Recurrent Pregnancy Loss

What is Recurrent Pregnancy Loss

Recurrent pregnancy loss is the loss of two or more pregnancies before 20 weeks of pregnancy (gestation).

11 Interesting Facts of Recurrent Pregnancy Loss

1. Recurrent Pregnancy Loss describes the involuntary loss of a pregnancy before 20 weeks of gestation or loss of fetus weighing 500 g or less; affects about 10% to 25% of all clinically recognized pregnancies 
   • Most are sporadic and caused by fetal chromosomal abnormalities (eg, trisomy, monosomy, polyploidy) 
   • Most common risk factors are advanced maternal age and prior early pregnancy loss 
2. Symptoms of miscarriage typically include vaginal bleeding and uterine cramping
3. Diagnose pregnancy loss by thorough history and physical examination combined with transvaginal ultrasonography and hCG values 
   • Basing diagnosis on single hCG level or ultrasonogram is often unreliable; trending of β-hCG values and examination findings are usually required for accuracy
4. Administer Rho(D) immunoglobulin to women who are Rh-negative 
5. No medical interventions exist to improve prognosis of threatened miscarriage
   • Patient may be discharged with patient education if stable; follow-up arrangements for ultrasonography and serial hCG levels are made in conjunction with obstetrician 
6. Treatment options for miscarriage (nonviable fetus) include expectant management, medical treatment, and surgical evacuation of uterus
7. About two-thirds of women with bleeding will have live fetus on ultrasonographic examination; nearly 85% of these women go on to deliver live-born infant 
8. Recurrent pregnancy loss is defined as 2 or more failed clinical pregnancies 
   • Common causes include embryonic chromosomal abnormalities, maternal anatomic abnormalities (eg, septate uterus), luteal phase defects, and antiphospholipid antibodies 
9. Diagnostic evaluation for recurrent pregnancy loss can be initiated after 2 failed clinical pregnancies (1 early miscarriage is relatively common) 
   • Investigation includes work-up for genetic, endocrine, anatomic, immunologic, and iatrogenic causes
10. Treatment of recurrent miscarriage is based on cause, if identified 
    • Up to 50% of cases will have no clearly defined cause 
11. Most women with recurrent pregnancy loss will have ultimately have successful pregnancy, even without intervention 

What are the causes of Recurrent Pregnancy Loss?

The most common cause of recurrent pregnancy loss is an abnormal number of chromosomes in the developing baby (fetus). Chromosomes are the structures inside a cell that hold all the genetic material.

Chromosome abnormalities can be inherited, but most of them occur by chance. In most cases of recurrent pregnancy loss, a missing or extra chromosome keeps the baby from developing. It may not be possible to identify which chromosome is defective.

Other possible causes of recurrent pregnancy loss include:

• Being born with an abnormal womb structure (septate uterus).
• Having noncancerous growths in your uterus (fibroids or polyps).
• Having a disease that causes scarring in your uterus (Asherman syndrome).
• Having a disease that causes your blood to clot (antiphospholipid syndrome).
• Having a disease that increases bleeding (thrombophilia).

What increases the risk?

The following factors may make you more likely to develop this condition:

• Being over the age of 35.
• Having diabetes.
• Having thyroid disease.
• Being Obese.
• Being a smoker.
• Using recreational drugs.
• Using too much alcohol or caffeine.

What are the symptoms of Recurrent Pregnancy Loss?

Symptoms of this condition include:

• Bleeding from the vagina.
• Passing clots and fetal tissue from the vagina.

How is this diagnosed?

Recurrent Pregnancy Loss is diagnosed with:

• A physical exam. This will include a pelvic exam to check the vagina and uterus for possible causes of pregnancy loss.
• An ultrasound. This is done:
  • To confirm the pregnancy loss.
  • To see if the structure of the uterus is normal.
  • To check for polyps or fibroids.

Sometimes other tests are done, such as:

• Blood tests to see if you have a condition that causes recurrent pregnancy loss.
• Blood tests to see if your blood clots normally.
• Genetic tests of you and your partner.

How is Recurrent Pregnancy Loss treated?

Treatment for Recurrent Pregnancy Loss depends on the cause of the pregnancy loss. Possible treatments include:

• Having your eggs fertilized outside your uterus (in vitro fertilization). By doing this, a health care provider may be able to select eggs without chromosome abnormalities.
• Taking a blood thinner to prevent clotting. This may be done if you have antiphospholipid syndrome.
• Having surgery to correct the abnormality in your uterus.
• Taking medicines to treat underlying causes of pregnancy loss.

