Approximately 20% of women experience at least one episode of vaginal or uterine bleeding during pregnancy [1]. In fact, the awareness of blood issuing from the vaginal area is one of the most common reasons for unscheduled calls and visits to the office and emergency room. This condition is potentially life-threatening and frightening for patients and family members. Studies indicate that 15% to 20% of recognized pregnancies abort spontaneously; the actual number may approach 50% of all pregnancies, but many are misinterpreted as a "late period" [1]. Because many patients do not recognize their own early signs of pregnancy, it is difficult to know how the incidence rate of preimplantation pregnancy losses compares with postimplantation pregnancy loss [1,2]. Patients with first trimester vaginal bleeding may be at higher risk for preterm delivery, low birth weight at term, and neonatal death [3]. Bleeding during pregnancy requires a thorough, compassionate evaluation to avoid possible complications, and address the meaning and importance of pregnancy to the patient and/or their family.

The most common complication of pregnancy is spontaneous abortion (SAB), also referred to as miscarriage. The working medical definition of abortion is termination of a pregnancy by any cause before the fetus is viable. In the United States, an abortion is considered to occur if the pregnancy ends before 20 weeks' gestation or before the fetus weighs more than 500 grams [5]. Because 80% of spontaneous miscarriages occur in the first trimester (i.e., the first 12 weeks of a pregnancy), this is becoming the more commonly used definition of miscarriage [6]. Because the word "abortion" is often associated with elective pregnancy termination, the terms "miscarriage" or "spontaneous pregnancy loss" are often used when talking with patients. The terms "early pregnancy failure" and "failed pregnancy" can be emotionally charged phrases that unintentionally imply failure to the patient and their family and should be avoided. Approximately 80% to 90% of women with a single spontaneous abortion are able to deliver a viable live infant in the next pregnancy [7].

One common cause of spontaneous abortion is a blighted ovum. The blighted ovum involves the fertilization of an egg that results in presence of a gestational sac and placenta but the absence of a fetus. Blighted ovum may be the result of a chromosomal abnormality and will always result in a miscarriage [10]. It has been estimated that at least 50% of clinically recognized SABs are the result of chromosomal anomalies, although some researchers have indicated that the frequency may be as high as 75% to 90% [7,11]. The most common genetic defect is trisomy (i.e., the possession of three copies of a particular chromosome instead of two), followed by X monosomy (i.e., possessing only one copy of a particular chromosome), and polyploidy (i.e., possessing several complete sets of the same chromosomes) [7,11]. Because these abnormalities are random genetic mutations, the statistics still fail to explain a large number of SABs.

There is no evidence that a modest intake of caffeine (e.g., 200 mg/day) alters the risk of pregnancy loss. There are data showing that caffeine consumption greater than 300 mg/day is associated with increased risk of spontaneous abortion, whether of a normal karyotype or chromosome complement fetus [16,17]. The amount of caffeine consumed in food and beverage obviously varies. As a general guide, a 6-ounce serving of coffee contains about 100 mg caffeine [16]. Chocolate consumption has not been associated with an adverse pregnancy outcome [18].

Anatomic uterine anomalies have been found in 15% of patients who undergo evaluation for recurrent spontaneous abortion, defined as three or more consecutive miscarriages [52]. Anomalies such as unicornuate uterus, bicornuate uterus, arcuate uterus, septate uterus, and uterine didelphys, have long been identified causes of spontaneous abortion. Theoretically, the mechanism is a combination of space constraints in the uterus and inadequate placental implantation due to vascular changes in the uterus [15]. Pregnancy outcome has been found to be better in uterus didelphys than in unicornuate uterus. Patients with a bicornuate uterus have a 60% likelihood of a successful pregnancy outcome; however, they are at high risk of cervical insufficiency. Septate uterus has generally been associated with poor obstetric outcome [53].

A drug or chemical must be very highly concentrated in seminal fluid to expose an unfertilized ovum directly, although a significant increase in spontaneous abortion has been identified when the father was exposed to lead [19]. While the mechanism is not well understood, it is well accepted that chronic alcohol misuse can impair male fertility by decreasing sperm production [19,59,60]. Studies on animals have shown that paternal alcohol abuse may have an adverse effect on the offspring's immune response and hormone secretion. Furthermore, these animal models indicate that consumption of alcohol may cause damage to sperm, in turn affecting the fetus. Advanced paternal age has been shown to increase the risk for spontaneous abortion as well as genetic abnormalities in offspring due to multiple factors, including DNA damage from abnormal apoptosis and reactive oxygen species [61]. Cellular mutations resulting in conditions such as neurofibromatosis and achondroplasia (a form of dwarfism) have been found more frequently in the children of older fathers [62]. Paternal age also may significantly affect the incidence of Down syndrome [63].

