa patients.
The gestational week and frequency of APH varied by patient with placenta previa and might have resulted in an increase in adverse maternal and neonatal outcomes. Clinicians should thus be cognizant of placenta previa as increasing the risk for prenatal bleeding, especially in the third trimester at approximately the 32nd gestational week. It is also important for clinicians to recognize that women who do experience APH may be at higher risk for requiring blood transfusions and undergoing emergent CD, and their newborns are at an increased likelihood for manifesting lower birth weight, asphyxia, and additional NICU admissions. Pediatric involvement in the delivery of these patients may therefore be warranted. Thus, healthcare providers should consider transferring patients with complete placenta previa to a tertiary medical center to tailor their personal antenatal management, identify potential risks and outcomes, and provide advanced, multidisciplinary care to prevent adverse consequences.
CD, Cesarean delivery; APH, Antepartum hemorrhage; PHS, Partners Healthcare System; EMR, Electronic medical records; BMI, Body mass index; IVF, In vitro fertilization; PRBC, Packed red blood cells; FFP, Fresh frozen plasma; PPH, Postpartum hemorrhage; EBL, Estimated blood loss; HGB, Hemoglobin; HCT, Hematocrit; SPSS, Statistical Package for the Social Sciences; SD, Standard deviation; OR, Odds ratio; CI, Confidence interval; SMFM, Society for Maternal-Fetal Medicine.
WJQ and LW drafted the manuscript and participated in data collection and analysis; DL, LMW and XY reviewed the manuscript; LL analyzed data and prepared the manuscript; AV performed the statistical analysis and reviewed the manuscript; and JZ contributed to the development of the study, the study design, and manuscript preparation for publication. All authors read and approved the final manuscript.
The authors confirm that they obtained approval by the Ethics Committee of Brigham and Women’s Hospital, Harvard Medical School (Protocol#2019P000028); and that written consent for use of the data in scientific research was also acquired from patients before operation.
We wish to thank Fan Li and Yan Gao to collect the data during the research in the Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School.
This research received no external funding.
The authors declare no conflict of interest.