Follow these instructions at home:

Lifestyle

• Do not use any products that contain nicotine or tobacco, such as cigarettes and e-cigarettes. If you need help quitting, ask your health care provider.
• Do not use drugs.
• Eat a balanced diet rich in fresh fruit and vegetables, whole grains, low-fat dairy, and lean meats.
• Manage any chronic health conditions, such as diabetes or thyroid disease.
• Get 30 minutes of moderate daily exercise.
• If you are overweight, ask your health care provider for support and resources to lose weight.
• Find ways to manage stress. These include journaling, yoga, or deep breathing. They also include spending time in nature and practicing meditation.

General instructions

• Take over-the-counter and prescription medicines only as told by your health care provider.
• Get support from friends and loved ones. Unexpected pregnancy loss can be a sad and stressful event.
• Consider meeting with a counselor, spiritual leader, or a pregnancy loss support group.
• Ask your health care provider about taking a folic acid supplement.
• Meet with a genetic counselor as part of genetic testing to understand the results of any testing.
• Keep all follow-up visits as told by your health care provider. This is important.

Contact a health care provider if:

• You have been trying to get pregnant without success.
• You are struggling with sadness or depression.

Get help right away if:

• You have feelings of sadness that take over your thoughts.
• You have thoughts of hurting yourself.

Additional Info

Miscarriage describes the involuntary loss of a pregnancy before 20 weeks of gestation or loss of fetus weighing 500 g or less 

Other terms for miscarriage include spontaneous abortion and early pregnancy loss

Commonly occurring event, affecting about 10% to 25% of all clinically recognized pregnancies 

Approximately 80% of losses occur within first trimester, often due to fetal chromosomal abnormalities (about 50%) 

Recurrent pregnancy loss is defined as 2 or more failed clinical pregnancies 

Less than about 5% of women will have 2 consecutive miscarriages, and only 1% of women will experience 3 or more 

Classification

• Early pregnancy loss: within first 12 6/7 weeks of gestation 
  • Denotes nonviable intrauterine pregnancy (gestational sac is empty or contains fetus with no cardiac activity)
• Preterm or stillbirth: pregnancy loss after 20 weeks of gestation 
  • Point of viability fluctuates
• Recurrent pregnancy loss: traditionally defined as 3 or more consecutive spontaneous losses, but more recently defined as 2 or more failed clinical pregnancies 
  • Clinical pregnancy is documented by ultrasonography or histopathologic examination 
  • Recurrent loss can be further stratified as primary, secondary, or tertiary 
    • Primary: patient has never had a viable infant
    • Secondary: patient previously delivered pregnancy beyond 20 weeks of gestation, with subsequent losses
    • Tertiary: multiple miscarriages interspersed with viable pregnancies
  • Most losses in women with recurrent pregnancy loss occur before 10 weeks of gestation 
• Terms to describe type of abortion by appearance of patient upon presentation (less useful today owing to widespread use of transvaginal ultrasonography in diagnosis of early pregnancy) 
  • Threatened abortion: vaginal bleeding in setting of viable intrauterine pregnancy and closed cervical os
  • Inevitable abortion: open cervical os with no passage of products of conception in setting of either a viable or nonviable intrauterine pregnancy
  • Incomplete abortion: intrauterine gestation at less than 20 weeks of gestation with open cervical os and partial passage of products of conception
  • Complete spontaneous abortion: closed cervical os and contracted uterus after passage of all products of conception in setting of intrauterine pregnancy
  • Missed abortion: nonviable intrauterine pregnancy with gestation less than 20 weeks and closed cervical os
    • Largely outdated term owing to early, widespread use of transvaginal ultrasonography; delayed diagnosis of fetal demise or anembryonic gestation are rare today
  • Septic abortion: any abortion with infection

Clinical Presentation of Recurrent Pregnancy Loss

• Miscarriage
  • Symptoms include:
    • Vaginal bleeding
      • About 25% of clinically pregnant women experience some vaginal bleeding; up to one-half of women who have bleeding during early pregnancy will miscarry 
      • May be spotting or heavy
    • Uterine cramping
  • Patient history should include: 
    • Estimated length of gestation
    • Time since last menstrual period
    • Symptoms of pregnancy (including evolution or loss of)
    • Degree and duration of bleeding
    • Attempts by patient to induce miscarriage
• For women with recurrent pregnancy loss, include pertinent historical questions regarding: 
  • Previous pregnancies
  • 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

