Miscarriage and Recurrent Pregnancy Loss

History

• Miscarriage
  • Symptoms include:
    • Vaginal bleeding ^c1
      • Approximately 25% of clinically pregnant patients experience some vaginal bleeding; up to one-half of patients who have bleeding during early pregnancy will miscarry ^r1
      • May be spotting or heavy ^c2c3
    • Uterine cramping ^c4
  • Patient history should include: ^r4
    • Estimated length of gestation ^c5
    • Time since last menstrual period
    • Symptoms of pregnancy (including evolution or loss of) ^c6
    • Degree and duration of bleeding
    • Attempts by patient to induce miscarriage ^c7
• For patients with recurrent pregnancy loss, include pertinent historical questions regarding: ^r1r7
  • Previous pregnancies ^c8
  • Pathologic tests performed on previous miscarriages
  • Previous gynecologic surgery
  • Cervical incompetence
  • Chronic or acute infections or diseases
  • Abnormal exposures
  • Family history of miscarriage or birth defects
  • Family history of unusual thrombosis
  • Open-ended questions exploring patient's ideas about possible causes

Physical examination

• Miscarriage
  • Abdominal examination
    • Uterus should not be palpable
    • Tenderness or peritoneal irritation may result from ectopic pregnancy or septic abortion ^c9c10
  • Pelvic examination can reveal: ^r4
    • Open or closed os ^c11c12
      • Typically determined visually through speculum examination ^r4
        • Clearly open os or visible products of conception may be seen
        • If uncertain, digital inspection on bimanual pelvic examination may reveal dilation
          • Internal os lies approximately 1.5 cm deep to external os
          • Parous patients normally have open or lax external os (insignificant finding)
    • Clots or products of conception ^c13c14
      • If present, gentle removal of fetal tissue from cervical os with ring forceps may slow bleeding ^r4
        • If products not removed easily with ring forceps, consult gynecologist because cervical ectopic pregnancy is possible and removal of products can cause severe hemorrhage
    • Degree of vaginal bleeding
    • Uterine size and tenderness
      • Significant tenderness raises concern for ectopic pregnancy or pelvic infection (less common)
    • Adnexal enlargement
      • Often unilateral, due to cystic corpus luteum or ectopic pregnancy
      • Significant tenderness raises concern for ectopic pregnancy or pelvic infection (less common)
  • Signs of septic abortion include:
    • Fever ^c15
    • Tender lower abdomen ^c16
    • Cervical motion tenderness ^c17
    • Purulent vaginal discharge ^c18

