Threatened Miscarriage

Etiology

The exact etiology of a threatened miscarriage may not always be determined; however, possible causes include subchorionic hemorrhage or hematoma, eventual spontaneous miscarriage, or nonobstetric bleeding. Bleeding due to subchorionic hemorrhage or hematoma occurs in 18% to 22% of pregnancies, secondary to bleeding between the fetal membranes and the decidua basalis.[1] Though small subchorionic hematomas are not associated with an increased risk of miscarriage, hematomas that measure large than two-thirds of the gestational sac circumference have been found to have an increased risk of progressing to pregnancy loss.[6] In cases where bleeding is related to an impending early pregnancy loss, fetal chromosomal abnormalities, the most common underlying etiology of all early miscarriages, are present in at least half of affected pregnancies.[2][7][8] Nonobstetric causes of bleeding in viable intrauterine pregnancies include vaginitis, cervicitis, or cervical polyps.[4]

Epidemiology

Threatened miscarriage can occur in any pregnancy regardless of maternal age, race, comorbidities, lifestyle, or socioeconomic status.[9] Approximately 25% of pregnant people have some amount of vaginal bleeding or spotting during the first trimester; in pregnancies with detectable fetal cardiac activity, 11% ultimately miscarry.[4]

Pathophysiology

The pathophysiology of threatened miscarriage depends on the underlying etiology of the symptoms. Subchorionic hemorrhage is caused by bleeding between the decidua basalis and the gestational sac.[1]  Conditions causing nonobstetric bleeding and cramping (eg, cervicitis or cervical trauma) include infectious processes leading to vascular permeability and cytokine-mediated inflammation of cervical and vaginal mucosa and trauma-related injury to the maternal abdomen or pelvic organs.[4][10][11]

History and Physical

History

Patients with a threatened miscarriage typically present with bleeding and cramping in the first trimester, though some patients may be unaware of their pregnancy and complain of irregular menstrual bleeding.[12]  These symptoms may occur during normal and abnormal gestations (eg, ectopic and molar pregnancies); therefore, a comprehensive evaluation must be conducted to exclude more concerning pregnancy complications.[2] A thorough medical history should be obtained, including an obstetrical and menstrual history. Clinicians can calculate an estimated due date using the first day of the last menstrual period; though, a first-trimester obstetrical ultrasound is considered more accurate and should be used to determine the gestational age if available.[4]  Previous ultrasounds can also help confirm that the pregnancy is located within the uterus.[4][12]

In a threatened miscarriage, the volume of bleeding can range from light spotting to bleeding heavier than a typical menstrual period; in general, the heavier the bleeding, the more concerning it is that the pregnancy will result in a miscarriage.[13][14] Patients with threatened miscarriages are almost always hemodynamically stable; even patients expectantly managed that proceed to have spontaneous pregnancy loss only require a blood transfusion 1% of the time.[15] The clinician should estimate the amount of bleeding a patient is experiencing by asking when the bleeding began, how often she is soaking or changing menstrual hygiene products, if she is passing any clots or tissue, and if she has any associated symptoms, such as dizziness or lightheadedness.[12] The provider should also ask about precipitating factors; if the bleeding started after cervical contact (eg, after intercourse or a pelvic exam), this might indicate cervical or vaginal, rather than uterine, pathology.[12]

Additionally, the provider should elicit the characteristics of any associated pain or cramping, the severity of which can vary widely.[12] On one end of the spectrum, bleeding may be completely painless, while for other patients, the bleeding may be accompanied by intensely painful menstrual-like cramping that radiates to the back and upper thighs. Like with bleeding, severe pain is more concerning for impending pregnancy loss.[14]

Physical Exam Findings

Key components of the physical examination should include an assessment of the patient's hemodynamic stability, including a review of the vital signs and a focused abdominal and pelvic examination.[12] Patients with only a threatened miscarriage will be hemodynamically stable and have normal cardiovascular and respiratory findings; hemodynamic instability indicates heavier bleeding that is more commonly seen with miscarriages in progress (eg, incomplete miscarriage).[2] The abdominal exam is also typically benign (eg, non-tender, non-distended, and soft), though patients may have mild tenderness to palpation in the lower pelvis over the uterus. Peritoneal signs, such as guarding, rebound tenderness, or abdominal rigidity, are not typically present in an uncomplicated threatened miscarriage; if found, they indicate the need for an emergent obstetrical or general surgery consultation.[4]

