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Bleeding in the second and third trimesters of pregnancy affects 6% of all pregnancies, and has distinct etiologies from first-trimester bleeding . In the vast majority of cases, antenatal bleeding is vaginal and obvious; however, rarely, it may be contained within the uterine cavity, the intraperitoneal space, or the retroperitoneal space. The etiologies of antenatal bleeding, also referred to as antepartum hemorrhage, are heterogeneous. In cases of severe antepartum hemorrhage, complications include preterm delivery, cesarean delivery, blood transfusion, coagulopathy, hemodynamic instability, multi-organ failure, salpingectomy/oophorectomy, peripartum hysterectomy, and in some cases, either perinatal or maternal death.
The goal of this Working Group was two-fold:
The charge to the Brighton Collaboration Working Groups to define various adverse obstetric and pediatric events includes an aim to more easily identify immunization-related adverse events. In the case of antenatal bleeding, our Working Group felt strongly that there is no biologic plausibility or mechanistic explanation linking immunizations to antenatal bleeding. Moreover, as immunizations and antenatal bleeding are common occurrences in the course of any individual pregnancy, it is quite likely that these events will co-occur without suggesting causation. To date, there is one case report of antenatal bleeding occurring in a pregnancy where a tetanus, diphtheria, and acellular pertussis vaccination was also administered . However, the definition used to identify the antenatal bleeding event is not clearly presented. Standardized definitions across trials, surveillance systems, or clinical settings will facilitate case ascertainment and analysis of potential risk factors for antenatal bleeding.
In this document, we focus on placenta previa, morbidly adherent placentation, vasa previa, placental abruption, cesarean scar pregnancy, intra-abdominal pregnancy, and uterine rupture as important sources of antenatal bleeding. Cesarean scar pregnancy and intra-abdominal pregnancy are rarely listed as causes of antenatal bleeding in the second and third trimester. Nonetheless, we included these causes as they are more likely to result in late presentation with a high risk of heavy maternal bleeding in settings in which ultrasound diagnosis of pregnancy is limited or unavailable.
Another common source of bleeding is labor, whether at term or preterm. Although preterm labor is pathologic and addressed in another document , bleeding in the context of labor alone is not. This is not addressed in our document. Non-obstetric genital tract bleeding may also occur during pregnancy, including neoplastic, infectious, traumatic, or iatrogenic causes. Urinary tract infections or hemorrhoids may also be misidentified as antenatal bleeding until additional workup is performed. This document will focus solely on the pregnancy-attributable etiologies of antenatal bleeding.
Following the process described in the overview paper  as well as on the Brighton Collaboration Website http://www.brightoncollaboration.org/internet/en/index/process.html, the Brighton Collaboration Antenatal Bleeding Working Group was formed in 2016 and includes members with a diverse background in clinical experience, location of practice, and scientific expertise in sources of antenatal bleeding. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html.
To guide decision-making for case definitions, a literature search was performed in PubMed, including the following terms: pregnancy, antenatal bleeding, antepartum bleeding, antepartum hemorrhage, placenta previa, vasa previa, abruptio placenta, placenta accreta, morbidly adherent placenta, abdominal pregnancy, cesarean scar pregnancy, uterine rupture, abdominal pregnancy, intra-abdominal pregnancy, and vaccination. Major obstetric textbooks and published guidelines from major obstetric societies throughout the world were also surveyed. This review resulted in a detailed summary of 33 articles used to establish case definitions for antenatal bleeding. The search also resulted in the identification of 1 reference containing information regarding vaccination administration and antenatal bleeding (as defined by the listed PubMed search terms above).
We first begin with a brief description of each etiology, the underlying pathophysiology, incidence, and risk factors. For most conditions, incidence data are derived from settings in which the condition has been most systematically studied, often North America and Western Europe. Incidence data not derived from these areas is specified in the following paragraphs.
Placenta previa occurs when the placenta partially or completely overlies the internal cervical os. This is in contrast with low-lying placenta, in which the placenta lies within 2 cm of the internal cervical os but does not extend across it. The etiology of placenta previa is unknown. Risk factors include smoking, advanced maternal age, multiparity, in vitro fertilization, multiple gestation, Asian race, prior endometrial damage, prior pregnancy termination or spontaneous abortion, prior cesarean delivery, and prior placenta previa , , . These risk factors suggest that the pathogenesis may be driven by endometrial damage or suboptimal endometrial perfusion in other areas of the uterus. The incidence of placenta previa at term is approximately 1 in 200 pregnancies; the incidence is higher earlier in gestation, but many placenta previas resolve as the lower uterine segment develops and the placenta preferentially expands towards more vascularized areas of the uterus , .