Causes

• Cause of miscarriage is often multifactorial, particularly in recurrent losses
  • Most common risk factors for early pregnancy loss are advanced maternal age and prior early pregnancy loss ^r3c19c20
    • Majority of sporadic losses before 10 weeks of gestation are due to random numeric chromosome errors (eg, trisomy, monosomy, polyploidy) ^c21
  • Recurrent pregnancy loss has been associated with several factors, including genetics, age, antiphospholipid syndrome, uterine abnormalities, hormonal or metabolic disorders, infection, autoimmunity, male parameters, and lifestyle issues ^{r6c22c23c24c25c26c27c28c29}
    • Cause for recurrent losses determined in approximately 50% of cases ^r1r2
• Maternal causes
  • Medical conditions
    • Endocrine causes
      • Progesterone deficiency ^r1
        • Decreased production of progesterone from corpus luteum (luteal phase deficiency) or inadequate endometrial response to normal levels; may result in inadequate endometrial development to support implanted blastocyst
        • May cause early pregnancy loss, typically before the 6th week of gestation
      • Thyroid disease ^r8c30
        • Untreated overt hypothyroidism and subclinical hypothyroidism are associated with increased risk of miscarriage ^r1
        • Presence of thyroid autoantibodies (antithyroperoxidase) in pregnant patients—even in those who are euthyroid—may be associated with higher risk of miscarriage and recurrent pregnancy loss ^r6r9
        • Maternal hyperthyroidism may be associated with increased risk of early and late pregnancy loss ^r10
      • Hyperprolactinemia ^c31
        • Elevated circulating serum prolactin levels can alter function of the hypothalamic-pituitary-ovarian axis, resulting in luteal phase defects ^r11
      • Diabetes or insulin resistance ^c32c33
        • Poorly controlled diabetes is associated with increased risk of early pregnancy loss; there is a direct correlation between hemoglobin A1C and rate of miscarriage ^r1
          • Well-controlled diabetes is not a risk factor for recurrent pregnancy loss ^r2
        • Insulin resistance is common in patients with recurrent miscarriage and is associated with increased risk of pregnancy loss
    • Immunologic factors ^c34
      • Alloimmune disorders
        • Miscarriage, especially recurrent, may be associated with abnormalities in maternal alloimmune response
          • Maternal immune system normally recognizes paternally derived antigens on embryonic tissues and produces alloantibodies to protect trophoblast from cytotoxic maternal immune response
          • Possible mechanisms may involve alterations in natural killer cells, regulatory T cells, dendritic cells, plasma cells, and the human leukocyte antigen system ^r12
      • Autoimmune disorders
        • Antiphospholipid syndrome
          • Characterized by production of moderate to high levels of antiphospholipid antibodies and vascular thrombosis, which may lead to deleterious effects on developing trophoblast ^r1
          • Associated with recurrent pregnancy loss ^r2
            • 5% to 20% of patients with recurrent pregnancy loss have positive test results for antiphospholipid antibodies ^r13
            • 84% of patients with antiphospholipid antibodies had at least 1 fetal death compared with 24% of patients without antiphospholipid antibodies ^r13
          • Miscarriages related to antiphospholipid antibodies typically occur at greater than 10 weeks of gestation (fetal period) ^r13
        • Celiac disease (sprue) ^r1
          • Systemic autoimmune disease caused by allergy to gluten
            • Antigliadin antibodies of celiac disease appear to be toxic to trophoblasts and are associated with miscarriage
    • Inherited thrombophilias ^c35
      • May be associated with both early and late pregnancy loss (more common in second and third trimester); however, association remains controversial ^r1
        • May lead to thrombus formation in placental microvasculature, with potential for pregnancy loss and other adverse pregnancy outcomes (eg, placental abruption, fetal growth restriction)
      • Includes factor V Leiden, prothrombin G20210A mutation, and deficiencies in protein C, protein S, and antithrombin III
    • Infections ^c36
      • Numerous infectious pathogens have been identified in cultures of patients with sporadic miscarriages; relationship to recurrent pregnancy loss is less clear ^r6
        • Listeria monocytogenes: risk for second trimester miscarriage ^r1
        • Chlamydia trachomatis: primary infection associated with pregnancy loss but not recurrent loss; no evidence that it causes miscarriage in asymptomatic patients ^r1