Rhesus factor (Rh) disease of the newborn is caused by an incompatibility between the blood of a fetus and its mother. It can cause destruction of the fetal red blood cells and subsequent multiorgan involvement. Fifteen percent of the White population and 7% of African Americans lack the Rhesus protein in their blood and are considered Rh negative [74]. If the fetus of an Rh-negative patient has Rh-positive blood, there is a danger that some of the fetus's blood may enter the maternal blood stream, causing the mother's immune system to produce antibodies against this "foreign" blood type. When antibody titers develop, the patient is said to be sensitized or alloimmunized. About 10% of alloimmunizations occur as a result of antenatal hemorrhage, although most occur in the third trimester [75,76]. The amount of fetal blood needed to cause sensitization is less than 0.1 mL, and spontaneous abortions have been associated with a 1.5% to 2% risk of alloimmunization [76].

Administration of RhoGAM decreases the risk of developing antibody titers in the event of a maternal-fetal transfusion. For antepartum prophylaxis, RhoGAM should be given at 28 weeks. If given early in pregnancy, it should be administered every 12 weeks to ensure adequate levels of passively acquired anti-Rh. For postpartum prophylaxis, the dose should be administered as soon as possible after delivery, preferably within 72 hours of the first episode of bleeding [76]. It may be given up to 28 days following delivery [39]. However, some experts have recommended administration of RhoGAM whenever the patient presents for bleeding evaluation.

Some providers order first trimester ultrasound exams to determine whether bleeding has occurred around or behind the placenta or amniotic membranes. Subchorionic hematomas are sometimes found on ultrasound. These hematomas are a collection of fluid believed to be caused by a partial separation of the trophoblast from the uterine wall. The incidence of subchorionic hemorrhage is approximately 1.3% of all pregnancies. Incidences as high as 20% to 25% have been identified in those with vaginal bleeding [83,179]. The clinical significance of subchorionic hemorrhages is unknown. Maternal age, gestational age at the time of diagnosis, and the volume of the hematoma may all contribute to the clinical outcome. Research has suggested that the diagnosis of a subchorionic hematoma at a gestational age less than nine weeks is significantly associated with spontaneous abortion [82].

Guidelines have been established for ultrasound detection of early pregnancy based on anticipated rise in hCG levels and sensitivity of ultrasonography. Patients with appropriately rising quantitative beta hCG levels should be examined with ultrasound as soon as the levels reach 2,000 mIU/mL [67]. However, the discriminatory hCG level varies with the type of ultrasound machine used; most radiology departments develop their own criteria regarding the level of hCG at which an early pregnancy should be visible. Providers should be familiar with their facilities' capabilities. Ectopic pregnancy can usually be ruled out by normally rising hCG levels and identification of an intrauterine pregnancy. Early pregnancy loss can be diagnosed in patients with ultrasound findings of a mean gestational sac diameter >25 mm with no embryo and no fetal cardiac activity when the crown-rump length is at least 7 mm [184].

Acknowledgment of a patient's grief and a discussion of the common feelings of guilt, anger, and helplessness are appropriate. Planned and unplanned pregnancies bring complex emotional responses. The loss of the pregnancy can be extremely stressful for patients and their support system [6]. Pregnancy loss can result in both acute stress disorder and post-traumatic stress disorder (PTSD) [89]. Most patients will adequately deal with their grief with the support of family, friends, and healthcare providers. However, the magnitude of the loss should not be underestimated. For some, the emotional trauma comes from realizing that the miscarriage is irreversible and is perceived as an unbearable, life-altering event. Some may mourn for much longer than expected, even after the birth of a healthy child [90]. Involved partners also struggle with the loss. Couples may grieve differently and move through the stages of grief at different paces. One should remember to ask the partner if they have any questions or if anything can be done for them [90]. Grief support groups for miscarriage are available, and many Internet sites can offer support and information (Appendix). Patients and their families should be reminded to call if any signs of depression occur, including appetite changes, daily crying for more than one week, sleep pattern changes, hopelessness, and suicidal thoughts or ideation.