A pelvic exam is mandatory whenever a pregnant patient presents with bleeding to assess the amount and site of bleeding, cervical dilation, possible nonobstetric sources of bleeding, and whether fetal tissue is present in the cervix or vagina.[4] During the pelvic exam, suction, cotton swabs, or ring forceps may be needed to remove blood in the vagina or cervix to allow for better visualization; the clinician should assess any vaginal discharge and collect specimens as needed for testing.[4][16]  

In a threatened miscarriage, the typical findings during vaginal examination are a closed cervical os with no fetal or embryonic tissue in the vaginal vault, though blood may be noted.[1] There is usually no cervical motion tenderness, though depending on the severity of cramping, patients may note some uterine or adnexal discomfort.[16] Significant tenderness of the pelvic organs, especially if purulent vaginal discharge is present, suggests the presence of an infection.[16]

The pelvic exam is also essential to rule out alternative causes of vaginal bleeding in pregnancy, including vulvar, vaginal, and cervical lacerations, erosions, dysplasia or neoplasms, polyps, fibroids, or friability in the setting of an infection (eg, vaginal candidiasis, Chlamydia trachomatis infection, condyloma acuminata). Additionally, an adnexal mass may suggest an ectopic pregnancy or other gynecologic pathologies, such as a cyst or ovarian torsion.[14]

Evaluation

Components of the Evaluation

In addition to a history and physical exam, components of the diagnostic evaluation of a threatened miscarriage include:

• Pelvic ultrasound
• Serum quantitative beta-human chorionic gonadotropin (β-hCG) 
• Blood type and Rh status
• Hemoglobin and hematocrit
• Additional labs for concerns of infection (eg, cultures of endocervical secretions, blood, and urine; complete blood count with a differential; comprehensive metabolic panel; and serum lactate)[4]

Pelvic Ultrasound

Transvaginal ultrasound is preferred over other modalities for the evaluation of first-trimester pregnancies.[6] In correlation with β-hCG levels, it is used to locate the pregnancy, determine the viability and gestational age of the pregnancy, and assess the pelvis for other contributing complications.[1] 

Assessing location: Threatened miscarriage is considered a diagnosis of exclusion; the most important diagnosis to rule out when evaluating bleeding in early pregnancy is an ectopic pregnancy, which commonly presents with bleeding and abdominal pain.[17] In a threatened miscarriage, an intrauterine pregnancy will be identified, or if neither an early intrauterine nor ectopic pregnancy is visualized, a pregnancy of unknown location (PUL) may be diagnosed. Embryonic or fetal structures (eg, a yolk sac or fetus) must be seen within the endometrial cavity to confirm an intrauterine pregnancy. A PUL is considered a temporary diagnosis that eventually must be determined to be an ectopic pregnancy, a miscarriage, or a very early intrauterine pregnancy through serial ultrasounds and β-hCG levels.[18]  

Assessing viability: The pregnancy is considered viable if fetal cardiac activity (FCA) is present. At earlier gestational ages before the development of FCA, intrauterine pregnancy failure may be identified based on a set of ultrasound criteria from a 2012 multispecialty panel from the Society of Radiologists in Ultrasound.[18][2][18] According to these criteria, pregnancy failure may be highly likely if one of the following is present: 

• A fetal crown-rump length (CRL) of ≥7 mm without FCA
• A mean sac diameter (MSD) of ≥25 mm without an embryo
• Absence of an embryo with FCA ≥14 days after a scan showing a gestational sac (GS) without a yolk sac (YS)
• Absence of an embryo with FCA ≥11 days after a scan showing a GS with a YS

Assessing the pelvis for nonobstetric causes of presentation: Ultrasound is the imaging modality of choice to evaluate the internal pelvic organs. In addition to looking for evidence of an ectopic pregnancy, ultrasound can assist in assessing other alternative diagnoses, including ruptured or torsed adnexal masses, gestational trophoblastic disease, and appendicitis.[14] Additional imaging, such as an abdominal radiograph or CT scan, can also be considered, depending on the severity of the presentation and clinical suspicion.[19]