        • Mycoplasma species (Ureaplasma urealyticum, Mycoplasma hominis): most common bacterial species found in cultures from patients with spontaneous miscarriage. There are no randomized placebo-controlled clinical trials to prove causal relationship and that treatment is effective ^r1
        • Toxoplasma gondii: may infect embryo and lead to pregnancy loss ^r1
        • Many viral agents may cause miscarriage if acquired as primary infection (associated with both first and second trimester loss) ^r1
          • Parvovirus B19: may be embryotoxic in first trimester; not cause of recurrent loss
          • Rubella, varicella, and cytomegalovirus: may cause miscarriage but not a cause of recurrent loss
          • HSV in genital tract: primary infection reported to cause miscarriage
            • No apparent association between HSV-2 infection in pregnancy and fetal death after 16 weeks of gestation
        • Bacterial vaginosis: risk factor for late miscarriage and preterm birth ^r1
    • Body weight ^c37
      • BMI of 25 kg/m² or higher increases risk of first trimester miscarriage and recurrence risk in patients with recurrent pregnancy loss ^r1r14r15
      • Being underweight increases risk of recurrent pregnancy loss ^r15
  • Anatomic factors ^c38
    • Loss at 18 to 20 weeks of gestation is typically caused by structural problems of uterus or cervix ^r1
      • Observed in about 12.6% of patients with recurrent pregnancy loss (4.3% of general population)
        • Increased rate of first and second trimester miscarriages ^r1
      • Uterine or cervical abnormalities may be congenital and/or acquired ^r16
        • Congenital
          • Abnormal uterine fusion
            • Septate uterus is most common; associated with poorest reproductive outcome ^r1
            • Other anomalies include unicornuate, bicornuate, didelphys, and arcuate uterus
        • Acquired
          • Submucous myomas
            • Leiomyomas (fibroids) are common benign uterine tumors present in approximately one-third of patients of reproductive age ^r1d1
            • Can distort uterine cavity, resulting in increased risk of miscarriage, especially submucosal fibroids
          • Intrauterine adhesions ^r1
            • Adhesions (scarring or synechiae) of the uterine cavity that can lead to partial or complete obliteration of the endometrium; often referred to as Asherman syndrome^r7
            • Can result in insufficient endometrium available to support fetal growth
            • Most frequently results from uterine curettage for pregnancy complications (eg, missed or incomplete abortion) or postpartum complications (eg, hemorrhage, retained placental remnants)
          • Uterine polyps (rare cause of miscarriage) ^r1
            • There appears to be an association between endometrial polyps and recurrent pregnancy loss, though evidence supporting polypectomy to reduce the risk of subsequent pregnancy loss is lacking ^r17
          • Chronic endometritis
            • Appears to be associated with recurrent pregnancy loss ^r18
        • Cervical incompetence (insufficiency; may be congenital or acquired^r1)
          • Painless dilation of internal cervical os that results in inability of the cervix to maintain pregnancy, leading to prolapse or rupture of fetal membranes and fetal expulsion
            • Typically occurs during second trimester rather than first
            • Acquired: most common; results from surgical trauma to cervix (eg, conization, loop electrosurgical excision procedures, mechanical dilation of cervix, obstetric lacerations)
            • Congenital: associated with uterine anomalies and congenital defects in cervical tissue
          • Rarely causes recurrent miscarriage; usually treated after first occurrence of loss
  • Environmental exposures ^c39
    • Smoking
      • Smoking increases risk of miscarriage in a dose-dependent manner; risk increases with level of smoking activity ^r1
        • Smoke contains agents (eg, nicotine, carbon monoxide, mutagens) that harm developing embryo; nicotine is a vasoconstrictor and may reduce blood flow to placenta
      • Paternal smoking also increases risk; when both parents smoke, rate of miscarriage may increase up to 4-fold ^r1
    • Alcohol
      • Alcohol consumption is a risk factor for miscarriage
      • Patients who consume alcohol at least 2 days per week have approximately 2-fold higher risk of miscarriage; those who consume more than 5 drinks per week (on average) have 3-fold higher risk of first trimester miscarriage ^r1
    • Cocaine use: associated with increased risk of miscarriage ^r6
    • Caffeine