• Recurrent Pregnancy Loss
  • Abdominal examination
    • Uterus should not be palpable
    • Tenderness or peritoneal irritation may result from ectopic pregnancy or septic abortion
  • Pelvic examination can reveal: 
    • Open or closed os
      • Typically determined visually through speculum examination 
        • 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 women normally have open or lax external os (insignificant finding)
    • Clots or products of conception
      • If present, gentle removal of fetal tissue from cervical os with ring forceps may slow bleeding 
        • If products not removed easily with ring forceps, consult gynecologist since 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
    • Tender lower abdomen
    • Cervical motion tenderness
    • Purulent vaginal discharge

Causes

• Cause of Recurrent Pregnancy Loss is often multifactorial, particularly in recurrent losses
  • Most common risk factors for early pregnancy loss are advanced maternal age and prior early pregnancy loss 
    • Majority of sporadic losses before 10 weeks of gestation are due to random numeric chromosome errors (eg, trisomy, monosomy, polyploidy)
  • 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 
    • Cause for recurrent losses determined in about 50% of cases 
• Maternal causes
  • Medical conditions
    • Endocrine causes
      • Progesterone deficiency 
        • 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
        • Untreated overt hypothyroidism and subclinical hypothyroidism are associated with increased risk of miscarriage 
        • Presence of thyroid autoantibodies (antithyroperoxidase) in pregnant women—even in those who are euthyroid—may be associated with higher risk of miscarriage and recurrent pregnancy loss 
        • Maternal hyperthyroidism may be associated with increased risk of early and late pregnancy loss 
      • Hyperprolactinemia
        • Elevated circulating serum prolactin levels can alter function of the hypothalamic-pituitary-ovarian axis, resulting in luteal phase defects 
      • Diabetes or insulin resistance
        • Poorly controlled diabetes is associated with increased risk of early pregnancy loss; there is a direct correlation between hemoglobin A1C and rate of miscarriage 
          • Well-controlled diabetes is not a risk factor for recurrent pregnancy loss 
        • Insulin resistance is common in women with recurrent miscarriage and is associated with increased risk of pregnancy loss
    • Immunologic factors
      • 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
      • 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 
          • Associated with recurrent pregnancy loss 
            • 5% to 20% of women with recurrent pregnancy loss have positive test results for antiphospholipid antibodies 
            • 84% of women with antiphospholipid antibodies had at least 1 fetal death compared to 24% of women without antiphospholipid antibodies 
          • Miscarriages related to antiphospholipid antibodies typically occur at greater than 10 weeks of gestation (fetal period) 
        • Celiac disease (sprue) 
          • 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
      • May be associated with both early and late pregnancy loss (more common in second and third trimester); however, association remains controversial 
        • 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
      • Numerous infectious pathogens have been identified in cultures of women with sporadic miscarriages; relationship to recurrent pregnancy loss is less clear 
        • Listeria monocytogenes: risk for second trimester miscarriage 
        • Chlamydia trachomatis: primary infection associated with pregnancy loss, but not recurrent loss; no evidence that it causes miscarriage in asymptomatic women 
        • Mycoplasma species (Ureaplasma urealyticum, Mycoplasma hominis): most common bacterial species found in cultures from women with spontaneous miscarriage. There are no randomized placebo-controlled clinical trials to prove causal relationship and that treatment is effective 
        • Toxoplasma gondii: may infect embryo and lead to pregnancy loss 
        • Many viral agents may cause miscarriage if acquired as primary infection (associated with both first and second trimester loss) 
          • 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 
    • Obesity
      • BMI of 30 kg/m² or higher increases risk of first trimester miscarriage and recurrence risk in women with recurrent pregnancy loss 
  • Anatomic factors
    • Loss at 18 to 20 weeks of gestation is typically caused by structural problems of uterus or cervix 
      • Observed in about 12.6% of women with recurrent pregnancy loss (4.3% of general population)
        • Increased rate of first and second trimester miscarriages 
      • Uterine or cervical abnormalities may be congenital and/or acquired
        • Congenital
          • Abnormal uterine fusion
            • Septate uterus is most common; associated with poorest reproductive outcome 
            • Other anomalies include unicornuate, bicornuate, didelphys, and arcuate
        • Acquired
          • Submucous myomas
            • Leiomyomas (fibroids) are common benign uterine tumors present in about one-third of women of reproductive age (Related: Fibroids (uterine myomas))
            • Can distort uterine cavity, resulting in increased risk of miscarriage, especially submucosal fibroids
          • Intrauterine adhesions 
            • 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 
            • 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) 
        • Cervical incompetence (insufficiency; may be congenital or acquired)
          • 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
    • Smoking
      • Smoking increases risk of miscarriage in a dose-dependent manner; risk increases with level of smoking activity 
        • 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 are smokers, rate of miscarriage may increase up to 4-fold 
    • Alcohol
      • Alcohol consumption is a risk factor for miscarriage
      • Women 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 
    • Cocaine use: associated with increased risk of miscarriage 
    • Caffeine
      • Moderate to heavy caffeine ingestion may be independent risk factor for miscarriage 
        • 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
      • While high-energy radiation exposure is associated with teratogenic effects and intrauterine growth restriction, no conclusive evidence demonstrates that similar exposure increases risk of miscarriage; presumably, a threshold effect extends from teratogenicity to miscarriage 
        • 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 
        • 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 
    • Environmental toxins 
      • Women 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 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 
        • 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
        • Women who receive counseling for depression associated with recurrent loss seem to have a higher successful pregnancy rate 
      • Exercise, employment, and work have no apparent association with miscarriage 
• Fetal causes
  • Chromosomal abnormalities
    • Major cause of early pregnancy loss 
      • 50% to 60% of miscarriages are due to chromosomal abnormalities 
        • 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 
    • 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, and 4% unbalanced translocations)
    • May be result of known parental abnormalities or de novo embryonic errors
    • Recurrent losses in women younger than 36 years are usually caused by sources other than chromosomal abnormalities 
      • 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) 
• Male factors
  • Standard semen parameters (eg, sperm morphology) do not appear be predictive of recurrent pregnancy loss, but this remains debatable 
  • Sperm aneuploidy and DNA fragmentation have been studied, but no solid association with recurrent pregnancy loss has been found 
• Septic abortion
  • Occurs in 1% to 2% of all miscarriages; incidence increased after induced abortions using nonsterile equipment 
  • 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 