Any event that impairs ability of the tube to transport gametes or embryos will predispose an individual to ectopic pregnancy [111,113]. The most common site of ectopic pregnancy is the fallopian tube, accounting for more than 98% of all ectopic gestations [113]. While most who present with ectopic pregnancy have no identifiable risk factors, several factors have been associated with ectopic pregnancy, including a history of PID, history of ectopic pregnancy, history of prior tubal surgery, use of ART, use of IUD for contraception, advanced maternal age, and altered tubal motility [40,111,112,113,114,115]. Because IUDs are effective contraception, the incidence of ectopic pregnancy in those using IUDs is low. However, if a person conceives while using a hormone-releasing IUD, there is an up to 50% chance the pregnancy will be ectopic [116,117]. The risk of ectopic pregnancy in clinical trials of women with IUDs and no other risk factors was about 1 in 1,000 users per year [116,117].

A high index of suspicion is necessary for any patient who has a positive pregnancy test, pelvic pain or tenderness, and spotting. Abdominal tenderness is present in 90% and rebound tenderness in 70% of patients with ectopic pregnancies [113]. Significant abdominal tenderness may suggest ruptured ectopic pregnancy [123]. On pelvic exam, the uterus is usually enlarged appropriate to gestational age. Uterine enlargement in early pregnancy is the result of hypertrophy of the uterine wall under stimulation by estrogen and progesterone. After the third month of pregnancy, uterine enlargement is also due in part to the mechanical stretching of the enlarging fetus [124]. Adnexal mass and/or tenderness may also be noted during pelvic examination. The cervix may be displaced to one side due to adnexal mass, and cervical motion tenderness may be present [85,123]. It is important to note that no combination of physical findings can reliably exclude ectopic pregnancy [123].

In hemodynamically stable patients, serial hCGs may be useful in the evaluation and diagnosis of ectopic pregnancy. As previously noted, the quantitative beta hCG levels in a normal intrauterine pregnancy should increase 66% during a 48-hour period [40]. An increase in beta hCG levels less than 66% reflects an abnormal intrauterine pregnancy or an ectopic pregnancy. However, it is important to note that approximately 10% of all ectopic pregnancies will have normally rising hCG levels [40,114]. Serial beta hCG levels that do not appropriately increase have been found to be only 36% sensitive and 65% specific for detection of ectopic pregnancy [123]. hCG levels alone cannot be used to diagnose ectopic pregnancy with absolute certainty. Although serum progesterone levels are useful for detecting pregnancy failure and identifying patients who may be at risk for ectopic pregnancy, they are not diagnostic of ectopic pregnancy and may create the potential for delayed diagnosis [114,125]. The sensitivity of progesterone levels is low (15%), and 85% of patients with ectopic pregnancy will have normal serum progesterone levels [123].

Treatment failures do occur with laparoscopic procedures [128]. After tubal-sparing surgery, hCG levels should be monitored. A fall in hCG levels of at least 20% every 72 hours is indicative of success [114]. Following surgical treatment of ectopic pregnancy, the elimination of hCG appears to follow a two-phase distribution. The major elimination phase has a half-life of 5 to 9 hours, and the second elimination phase has a 22- to 32-hour half-life [129]. Treatment with methotrexate may be necessary if falling hCG levels do not indicate successful surgical treatment [114,126].

Candidates for methotrexate treatment must be hemodynamically stable; patients must also be reliable and able to return for follow-up. Additionally, the gestational age and size are factors in determining the appropriateness of methotrexate use. Relative contraindications include an unruptured mass greater than 3.5 cm in size, fetal heart activity, quantitative hCG levels greater than 6,000–15,000 IU/L, and the presence of fluid in the cul-de-sac [113,114,186]. Absolute contraindications to methotrexate include hypersensitivity or allergy to the drug, immunodeficiency, alcoholism, chronic liver disease, blood dyscrasias (leukopenia, thrombocytopenia, anemia), pulmonary disease, and peptic ulcer disease [39,114]. In addition, patients with intrauterine pregnancy and those who are breastfeeding are also not candidates for methotrexate treatment. Methotrexate, even at low doses, can be fatal in patients with renal insufficiency [39,130].