      • Moderate to heavy caffeine ingestion may be independent risk factor for miscarriage ^r1
        • Modest increase in risk associated with more than 300 mg/day of caffeine (equivalent to 3 cups of coffee)
        • Preconception caffeine consumption is not associated with spontaneous miscarriage
    • Radiation and magnetic fields
      • Although high-energy radiation exposure is associated with teratogenic effects and intrauterine growth restriction, no conclusive evidence supports that similar exposure increases risk of miscarriage; presumably, a threshold effect extends from teratogenicity to miscarriage ^r1
        • Embryo is most sensitive to lethal effects of radiation during implantation and first few days after; sensitivity decreases during early embryogenesis and levels off by term gestation (extrapolated from animal models)
      • No increased risk of abortion with radiation exposures less than 0.05 Gy ^r1
        • Exposures from diagnostic procedures are several-fold less than 0.05 Gy and are unlikely to cause miscarriage, even if administered at time of implantation
      • Exposure to magnetic fields induced by electric currents has not been associated with significantly higher rate of miscarriage; video display terminals, electric blankets, and power lines are not harmful to pregnancy ^r1
    • Environmental toxins ^r1
      • Patients occupationally exposed to anesthetic gases may be at increased risk for spontaneous abortion
        • Current practice in hospitals and offices provides adequate scavenging of gases
      • Occupational exposure to chemotherapeutic agents (eg, nurses, pharmacy technicians) may have increased risk of miscarriage
      • Heavy metals, lead, cadmium, mercury, and arsenic are embryotoxic
        • Lead is most common exposure and is associated with miscarriage
      • Organic solvents (especially those used in computer industry) and organic pesticides may induce miscarriage
    • Exercise, stress, and depression
      • Interaction between stress, depression, and pregnancy is complex; relationship with pregnancy loss is equivocal ^r1
        • Severe stress may lead to higher incidence of adverse late pregnancy outcomes but has not been associated with early pregnancy loss; may affect uteroplacental function
        • Patients who receive counseling for depression associated with recurrent loss seem to have a higher successful pregnancy rate ^r1
      • Exercise, employment, and work have no apparent association with miscarriage ^r1
• Fetal causes
  • Chromosomal abnormalities ^c40
    • Major cause of early pregnancy loss ^r1
      • 50% to 60% of miscarriages are due to chromosomal abnormalities ^r1
        • Up to 85% of nonviable pregnancies (determined by ultrasonography) demonstrate aneuploidy on pathologic review
      • Loss at less than 10 weeks of gestation is usually caused by chromosomal abnormality ^r1
    • Fetal aneuploidy is the most common cause of miscarriage, with autosomal trisomies accounting for majority of cases (56% trisomic, 20% polyploid, 18% chromosome X monosomies, 4% unbalanced translocations^r1)
    • May be result of known parental abnormalities or de novo embryonic errors
    • Recurrent losses in patients younger than 36 years are usually caused by sources other than chromosomal abnormalities ^r1
      • Rate of chromosomal abnormalities in aborted fetuses of couples with recurrent pregnancy loss does not differ from matched cohorts in general population
  • Derangement of organ development (may have chromosomal component) ^r1
• Male factors ^c41
  • Advanced paternal age is associated with an increased risk of recurrent pregnancy loss ^r19
  • Paternal health, particularly metabolic syndrome, may contribute to pregnancy loss ^r19
  • Standard semen parameters (eg, sperm morphology) do not appear be predictive of recurrent pregnancy loss, but this remains debatable ^r2r6
  • Y-deletions have been studied, but no solid association with recurrent pregnancy loss has been found ^r6r19
  • Chromosomal abnormalities, including balanced translocations, may lead to spontaneous abortion of potential offspring ^r19
  • Sperm DNA fragmentation appears to be correlated with the occurrence of miscarriage based on multiple meta-analyses ^r19
• Septic abortion ^c42
  • Occurs in 1% to 2% of all miscarriages; incidence increased after induced abortions using nonsterile equipment ^r1
  • Most frequent cause is polymicrobial, involving Escherichia coli and other aerobic gram-negative rods; group B β-hemolytic streptococci, anaerobic streptococci, Bacteroides species, and Clostridium perfringens may also be implicated ^r1