Morbidly adherent placentation occurs when the placenta implants abnormally into the uterine myometrium, rather than the normal implantation of the placenta into the uterine decidua basalis , , . Invasive placentation occurs as a result of the absence of the decidua basalis and incomplete development of or injury to Nitabuch’s layer , , . The incidence of morbidly adherent placentation is 1 in 300 to 1 in 500 pregnancies . The most significant risk factor is placenta previa in the context of one or more prior cesarean deliveries, or other uterine surgery. With one prior cesarean delivery and a placenta previa, the risk is 11%; with 3 or more cesarean deliveries and a placenta previa, the risk is greater than 60% . Other common risk factors include advanced maternal age, advanced parity, cesarean scar pregnancy, and in vitro fertilization , , , , .
Placental abruption occurs when the placenta detaches prematurely from its implantation site. Traditionally conceptualized as primarily an “acute” event often resulting from physical trauma to the abdomen, contemporary data suggest that placental abruption is often chronic , , , , . Nevertheless, acute placental abruptions still occur. Abruptions may either be revealed, with vaginal bleeding as an early symptom, or concealed, with blood remaining trapped within the uterus. Pathophysiologic mechanisms involved in abruption include uteroplacental underperfusion, ischemia, placental infarctions, and chronic hypoxia , , . In very rare circumstances abruption can follow second trimester diagnostic and therapeutic intrauterine procedures (amniocentesis, CVS, fetal surgery). Abruption affects about 1% of pregnancies, but is associated with a recurrence risk of about 10–15% for one prior abruption, 20–30% after two, and ≥30% after three or more abruptions , . Other risk factors include first trimester bleeding, hypertension, thrombophilia, illicit drug use (especially cocaine), smoking, trauma, in vitro fertilization, and premature rupture of membranes , , , . Pregnancies diagnosed with abruption end 3–4 weeks earlier than other pregnancies, with well over half delivering preterm. This is in contrast to a preterm birth rate of 12% among unaffected pregnancies , , , .
Vasa previa occurs when fetal blood vessels course within the amniotic membranes across the internal cervical os or within 2 cm of the os. Type I vasa previa occurs with a velamentous umbilical cord insertion into the membranes, consequently allowing for fetal vessels to run free within the membranes between the umbilical cord and placenta. Type II vasa previa occurs with the development of a succenturiate placental lobe and main placental lobe, connected by fetal vessels that freely course within the membranes. Vasa previa is rare, with an incidence of 1 in 2500 deliveries. Risk factors include resolved low-lying placenta, placenta previa, and multiple gestation , .
A cesarean scar pregnancy is an ectopic pregnancy implanted in a previous cesarean (hysterotomy) scar, surrounded by myometrium and connective tissue. This occurs due to a small defect in the cesarean scar, as a result of poor healing and poor vascularization of the lower uterine segment with resultant fibrosis . The pathophysiology of cesarean scar pregnancies is similar to an intrauterine pregnancy with morbidly adherent placentation . Cesarean scar pregnancies occur in about 1 in 2000 pregnancies and account for 6% of ectopic pregnancies among women with a prior cesarean delivery . As the recognition of cesarean scar pregnancies is relatively recent, risk factors are not yet clear; however, as with morbidly adherent placentation, the incidence appears to correlate with the number of prior cesarean deliveries .
Intra-abdominal pregnancy is a rare form of an ectopic pregnancy, in which a pregnancy implants into the peritoneal cavity or abdominal organs. Most commonly, this occurs due to tubal ectopic pregnancy with tubal extrusion or rupture and secondary implantation; primary implantation into the peritoneal cavity is also possible. Pregnancies may be asymptomatic, or may present with life-threatening intra-abdominal hemorrhage. The incidence is difficult to ascertain, as data are derived from case reports, but is reported to be 1–2 in 10,000. Risk factors are artificial insemination, in vitro fertilization, uterine surgeries, and prior tubal or cornual pregnancy , .
Uterine rupture is the complete nonsurgical disruption of all layers of the uterus. Uterine rupture may occur either in an unscarred uterus or at the site of a prior hysterotomy scar. The incidence of rupture of the unscarred uterus is approximately 1 in 20,000 deliveries in high-resource settings, but can be as high as 1 in 100 deliveries in low-resource settings, where the majority of this type of rupture occurs , , . Risk factors for uterine rupture in an unscarred uterus include a contracted pelvis, prolonged dystotic labor, multiparity, morbidly adherent placentation, malpresentation, use of strong uterotonic drugs perhaps with cephalopelvic disproportion, operative vaginal deliveries at high station, and congenital weakness of the myometrium . In high-resource settings, uterine rupture most commonly occurs in the context of a prior hysterotomy scar or transfundal surgery . The incidence of this event ranges from approximately 1 in 200 up to 1 in 10, depending on the type of hysterotomy and the use of labor augmentation , . Additional risk factors include the number of prior cesarean deliveries, interdelivery interval less than 18 months, one-layer uterine closure, and open fetal surgery , , .