Sixty percent of patients will experience at least one episode of increased abdominal pain after methotrexate injection [114,126]. This discomfort is believed to be caused by the separation of the placenta from the implantation site and expulsion of the products of conception from the fallopian tube. This pain usually occurs two to seven days after the onset of treatment, is mild, and lasts 24 to 48 hours [113,114]. The presence of pain can be confusing for the patient and the attending healthcare professional. Patients should be taught to expect the discomfort, but to call their providers with severe pain or any questions.

Adverse effects of methotrexate may include nausea and vomiting, diarrhea, gastric upset, dizziness, and occasionally, transient elevations in liver enzymes. The side effects usually abate within three to seven days of therapy being discontinued [39,113,114]. Serious side effects, such as bone marrow suppression, are rare at the doses used to treat ectopic pregnancy. A variable dose regimen has been shown to improve treatment success equal to that of laparoscopic salpingostomy [128]. However, the multiple dosage regimen has fallen out of favor in the United States due to the higher incidence of adverse effects and the increased need for patient motivation and compliance [98]. The more frequently used dosing regimen of methotrexate is a single-dose injection [114]. The efficacy of systemic single-dose methotrexate alone has been shown to be significantly less successful than when combined with mifepristone [128]. Those being treated with methotrexate should be cautioned to avoid alcohol, multivitamins with folic acid, and NSAIDs. Vaginal abstinence is advised until therapy is completed and hCG levels are negative. Exposure to the sun should be avoided due to the increased photosensitivity caused by methotrexate [114].

hCG levels should be observed at four days and seven days after methotrexate injection. An initial increase is not uncommon, peaking three to four days after treatment [114,129]. Four to seven days post-injection, the level should decline by at least 15% [114]. Treatment is considered successful if the hCG level has declined by 15% from day 4 to day 7. However, a second dose may be administered if a 15% drop is not observed, or surgery may be indicated [114,129,186]. With appropriately declining levels at day 7, hCG can be evaluated weekly until negative.

Gestational trophoblastic disease (GTD) is a heterogeneous group of benign and malignant conditions arising from developmental anomalies and malformations of the placenta [107]. Trophoblasts are specialized cells derived from a normally developing embryo. These cells facilitate implantation of the embryo into the uterus and become components of the placenta that promote normal growth and development of the fetus. During formation of the placenta, there is rapid expansion and differentiation of trophoblast cells into villous cytotrophoblasts and syncytiotrophoblasts, eventually forming an intricate network to anchor the embryonic sac into the endometrium. On rare occasions, when a defective ovum (egg) is fertilized, this intricate developmental process becomes distorted; instead of normal placenta, abnormal growths, or tumors arise from placental villous and extravillous trophoblast cells.

The most common benign form of GTD is hydatidiform mole (complete or partial), so named because diffuse villous enlargement and hydropic change gives the appearance of a "bunch of grapes". Hydatidiform moles are caused by abnormal gametogenesis and fertilization. The incidence varies geographically and is higher in Asia (1 in 500) and Africa (1 in 1,000) than in Europe and North America (1 in 1,500) [107]. A complete hydatidiform molar pregnancy occurs when an empty ovum (egg) is fertilized by one sperm, 90% followed by duplication of paternal chromosomes to a 46XX karyotype. A partial molar pregnancy occurs when an empty egg is fertilized by two sperm, resulting in triploid karyotypes (69XXX, 69XXY, or 69XYY) [107,132,133,134]. Examination of complete molar pregnancies usually shows absence of embryonic sac and an absent or remnant fetal tissue; partial molar pregnancies often contain a nonviable fetus and remnant amniotic sac. GTD is a collective term encompassing complete hydatidiform molar pregnancy, partial hydatidiform molar pregnancy, and placental site trophoblastic disease [135]. The incidence of GTD is about 1 in 1,500 to 1 in 2,000 pregnancies [131,136].

While the hydatidiform mole is usually a benign condition, it does have the potential to develop into a malignant choriocarcinoma [136]. The risk of developing choriocarcinoma is 20% following a complete molar pregnancy, with a lower risk after a partial molar pregnancy [137,138]. Clinical risk factors that appear to increase the probability of persistent GTD include delayed hemorrhage after a pregnancy immediately preceding the current one, excessive uterine enlargement, theca-lutein cysts, hCG levels greater than 100,000 mIU/mL, prior molar pregnancy, prior miscarriage, blood type A or AB, use of birth control pills, and maternal age older than 40 years and younger than 20 years. The risk is highest for patients older than 50 years; recurrence rates are 1% to 2% [137,138]. Twin gestations involving a complete molar pregnancy and a normal fetus are rare [132,133].