Risk factors and/or associations

Primary diagnostic tools

• Miscarriage
  • Ultimately diagnosed through confirmation of nonviable gestation
  • Diagnose pregnancy loss by thorough history and physical examination combined with transvaginal ultrasonography and hCG values ^r3
    • Obtain β-hCG level ^c47
      • β-hCG level trending is usually required for accuracy
    • Obtain transvaginal ultrasonogram in pregnant patients with vaginal bleeding to determine health and location of fetus ^r22c48
      • If intrauterine gestation cannot be reliably identified, serial ultrasonographic examinations and β-hCG levels may be required before treatment to rule out possibility of ectopic pregnancy ^r3
    • Use caution when basing diagnosis on single level or ultrasonogram, as single point-in-time test results are often unreliable
  • Determine Rh type; order blood type and antibody screen (if not already tested and after 8 weeks of gestation) ^r4r23c49c50
    • Rh D genotyping is required when routine blood typing identifies D variants (weak or partial D), as Rho(D) immune globulin prophylaxis is not required for weak D types 1, 2, or 3 ^r23
  • Order hemoglobin level to provide baseline measurement and evaluate degree of blood loss with persistent bleeding ^r4
• Septic abortion
  • Suspect with symptoms of bleeding or spotting and clinical signs of infection during first 20 weeks of pregnancy
  • Perform CBC, urinalysis, blood chemistry, and electrolyte panel in all patients ^r1
    • Obtain blood cultures, chest radiograph, and panels for coagulation and disseminated intravascular coagulation in acutely ill patients
  • Acquire cervicouterine cultures; Gram stain may provide rapid preliminary analysis ^r1c51
• Recurrent pregnancy loss
  • Initiate diagnostic evaluation after 2 failed clinical pregnancies ^r1
    • Consider evaluation after only 1 second trimester loss as cause is more likely to recur
  • Evaluation typically involves investigation into genetic, endocrine, metabolic, anatomic, and immunologic causes ^r2
    • Patient history often elicits lines of investigation to initiate
    • Laboratory testing commonly includes measuring levels of TSH, thyroid autoantibodies, prolactin, hemoglobin A1C, and markers for antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG and IgM, and anti–β₂-glycoprotein I IgG and IgM) ^{r1r2r24r25c52c53c54c55c56}
    • Evaluate uterine cavity ^r1
      • Recommended to assess for uterine abnormalities, although role in first trimester loss is debatable ^r2
      • Additional imaging studies may include hysterosalpingogram, saline sonohysterogram, 3-dimensional ultrasonography, hysteroscopy, or MRI ^c57c58c59c60
    • Perform parental karyotype to determine if any balanced structural chromosomal abnormalities exist ^r1r2r24
      • Balanced reciprocal translocations and Robertsonian translocations are observed in 2% to 5% of couples with recurrent miscarriage ^r2
  • More controversial studies for the workup of an underlying cause can include: ^r1
    • Luteal phase progesterone ^r26
    • Sperm DNA for aneuploidy and fragmentation
    • HLA typing for alloimmune disorders
      • European guideline does not recommend ^r27
    • Endocervical cultures for infectious agents
  • Evaluating male partner ^r27
    • Assess lifestyle factors such as smoking, alcohol consumption, weight, exercise, age
    • Consider assessment of sperm DNA fragmentation
  • Evaluation of products of conception
    • Genetic testing of the products of conception with SNP (single nucleotide polymorphism) microarray may be offered ^r24
• Evaluation of specific conditions
  • Structural issues of cervix or uterus (eg, adenomyosis) ^r27
    • Preferred imaging options include MRI pelvis, 3-dimensional pelvic ultrasonography, and ultrasound sonohysterography ^r28
      • Sonohysterography is a sensitive, specific, and accurate screening tool for assessing abnormalities of uterine cavity; avoids radiation ^r1
      • MRI and 3-dimensional ultrasonography can better characterize congenital anomalies as they provide full view of uterus ^r6r28
      • The role of fluoroscopy hysterosalpingography is controversial but may be appropriate in some patients ^r28
    • Diagnostic hysteroscopy is the gold standard for uterine cavity evaluation but more invasive ^r6
    • Intrauterine adhesions may be noted on hysterosalpingogram or sonohysterography; diagnosis best confirmed by hysteroscopy ^r1
    • No absolute test for definitive diagnosis of cervical incompetence ^r1
      • History of second trimester pregnancy loss without contractions or labor and absence of other clear cause (eg, bleeding, infection, ruptured membranes) aids in diagnosis
      • Cervix may be noted to be unexpectedly dilated on midtrimester ultrasonography
      • Sonographic measurements of cervical length can help distinguish patients that may benefit from cervical cerclage ^r1
  • Medical conditions
    • Endocrine causes
      • Progesterone deficiency (luteal insufficiency)
        • Difficult to diagnose; measurement of serum progesterone level in luteal phase is unreliable owing to pulsatile nature of release, and endometrial biopsy is of limited value owing to significant inter- and intraobserver variability ^r1
        • Luteal phase deficiency has not been proven to be an independent cause of recurrent pregnancy loss ^r26
      • Thyroid disease can be initially screened with TSH levels ^r6r8
        • TSH measurement alone is sufficient for screening purposes or to exclude hypothyroidism
          • Obtain serum-free thyroxine with the initial draw if suspicion is strong or if initial TSH level is outside reference range
        • Testing for thyroid peroxidase antibodies may be warranted ^r9
      • Prolactin levels may be measured to detect hyperprolactinemia
      • Diabetes is diagnosed with laboratory assessment of blood glucose;^r7short-term glycemic status can be evaluated by testing hemoglobin A1C^r7d2
    • Immunologic factors
      • Alloimmune disorders: testing is not clinically indicated, as there is no current therapy
      • Antiphospholipid syndrome: diagnosis requires 1 of the following clinical and 1 of the following laboratory criteria to be met: ^r13
        • Clinical criteria for laboratory testing of antiphospholipid antibodies:
          • Vascular thrombosis (arterial, venous, or small vessel) in any tissue or organ, or
          • Pregnancy morbidity
            • 1 or more unexplained deaths of a morphologically normal fetus (documented by ultrasonography or direct fetal examination) at or beyond 10th week of gestation, or
            • 1 or more premature births of morphologically normal neonate before 34 weeks of gestation owing to eclampsia, severe preeclampsia, or features consistent with placental insufficiency, or
            • 3 or more unexplained consecutive spontaneous losses before 10th week of pregnancy, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded
        • Laboratory tests, obtained on 2 or more occasions, at least 12 weeks apart
          • Lupus anticoagulant (ideally performed before treatment with anticoagulants)
          • Anticardiolipin antibody of IgG and/or IgM isotype
          • Anti–β₂-glycoprotein IgG and/or IgM isotype
      • Celiac disease or gluten intolerance: test patients with personal or family history of celiac disease or gluten intolerance and miscarriage for antigliadin and antiendomysial antibodies ^r1
    • Inherited thrombophilias
      • Routine testing for inherited thrombophilias is not recommended in patients with recurrent pregnancy loss; no clear evidence of association and treatment (eg, heparin) benefit ^r1
      • May be useful in patients with personal history of venous thromboembolism in nonrisk setting or with first-degree relative with known or suspected high-risk thrombophilia ^r2
    • Infection
      • Routine testing for infectious agents in patients with recurrent pregnancy loss is not recommended owing to lack of prospective studies linking any agent with loss ^r1
        • Some clinicians test patients with recurrent pregnancy loss for common pathogens (eg, Mycoplasma, Ureaplasma, Chlamydia) owing to association with sporadic pregnancy losses and ease of diagnosis ^r7

