Miscarriage and Recurrent Pregnancy Loss

History

• Miscarriage
  • Symptoms include:
    • Vaginal bleeding ^c1
      • About 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 about 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 ^r2c19c20
    • 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 about 50% of cases ^r1r3
• 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 ^r3
        • 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 ^r3
            • 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 about 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
        • 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 about 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, 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
  • Standard semen parameters (eg, sperm morphology) do not appear be predictive of recurrent pregnancy loss, but this remains debatable ^r3r6
  • Sperm aneuploidy and DNA fragmentation have been studied, but no solid association with recurrent pregnancy loss has been found ^r6
• 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 ^r2
    • 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 ^r19c48
      • 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 ^r2
    • 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) ^r4r20c49c50
  • 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 ^r3
    • Patient history often elicits lines of investigation to initiate
    • Laboratory testing commonly includes measuring levels of TSH, thyroid autoantibodies, prolactin, hemoglobin A1C, and antiphospholipid antibodies ^{r1r3r21c52c53c54c55c56}
    • Evaluate uterine cavity ^r1
      • Recommended to assess for uterine abnormalities, although role in first trimester loss is debatable ^r3
      • 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 ^r1r3
      • Balanced reciprocal translocations and Robertsonian translocations are observed in 2% to 5% of couples with recurrent miscarriage ^r3
  • More controversial studies for the workup of an underlying cause can include: ^r1
    • Luteal phase progesterone
    • Sperm DNA for aneuploidy and fragmentation
    • HLA typing for alloimmune disorders
    • Endocervical cultures for infectious agents
• Evaluation of specific conditions
  • Structural issues of cervix or uterus
    • Preferred imaging options include MRI pelvis, 3-dimensional pelvic ultrasonography, and ultrasound sonohysterography ^r22
      • 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 ^r6r22
      • The role of fluoroscopy hysterosalpingography is controversial but may be appropriate in some patients ^r22
    • 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 ^r23
      • 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 ultrasonogram 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
        • Laboratory tests, obtained on 2 or more occasions, at least 12 weeks apart
          • Lupus anticoagulant (ideally performed before treatment with anticoagulants)
          • Anticardiolipin antibody of immunoglobulin G and/or immunoglobulin M isotype
          • Anti–β₂-glycoprotein I of immunoglobulin G and/or immunoglobulin M 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 ^r3
    • 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 ^r21
    • Elevated (positive) thyroperoxidase antibody status is associated with increased likelihood of developing hypothyroidism in gestation ^r24
    • 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 ^r25
  • Pregnancy evaluation
    • Gestational sac is first sonographic evidence of intrauterine pregnancy ^r25
      • Small, spherical fluid collection with hyperechoic rim located within endometrium ^r25
        • 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 ^r25
          • 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) ^r25
        • 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 ^r25
            • 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 ^r25
    • Yolk sac is first sonographic feature confirming intrauterine pregnancy ^r25
      • 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 ^r25
      • Typically seen by 6 weeks of gestational 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 ^r25
        • 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 ^r25
      • 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: ^r26
      • 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 ultrasonogram) ^r25r26
      • 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 ultrasonogram showing gestational sac without yolk sac
      • Absence of embryo with heartbeat 11 days or more after ultrasonogram 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 ^r25
      • 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 ^r25
  • Cervical evaluation
    • Typical cervical length is about 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) ^r27
    • 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 ^r28
  • If needed, serial serum hCG levels can be used to distinguish between the two
    • 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 ^r29
  • 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

• Misoprostol ^c65
  • Administered either orally or vaginally ^r1
    • Vaginal route preferred to maintain steady serum levels and to avoid gastrointestinal adverse effects.
    • Misoprostol Oral tablet; Adult females: As an alternative to traditional management, such as surgical or expectant management, misoprostol has shown efficacy and safety in women <= 13 weeks gestation with indicators of pregnancy failure. 800 mcg intravaginally (placed into the posterior vaginal fornix) on day 1, followed by a repeat dose on day 3 if expulsion incomplete. Follow by vacuum aspiration on day 8 if expulsion still incomplete.
• Mifepristone ^r39c66
  • Mifepristone Oral tablet [Pregnancy Termination]; Adult and Adolescent pregnant females through 70 days (10 weeks) gestation: On day 1, administer one 200 mg mifepristone tablet PO as a single dose. Between 24 to 48 hours later, administer misoprostol 800 mcg buccally; the patient should place two 200 mcg misoprostol tablets in each cheek pouch for 30 minutes and then swallow any remnants with water or another liquid. Expulsion typically occurs within 2 to 24 hours. Patients should be given emergency healthcare contact numbers and a follow-up visit should occur approximately 7 to 14 days after mifepristone administration. If complete expulsion has not occurred, but the pregnancy is not ongoing, may give additional misoprostol 800 mcg buccally, then another visit approximately 7 days later.
• Rho(D) immunoglobulin ^c67
  • For loss of pregnancy during first trimester (12 weeks of gestation or less) ^r4
    • Rho(D) Immune Globulin (Human) Solution for injection; Adult and adolescent females: 50 mcg (250 International Units) IM as soon as possible. Give within 3 hours of spontaneous or surgical removal of aborted tissues, if possible, and within 72 hours of exposure.
  • For loss of pregnancy after first trimester ^r4
    • Rho(D) Immune Globulin (Human) Solution for injection; Adult and adolescent females: 300 mcg (1,500 International Units) IM as soon as possible and within 72 hours of the event.
• Progesterone ^c68
  • Consider in patients who have had 3 or more consecutive miscarriages. ^r1
  • Available as vaginal suppository (50-100 mg twice daily^r7) to begin 3 days after ovulation and continued throughout first trimester. ^r1
    • Vaginal suppository
      • Progesterone Vaginal insert; Adult females: 100 mg PV 2 to 3 times per day starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. In women 35 years and older, the appropriate dosage for efficacy has not been definitively determined.
• Unfractionated heparin ^c69
  • For prophylaxis in antiphospholipid syndrome; initiated with positive pregnancy test result.
    • Heparin Sodium (Porcine) Solution for injection; Adult females: Usually 5000 to 10,000 units by subcutaneous injection every 12 hours given along with aspirin 81 mg PO daily. ^r1
• Bromocriptine ^c70
  • For normalization of prolactin levels before pregnancy in patients with history of 2 or more pregnancy losses. ^r6
  • Bromocriptine Mesylate Oral tablet; Adults and Adolescents 16 years and older: Initially, 1.25 mg to 2.5 mg PO daily with food, with titration of 2.5 mg/day PO at 2 to 7 day intervals as needed until the desired therapeutic response occurs; individualize. In amenorrheic or infertile patients without demonstrably elevated serum prolactin levels, the usual dose is 2.5 mg PO twice daily (with food). Usual dosage range: 2.5 mg to 15 mg/day PO, in divided doses. Max: 30 mg/day PO, in divided doses, may be necessary for some patients.

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 ^r1r2
  • If contraception is desired and appropriate, hormone-based contraception may be initiated immediately after completion of early miscarriage ^r2
• Advise adoption of lifestyle modifications ^c71
  • 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 toxins (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 ^c72

• 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