Three types of placentae previa have traditionally been recognized [142,143,144,145,146]:

The risk factors that are associated with placenta previa include maternal age older than 35 years, African American or other minority races, increased gravidity and parity, prior uterine surgery or cesarean section, prior induced abortion, cigarette smoking, large placenta, multiple gestation, and a prior history of placenta previa [142,145,146]. Some reports have additionally documented a higher association of fetal malpresentation, preterm premature rupture of membranes, and intrauterine growth restriction with placenta previa [145]. The exact pathophysiology is unknown, although placenta previa has been associated with scarring in the endometrium, presumably decreasing the surface area available for placental implantation [143,144,146].

There are three recognized grades of placenta abruption [145]:

While the exact causes of placenta abruption are unknown, some factors have been associated with their occurrence. These factors include [144,145]:

While the exact causes of placenta abruption are unknown, some factors have been associated with their occurrence. These factors include [144,145]:

Timing of delivery is dependent on the degree of separation and maternal or fetal status. With grade 1 abruption, close observation of maternal and fetal status is essential. When the fetus is mature, a controlled induction of labor can be pursued [145]. In patients remote from term and clinically stable, the use of tocolytic agents to inhibit contractions has been described [145]. Unfortunately, a small placenta abruption can stimulate uterine irritability, which causes the placenta to separate further. While bleeding was once considered to be a contraindication to tocolytics, it has become more acceptable to consider a short course of tocolytics in patients with mild bleeding and contractions. If the patient is stable and fetal well-being is established, tocolysis may be valuable to prolong pregnancy 48 hours in order to initiate antenatal steroids for fetal lung maturation. Magnesium sulfate is the most accepted agent for this purpose, although use as a labor tocolytic is off-label for this medication and controversial [144,160]. Evidence of fetal distress can prompt immediate cesarean section. Sixty percent of fetuses will become distressed in labor; continuous electronic fetal monitoring is associated with excellent fetal survival in these cases [145]. The cesarean rate associated with placenta abruption has been reported as 50% to 75% [145].

Evaluation for lower genital tract malignancy should be considered whenever one encounters vaginal bleeding. Overall, 1 of every 34 persons diagnosed with cervical cancer is pregnant [164]. Although cervical cancer is a rare complication of pregnancy, it remains the most common gynecologic malignancy associated with pregnancy [137,165]. While the incidence of cervical cancer has decreased worldwide, largely due to screening in Westernized societies, the mean age of diagnosis of cervical cancer is 50 years of age [166,167]. The most common complaint of pregnant patients with cervical cancer is bleeding [164]. In general, increases in vaginal discharge and bleeding are the most common symptoms reported with this malignancy. More advanced cancers may be accompanied by malodorous, serosanguineous, or yellow discharge [164]. However, many with cervical cancer are asymptomatic, and diagnosis is made on routine screening [166]. Pelvic pain is less common. Pap tests should be done if any suspicion of cervical pathology exists. False-negative cervical cytology is possible due to the increased mucus and bleeding from cervical eversion in pregnancy. Biopsy by a physician skilled in the procedure may be indicated in ulcerative lesions. If a Pap test is not performed in an urgent care facility or emergency room, the patient should be specifically told it was not obtained. Many arrive in their primary providers' offices assuming that if a speculum examination was conducted, a Pap test was obtained.

Vaginal infections are another possible cause of bleeding during pregnancy. Infections such as candidiasis, trichomoniasis, and bacterial vaginosis may cause tissue damage significant enough to result in vaginal bleeding during pregnancy. Microscopic evaluation of vaginal discharge and pH testing can quickly diagnose infections that should be treated. Initial herpes infections may result in bleeding from vesicles that have been scratched or from attempted home treatments. Visible lesions should be cultured for herpes simplex virus, and open sores should alert the clinician to the need for additional testing for syphilis and other STIs. As noted, all STIs diagnosed during pregnancy should be treated according to CDC guidelines [161]. Vaginitis treatments are also appropriate during pregnancy.