Laboratory

• Miscarriage (for diagnosis)
  • β-hCG
    • Levels should rise predictably in normally developing pregnancy
      • Minimal increase of 24% in 24 hours and 53% in 48 hours ^r1
    • Peak around 100,000 international units at 10 weeks; steepest rate of increase seen within first 6 weeks, followed by slower rise and eventual fall after peak ^r1
  • Leukocytosis may be sign of septic abortion
• Recurrent pregnancy loss (for evaluation of underlying cause/contributing factor)
  • TSH
    • If TSH level is outside reference range (varies by laboratory), follow with assessment of peripheral thyroid hormone levels
    • Generally (as a simplification) elevated TSH levels may reflect primary hypothyroidism, whereas undetectable TSH levels may reflect hyperthyroidism
      • Repeat test to confirm result if levels are outside reference range ^r6
  • Thyroperoxidase antibodies ^r25
    • Elevated (positive) thyroperoxidase antibody status is associated with increased likelihood of developing hypothyroidism in gestation ^r29
    • Thyroperoxidase antibody positivity was associated with a reduced live birth rate in a large cohort of patients with recurrent pregnancy loss ^r9
  • Antiphospholipid antibodies
    • In addition to clinical features, diagnosis of antiphospholipid syndrome requires the following results confirmed on 2 or more occasions, at least 12 weeks apart: ^r13
      • Lupus anticoagulant present in plasma, or
      • Anticardiolipin antibody (IgG or IgM isotype) in serum or plasma present in medium or high titer (ie, greater than 40 GPL or MPL, or greater than 99th percentile), or
      • Anti–β₂-glycoprotein I antibody (IgG or IgM isotype) in serum or plasma in titer greater than 99th percentile
  • Hemoglobin A1C
    • Elevated levels (especially greater than 8%) are associated with increased risk of miscarriage ^r6
  • Prolactin
    • Elevated levels (hyperprolactinemia) are associated with increased risk of miscarriage ^r6
    • If elevated levels are found, pursue further testing to determine underlying cause

Imaging

• Transvaginal ultrasonography
  • Primary imaging modality in evaluating first trimester vaginal bleeding ^r30
  • Pregnancy evaluation
    • Gestational sac is first sonographic evidence of intrauterine pregnancy ^r30
      • Small, spherical fluid collection with hyperechoic rim located within endometrium ^r30
        • Gestational sacs only 2 to 3 mm in mean sac diameter, corresponding to 4.5 to 5 weeks of gestation, may be seen using high-frequency vaginal transducer ^r30
          • Pseudogestational sac (fluid in endometrial cavity) can usually be differentiated from gestational sac based on shape (acute angle at edge), contents (internal echoes), or location (in endometrial cavity) ^r30
        • Discriminatory level of hCG: level at which gestational sac should be visualized on transvaginal ultrasonography
          • β-hCG of 1500 international units (range, 1000-2000 milliunits/mL)^r4 traditionally accepted as level at which transvaginal ultrasonography should reveal intrauterine gestational sac; use of this data point is under discussion ^r1
            • These values may be too low to exclude a normal intrauterine pregnancy ^r30
            • American College of Radiology Appropriateness Criteria state that if there is no transvaginal ultrasonographic evidence of a gestational sac when single serum hCG level is 3000 milliunits/mL or higher, it is unlikely there will be a viable intrauterine pregnancy ^r30
    • Yolk sac is first sonographic feature confirming intrauterine pregnancy ^r30
      • Thin-walled, spherical structure with anechoic center usually seen within gestational sac greater than 8 mm in mean sac diameter; in some normal pregnancies, gestational sac may be larger before yolk sac visualized
    • Embryo first appears as thickened, linear echogenic structure at edge of yolk sac ^r30
      • Typically seen by 6 weeks of gestation and by the time gestational sac has reached 16 mm mean sac diameter, though it may be larger in some normal pregnancies before it can be visualized
      • Diagnose a nonviable intrauterine pregnancy if mean sac diameter is 25 mm or more and no embryo is visible with technically adequate transvaginal ultrasonography ^r30
        • Only a minority of nonviable pregnancies have diameter this large; criteria are set high to maximize diagnostic certainty and avoid inadvertent harm to viable embryo
    • Cardiac activity is normally evident in an embryo of any crown-rump length ^r30
      • Initial fetal heart rate should be in a range of 80 to 100 beats per minute; will often increase into 180 to 220 beats per minute for first few months, but should return to 110 to 160 beats per minute by 12 weeks ^r1
    • Findings suggestive of (but not diagnostic for) pregnancy loss generally require follow-up transvaginal ultrasonography in 7 to 10 days to assess pregnancy viability. These findings include: ^r31
      • No heartbeat in embryos with crown-rump length less than 7 mm
      • Mean sac diameter of 16 to 24 mm and no embryo
      • Absence of embryo with heartbeat 7 to 13 days after scan showing gestational sac without yolk sac
      • Absence of embryo with heartbeat 7 to 10 days after scan showing gestational sac with yolk sac
      • Absence of embryo 6 or more weeks after last menstrual period
      • Empty amnion (amnion seen adjacent to yolk sac, with no visible embryo)
      • Enlarged yolk sac (greater than 7 mm)
      • Small gestational sac relative to size of embryo (less than 5 mm difference between mean sac diameter and crown-rump length)
    • Criteria for diagnosis of pregnancy loss (by transvaginal ultrasonography) ^r30r31
      • Mean sac diameter of 25 mm or more with no embryo
      • Crown-rump length of 7 mm or more with no heartbeat
      • Absence of embryo with heartbeat 2 weeks or more after ultrasonography showing gestational sac without yolk sac
      • Absence of embryo with heartbeat 11 days or more after ultrasonography showing gestational sac with yolk sac but no embryo
  • Subchorionic hematoma
    • Fairly common finding during first trimester; usually small and not considered to substantially increase risk of nonviable pregnancy ^r30
      • Visualized as lucency behind brighter placental disk
    • Large subchorionic hematomas (two-thirds or more of gestational sac circumference) may be associated with increased risk of nonviable pregnancy ^r30
  • Cervical evaluation
    • Typical cervical length is approximately 3.5 cm or greater ^r1
      • Cervical shortening is a marker of preterm birth rather than cervical insufficiency; however, cerclage may be beneficial in patients with short cervix ^r1