Laboratory Evaluation

Quantitative β-hCG level: Early in gestation, the serum β-hCG increases at a relatively predictable rate in viable intrauterine pregnancies (IUPs); this increase may be abnormally slow in ectopic pregnancy or decrease in failing pregnancies. Therefore, serial β-hCG levels can help identify abnormal early pregnancies. For patients with a PUL, the trend in serial β-hCG levels, interpreted in conjunction with serial pelvic ultrasound examinations, is used to make the final diagnosis.[2][18] Once FCA is visible, however, normal β-hCG values can vary widely, with the rate of increase slowing over time, ultimately plateauing by about 10 weeks of gestation. For this reason, once FCA has been detected in an IUP, an β-hCG level is generally not indicated, and transvaginal ultrasound should primarily be used for diagnosis.[4]  In patients who already have evidence of an IUP but do not yet demonstrate a fetus with FCA (eg, a transvaginal ultrasound demonstrating only an intrauterine GS with a YS), an β-hCG level can be appropriate, as falling levels may identify a miscarriage sooner than if the clinician is relying on ultrasound alone; in these situations, however, a repeat β-hCG level is not strictly required since ectopic pregnancy has already been ruled out based on the ultrasound findings.[20][21][22]

Blood count: Assessment of the hemoglobin and hematocrit, typically with a complete blood count, is usually recommended except in cases where bleeding is scant (eg, an episode of spotting) and a baseline blood count was recently done (eg, at a recent initial prenatal visit). However, assessing the degree of blood loss is appropriate for most patients.[4][23]

Blood type and Rh status: In patients with significant vaginal bleeding, blood type and Rh status should be confirmed in anticipation of possible blood transfusion, surgical blood loss, or Rh(D)-alloimmunization prophylaxis.[4] If the pregnant person is Rh(D)-negative, they may develop antibodies against the Rh(D) antigen if they are exposed to Rh(D)-positive fetal blood. This is known as alloimmunization and can lead to future hemolytic disease of the newborn.[24] Knowledge of a patient's Rh status becomes more important as the pregnancy progresses due to the risk of Rh(D)-alloimmunization increasing as the number of fetal erythrocytes increases.[2] Approximately 11% of patients with a threatened miscarriage may experience maternal exposure to fetal blood and thus be at risk for alloimmunization.[25] Patients at risk of alloimmunization (eg, an Rh-negative pregnant person with bleeding) can be given Rh(D)-immune globulin to prevent the development of these antibodies; however, international guidelines vary regarding its use in the first trimester.[24]

Additional labs: A urinalysis is typically obtained as a urinary tract infection (UTI) may present with similar signs and symptoms. If there is a concern for a pelvic infection based on the patient's history and exam, additional testing is recommended, including blood and urine cultures,  sexually transmitted infection cultures, serum lactate, and a comprehensive metabolic panel.[19] 

Treatment / Management

Expectant Management

Patients with viable intrauterine pregnancies diagnosed with a threatened miscarriage should be expectantly managed after the exclusion of differential diagnoses. A pelvic ultrasound should be repeated if any further bleeding occurs. In patients in which the pregnancy's viability or location is uncertain, pelvic ultrasound should be repeated and serial β-hCG levels performed. For PULs in patients who remain hemodynamically stable, an β-hCG level should be obtained every 48 hours until the location of the pregnancy or pregnancy failure is identified.[2]

Progesterone supplementation has been investigated as a possible therapy to reduce the risk of pregnancy loss in patients at high risk for miscarriage, including those with a threatened miscarriage or a shortened cervix.[26][27] For people without a history of miscarriage, vaginal progesterone likely has little to no benefit. It is generally not recommended unless they are found to have a cervical length of 25 mm or less.[27][28][27][29] Evidence from the recent PRISM and PROMISE trials suggests that for people with a history of prior early pregnancy loss, vaginal progesterone does appear to be beneficial. Study authors recommended vaginal micronized progesterone 400 mg twice daily, initiated when a patient presents with symptoms of vaginal bleeding, continuing until 16 weeks of gestation.[26] (A1)

Prevent Alloimmunization

Alloimmunization can be prevented by administering Rh(D)-immune globulin; however, guidelines vary, and its use in the first trimester is somewhat controversial due to the low risk of alloimmunization in the first trimester.[24] The Rh(D)-antigen is found on fetal erythrocytes, so alloimmunization is theoretically improbable before the development of these cells. The Rh(D)-antigen has been identified as early as 7 3/7 weeks of gestation.[24] Additionally, only 3% to 11% of pregnant people may be exposed to fetal blood during a threatened miscarriage, with the risk of alloimmunization increasing with heavier bleeding, older gestational age, and surgical procedures, such as chorionic villus sampling.