The number of signs, symptoms, and diagnostic tests that will be documented for each case may vary considerably. The case definition has been formulated such that the Level 1 definition is highly specific for the condition. As maximum specificity normally implies a loss of sensitivity, an additional diagnostic level has been included in the definition to increase sensitivity while retaining an acceptable level of specificity. In this way, it is hoped that all possible cases of antenatal bleeding can be systematically captured.
The grading of definition levels is about diagnostic certainty, not clinical severity of an event. Thus, a clinically very severe event may appropriately be classified as Level 2 or 3 rather than Level 1 if it could reasonably be of an alternative etiology – either another cause of antenatal bleeding, or unrelated to antenatal bleeding entirely. Detailed information about the severity of the event should always be recorded, as specified by the data collection guidelines .
In certain cases, pathologic findings serve as the gold standard to confirm the presence of a pathologic entity. This is the case for morbidly adherent placentation, where the surgical specimen is often the hysterectomy specimen with placenta in-situ. Pathologic findings for cesarean scar pregnancy managed by hysterectomy with the gestational sac in-situ is also the gold standard for diagnosis; however, a hysterectomy is not always performed, and histologic confirmation may not be possible. Histological findings identify many but not all cases of placental abruption. The other etiologies of antenatal bleeding included within this document do not lend themselves to a histologic diagnosis.
No specific laboratory findings were included in case definitions of antenatal bleeding, as none of these clinical entities are associated with specific or identifiable laboratory parameters. Anemia and coagulopathy associated with significant antenatal bleeding are to be diagnosed and managed using usual clinical algorithms.
Ultrasound findings in a pregnancy complicated by antenatal bleeding are highly important in identifying and differentiating several conditions and thus are included in many case definitions. MRI findings may be used in some circumstances when this modality is available. See below regarding safety data.
Prenatal ultrasound uses sound waves passing through an acoustic window to visualize deeper tissue and structures, including a fetus. Ultrasound is considered safe in pregnancy, and there have been no reports of adverse fetal or neonatal outcomes from prenatal ultrasound imaging. Applying the ALARA (As Low As Reasonably Achievable) principle is recommended during diagnostic imaging procedures , . Magnetic resonance imaging (MRI) technology has also been used in pregnancy for several indications after inconclusive or nondiagnostic prenatal ultrasound. There has never been any documented fetal or neonatal harm and the procedure is considered safe in pregnancy. While the quality of imaging may be superior with gadolinium-enhanced imaging, its use is not currently recommended in pregnancy due to theoretical harms. Nonetheless, clear harm from gadolinium has not been demonstrated .
As noted in the preamble of this document, both immunizations and antenatal bleeding are common events in pregnancy. We feel strongly there is no current evidence or biological plausibility to suggest a causal link between immunization and antenatal bleeding. In order to appropriately assess this question, pregnant women who are and are not exposed to immunizations would need to be prospectively studied to identify any association with antenatal bleeding. However, withholding immunizations in pregnancy would not be ethical, and thus we are left with case reports and other epidemiologic studies of association that may lead to inappropriate conclusions.
As previously discussed, the focus of this Working Group is to define pathologic primary causes of antenatal bleeding. Labor, whether at term or preterm, may present with vaginal bleeding, yet in this instance, the pathway of preterm labor is the primary pathologic event. The Brighton Working Group on Pathways of Preterm Birth describes the pathophysiology of preterm labor in detail .
As mentioned in the overview paper, the case definition is accompanied by guidelines that are structured according to the steps of conducting a clinical trial, i.e. data collection, analysis and presentation. Case definitions and guidelines are not intended to guide or establish criteria for management of ill infants, children, or adults. Both were developed to improve data comparability.
Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed.
Antenatal bleeding is a clinical syndrome characterized by bleeding in the second or third trimester of pregnancy. Pathologic etiologies attributable to the pregnant state include placenta previa, morbidly adherent placenta, vasa previa, placental abruption, cesarean scar pregnancy, intra-abdominal pregnancy, and uterine rupture.
For both levels of diagnostic certainty for each etiology of antenatal bleeding:
For each definition, the diagnostic levels reflect diagnostic certainty and must not be misunderstood as reflecting different grades of clinical severity. Moreover, defining levels of clinical severity of antenatal bleeding is beyond the scope of this document.