Most common

• Ectopic pregnancy ^c61d3
  • Pregnancy occurring outside the uterine cavity, most commonly in the fallopian tube
  • Similar to threatened miscarriage in early pregnancy, can present with abdominal or pelvic pain, vaginal bleeding, and history of delayed or absent menses
    • Consider in any patient who has abdominal pain or vaginal bleeding and a positive pregnancy test result ^r4
    • Patients with hemodynamic instability or an acute abdomen are evaluated and treated urgently
  • Patient may have palpable adnexal mass or suggestive history (eg, ectopic pregnancy, tubal surgery, assisted reproductive techniques, pelvic inflammatory disease, endometriosis, intrauterine device use)
  • Diagnostic evaluation includes transvaginal ultrasonographic evaluation and hormonal confirmation of pregnancy (eg, serum hCG level) ^r32
    • Serial evaluation with transvaginal ultrasonography, serum hCG levels, or both, is often required to confirm diagnosis
  • Ectopic pregnancy in an unstable patient is a medical emergency and requires prompt surgical intervention
• Implantation bleeding
  • Small amount of bleeding may occur during implantation of blastocyst into endometrium and at the time of first missed menses
  • Bleeding from implantation is scant, is lighter colored without clots, and lasts only a few hours to a few days, whereas bleeding associated with an impending miscarriage typically turns heavy with a dark color and visible clots ^r33
  • If needed, serial serum hCG levels can be used to distinguish between the 2
    • If bleeding is simply due to implantation, β-hCG levels will continue to rise predictably as in a normally developing pregnancy, whereas levels will decline with miscarriage ^r1
• Hydatidiform mole (molar pregnancy) ^c62d4
  • Premalignant form of gestational trophoblastic disease occurring when a nonviable fertilized ovum implants in the uterus and develops into a placenta-derived tumor ^r34
  • Similar to threatened miscarriage; characterized by first trimester vaginal bleeding
  • Differences can include uterine enlargement and level of hCG greater than expected for gestational age
  • Diagnosis is suspected on basis of initial total serum hCG levels greater than 80,000 milliunits/mL and characteristic ultrasonographic appearance; histopathologic evaluation is required for definitive diagnosis
• Cervical polyps ^c63
  • May cause vaginal spotting or bleeding, especially postcoital, owing to increased estrogen levels and cervical vascularization during pregnancy
  • Can be identified on visual examination of cervix/endocervix
• Subchorionic hemorrhage ^c64
  • Collection of blood between chorion and uterine wall formed from bleeding at advancing margin of expanding placenta
  • Can cause first trimester vaginal bleeding
    • Small subchorionic hemorrhages are usually asymptomatic
  • Identified by ultrasonography

Admission criteria

• Patients with significant hemorrhage, hemodynamic instability, or signs of infection

Recommendations for specialist referral

• Refer to obstetrician/gynecologist for evaluation and management
• Refer patients with chromosomal abnormalities to genetic counselor
• Consider referral to endocrinologist for assistance with managing thyroid disease in pregnancy