Given a lack of clear evidence to guide decision-making, the American College of Obstetricians and Gynecologists (ACOG) recommends that Rh(D)-immune globulin be considered for all Rh(D)-negative patients who have vaginal bleeding in early pregnancy, "especially those that are later in the first trimester."[24][30] Conversely, the National Institutes of Health and Care Excellence (NICE) guidelines from the UK explicitly recommend against its use before 12 weeks of gestation, while guidelines from the British Committee for Standards in Haematology (BCSH) that are supported by the Royal College of Obstetricians and Gynaecologists (RCOG) do consider it appropriate to give before 12 weeks when uterine bleeding is "repeated, heavy, or associated with abdominal pain."[31](A1)

If given in the first trimester, a dose of Rh(D)-immune globulin 50-120 mcg IM once is effective at alloimmunization prevention; after 12 weeks of gestation, Rh(D)-immune globulin 300 mcg IM once is typically preferred in the US, though other guidelines recommend lower doses depending on the situation.[32] 

Discharge Instructions and Appropriate Follow-up

The importance of follow-up should be emphasized, and patients should be instructed to return for evaluation earlier than scheduled if they experience excessive vaginal bleeding, typically defined as soaking at least 1 to 2 pads for at least 2 hours in a row, worsening abdominal pain, or fever. Patients should also be reassured that they are not at fault for causing symptoms.[2]

There is no evidence that bed rest prevents early pregnancy loss and should not be recommended.[4][33][34]  Some clinicians prefer to advise patients to avoid strenuous activities and maintain pelvic rest (ie, avoiding vaginal intercourse) at least until the cessation of vaginal bleeding. However, this recommendation is not based on evidence. Clinicians should recommend that patients start or continue to take prenatal vitamins with folic acid supplementation.[35][36][37][38](A1)

Differential Diagnosis

Clinicians should consider several differential diagnoses when a pregnant person presents with vaginal bleeding and pelvic pain, as threatened miscarriage is ultimately a diagnosis of exclusion.[14][39] The differential diagnosis includes:

• Obstetric diagnoses
  • Ectopic pregnancy
  • Early pregnancy loss (eg, inevitable, incomplete, complete, or septic miscarriage)
  • Gestational trophoblastic disease
  • Cervical incompetence, typically in the second trimester
• Vulvar, vaginal, and cervical diagnoses (eg, trauma, vaginal candidiasis, bacterial vaginosis, Chlamydia trachomatis infection, condyloma acuminata, cervical polyps, cervical malignancy)
• Adnexal diagnoses (eg, ruptured corpus luteal cyst, adnexal torsion)
• Other diagnoses (eg, appendicitis, urinary tract infection, inflammatory bowel disease) 

Ultrasound and β-hCG assessments can rule out ectopic pregnancy and early pregnancy loss. Differentiation of threatened miscarriage from other early pregnancy loss is primarily based on pelvic ultrasound and physical examination findings. In a threatened miscarriage, the cervical os is closed, and an ultrasound demonstrates evidence of a viable pregnancy.[40] These observations differentiate a threatened miscarriage from other types of miscarriage. For example, with an inevitable miscarriage, the cervical os is open without visualization of POC in the vaginal vault. In contrast, an open cervix with partial passage of POC characterizes an incomplete miscarriage. A nonviable pregnancy excludes the diagnosis of threatened miscarriage.[1] Ultrasound and history can also help rule out other adnexal and nonobstetric causes, such as appendicitis. Physical examinations and clinically appropriate testing can typically rule out vulvar, vaginal, and cervical causes.

Prognosis

Bleeding and cramping in early pregnancy are extremely common. Studies have shown that about 25% of pregnant people experience vaginal bleeding before 20 weeks of gestation, and between 12% to 57% of these patients will ultimately progress to early pregnancy loss. Heavy bleeding, especially when accompanied by pain or cramping, carries a significantly worse prognosis than light bleeding or spotting.[4][23]

Pregnancies complicated by threatened miscarriage also have an increased risk of adverse outcomes later in pregnancy, including pregnancy loss, preterm birth, preterm premature rupture of membranes, intrauterine fetal growth restriction, and placental abruption. Furthermore, patients who proceed to experience early pregnancy loss have an increased risk of depression, sleep disturbance, anger, and marital disturbances.[27]

Complications

Complications of threatened miscarriage include:

• Early pregnancy loss 
• Anemia
• Poor mental health (eg, depression, anxiety)
• Adverse outcomes later in pregnancy (eg, preterm labor, placental abruption) [27]