It was the consensus of the Brighton Collaboration Antenatal Bleeding Working Group to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about antenatal bleeding. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, post-marketing surveillance or epidemiological study, or an individual report of antenatal bleeding. Also, as explained in more detail in the overview paper in this volume, these are intended as guidelines and are not to be considered a mandatory requirement for data collection, analysis, or presentation.
These guidelines represent a desirable standard for the collection of available data following immunization to allow for comparability of data, and are recommended as an addition to data collected for the specific study question and setting. They are not intended to guide the primary reporting of antenatal bleeding for a surveillance system or study monitor. Investigators developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition, which are not repeated in these guidelines.
Guidelines numbers below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use , and the form for reporting of drug adverse events by the Council for International Organizations of Medical Sciences . These data elements include an identifiable reporter and patient, one or more prior immunizations, and a detailed description of the adverse event of antenatal bleeding. Additional guidelines have been developed as direction for the collection of additional information to allow for a more comprehensive understanding of antenatal bleeding , .
For all cases and/or all study participants, as appropriate, the following information should be recorded:
For all cases and/or all study participants, as appropriate, the following information should be recorded:
For all cases and/or all study participants, as appropriate, the following information should be recorded:
The following guidelines represent a desirable standard for analysis of data on antenatal bleeding to allow for comparability of data, and are recommended as an addition to data analyzed for the specific study question and setting.
Event classification in 5 categories11
Subjects with Antenatal Bleeding (specify which etiology) by Interval to Presentation
These guidelines represent a desirable standard for the presentation and publication of data on antenatal bleeding that occurs in a pregnancy in which immunizations are also administered to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomized controlled trials, systematic reviews, and meta-analyzes of observational studies in epidemiology (e.g. statements of Consolidated Standards of Reporting Trials (CONSORT), of Improving the quality of reports of meta-analyzes of randomized controlled trials (QUORUM), and of meta-analysis Of Observational Studies in Epidemiology (MOOSE), respectively).
The findings, opinions and assertions contained in this consensus document are those of the individual scientific professional members of the working group. They do not necessarily represent the official positions of each participant’s organization.
The authors are grateful for the support and helpful comments provided by the Brighton Collaboration and the reference group (see https://brightoncollaboration.org/public/what-we-do/setting-standards/case-definitions/groups.html for reviewers), as well as other experts consulted as part of the process. The authors are also grateful to Jan Bonhoeffer, Jorgen Bauwens of the Brighton Collaboration Secretariat and Sonali Kochhar of Global Healthcare Consulting for final revisions of the final document. Finally, we would like to acknowledge the Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project, funded by the Bill and Melinda Gates Foundation.
3The case definition should be applied when there is no clear alternative diagnosis for the reported event to account for the combination of symptoms.
4If the reporting center is different from the vaccinating center, appropriate and timely communication of the adverse event should occur.
5The date and/or time of onset is defined as the time post immunization, when the first sign or symptom indicative for antenatal bleeding occurred. This may only be possible to determine in retrospect.
6The date and/or time of first observation of the first sign or symptom indicative for antenatal bleeding can be used if date/time of onset is not known.
7The date of diagnosis of an episode is the day post immunization when the event met the case definition at any level.
8The end of an episode is defined as the time the event no longer meets the case definition at the lowest level of the definition.
9E.g. recovery to pre-immunization health status, spontaneous resolution, therapeutic intervention, persistence of the event, sequelae, death.
10An AEFI is defined as serious by international standards if it meets one or more of the following criteria: (1) it results in death, (2) is life-threatening, (3) it requires inpatient hospitalization or results in prolongation of existing hospitalization, (4) results in persistent or significant disability/incapacity, (5) is a congenital anomaly/birth defect, (6) is a medically important event or reaction.
11To determine the appropriate category, the user should first establish, whether a reported event meets the criteria for the lowest applicable level of diagnostic certainty, e.g. Level three. If the lowest applicable level of diagnostic certainty of the definition is met, and there is evidence that the criteria of the next higher level of diagnostic certainty are met, the event should be classified in the next category. This approach should be continued until the highest level of diagnostic certainty for a given event could be determined. Major criteria can be used to satisfy the requirement of minor criteria. If the lowest level of the case definition is not met, it should be ruled out that any of the higher levels of diagnostic certainty are met and the event should be classified in additional categories four or five.
12If the evidence available for an event is insufficient because information is missing, such an event should be categorized as “Reported antenatal bleeding with insufficient evidence to meet the case definition”.
13An event does not meet the case definition if investigation reveals a negative finding of a necessary criterion (necessary condition) for diagnosis. Such an event should be rejected and classified as “Not a case of antenatal bleeding”.
14Use of this document should preferably be referenced by referring to the respective link on the Brighton Collaboration website (http://www.brightoncollaboration.org).