Drug therapy

• Synthetic prostaglandin E1 analog
  • Misoprostol
    • Misoprostol monotherapy ^c65
      • Misoprostol Oral tablet; Adolescents: 800 mcg intravaginally on day 1. A second misoprostol dose may be given at least 3 hours after the first dose and within 1 to 7 days later if needed for incomplete expulsion.
      • Misoprostol Oral tablet; Adults: 800 mcg intravaginally on day 1. A second misoprostol dose may be given at least 3 hours after the first dose and within 1 to 7 days later if needed for incomplete expulsion.
    • Misoprostol in combination with mifepristone regimen
      • Misoprostol Oral tablet; Adolescents: 800 mcg intravaginally as a single dose 24 to 36 hours after an initial oral mifepristone dose. A second misoprostol dose may be given at least 3 hours after the first dose and within 1 to 7 days later if needed for incomplete expulsion.
      • Misoprostol Oral tablet; Adults: 800 mcg intravaginally as a single dose 24 to 36 hours after an initial oral mifepristone dose. A second misoprostol dose may be given at least 3 hours after the first dose and within 1 to 7 days later if needed for incomplete expulsion.
• Synthetic steroid
  • Mifepristone
    • Mifepristone in combination with misoprostol regimen ^r52c66
      • Mifepristone Oral tablet [Pregnancy Termination]; Adolescents: 200 mg PO as a single dose, followed by intravaginal misoprostol 24 to 36 hours later.
      • Mifepristone Oral tablet [Pregnancy Termination]; Adults: 200 mg PO as a single dose, followed by intravaginal misoprostol 24 to 36 hours later.
• Rho(D) immune globulin ^c67
  • For loss of pregnancy during first trimester (12 weeks of gestation or less) ^r4
    • Rho(D) Immune Globulin (Human) Solution for injection; Adolescents: 50 mcg (250 International Units) IM within 3 hours or as soon as possible after spontaneous or induced abortion and within 72 hours after pregnancy termination.
    • Rho(D) Immune Globulin (Human) Solution for injection; Adults: 50 mcg (250 International Units) IM within 3 hours or as soon as possible after spontaneous or induced abortion and within 72 hours after pregnancy termination.
  • For loss of pregnancy after first trimester ^r4
    • Rho(D) Immune Globulin (Human) Solution for injection; Adolescents: 300 mcg (1,500 International Units) IM as soon as possible and within 72 hours after pregnancy termination.
    • Rho(D) Immune Globulin (Human) Solution for injection; Adults: 300 mcg (1,500 International Units) IM as soon as possible and within 72 hours after pregnancy termination.

Nondrug and supportive care

Follow-up care after early pregnancy loss

• Essential part of care for patients with miscarriage
• Discuss and implement plans for future pregnancy
  • Delaying conception after early pregnancy loss has no significant evidence for decreasing risk of subsequent miscarriage ^r1r3
  • If contraception is desired and appropriate, hormone-based contraception may be initiated immediately after completion of early miscarriage ^r3
• Advise adoption of lifestyle modifications ^c68
  • Encourage patients to stop smoking and refrain from drinking alcohol during pregnancy
  • Recommend limiting caffeine intake to patients who become pregnant ^r1
  • Avoid contact with environmental toxicants (eg, anesthetic gases and chemotherapeutic agents for hospital personnel, organic solvents, organic pesticides, heavy metals, lead, cadmium, mercury, arsenic)
    • For patients with elevated lead levels, treat with chelation therapy before pregnancy; can be used during pregnancy as well ^r1
  • Recommend weight reduction in obese patients
  • Encourage counseling for depression associated with recurrent loss
• Emotional/psychological care
  • Ask patient open-ended questions about experience and thoughts to assess mood and status ^r1
    • Anger or difficulty with health care system during time of miscarriage: managing these frustrations can improve future interactions and may decrease risk of depression after loss
    • Guilt: many patients feel the loss was something they caused by some action they performed; reassure that exercise, intercourse, and dietary indiscretions do not cause miscarriage ^r7
    • Grieving and depression: grieving may cause physical symptoms of depression (eg, fatigue, anorexia, sleeplessness, headache, back pain); depression can affect up to 30% of patients after miscarriage ^r1
      • Advise patients to return if symptoms occur
      • Depression may be treated with counseling and antidepressant therapy

For couples with recurrent pregnancy loss, explanation and appropriate emotional support are important aspects of treatment ^c69

• Consider testing for cause after 2 or more miscarriages;^r1unexplained reproductive failure can lead to anger, guilt, and depression^r7
• Antenatal counseling and psychological support are shown to increase success rates for couples with recurrent pregnancy loss ^r7