Risk factors of Recurrent Pregnancy Loss

Age

• More common in women younger than 18 years and older than 35 years 
• Frequency of clinically recognized miscarriage by patient age: 
  • 20 to 34 years: 9% to 17%
  • 35 to 40 years: 20%
  • Older than 40 years: 40%
  • 45 years and older: near 80%
• Older paternal age
  • Increasing paternal age is associated with increasing rate of spontaneous abortion 
    • May only result in a slight increase in the chance of spontaneous abortion for a specific couple
    • Independent of maternal age and other factors

Genetics

• Miscarriage and aneuploidy
  • Most sporadic pregnancy losses result from random numeric chromosomal errors (eg, trisomy, monosomy, polyploidy)
    • Risk of aneuploidy increases with maternal age
• Recurrent pregnancy loss
  • Parental chromosomal disorders (eg, translocations, inversions, rare ring chromosomes) 
    • Occur in 3% to 5% of couples with recurrent pregnancy loss (0.7% of general population)
    • Balanced translocations are most common contributing chromosomal disorder in recurrent losses

Other risk factors/associations

• Risk factors
  • Previous pregnancy losses
    • Risk of miscarriage with 2 prior losses and no live births is 25%; rises to nearly 45% with 3 previous consecutive losses 
      • With at least 1 live birth and 3 spontaneous abortions, chance that next pregnancy will result in miscarriage is about 30%
  • Increased parity 
• Associations
  • Nearly 80% of all clinical miscarriages occur within first trimester 
    • Majority of losses before 10 weeks of gestation are due to chromosomal abnormalities 
    • Incidence decreases with advancing gestational age; loss rate remains stable through 12 weeks of gestation and decreases over following weeks
    • First trimester bleeding (with confirmed fetal cardiac activity) confers 15% risk of miscarriage 
  • Maternal or environmental factors are more likely causes of recurrent pregnancy loss than chromosomal abnormalities 
    • Distribution of chromosomal abnormalities seen in couples with recurrent miscarriage is same as general population 
    • Women with recurrent miscarriage tend to abort later in gestation

• Miscarriage
  • Ultimately diagnosed through confirmation of nonviable gestation
  • Diagnose pregnancy loss by thorough history and physical examination combined with transvaginal ultrasonography and hCG values 
    • Obtain β-hCG level
      • β-hCG level trending is usually required for accuracy
    • Obtain transvaginal ultrasonogram in pregnant women with vaginal bleeding to determine health and location of fetus 
      • 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 
    • Use caution basing diagnosis on single level or ultrasonogram, as single point-in-time test result is often unreliable
  • Determine Rh type; order blood type and antibody screen (if not already tested) 
  • Order hemoglobin level to provide baseline measurement and evaluate degree of blood loss with persistent bleeding 
• 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 
    • Obtain blood cultures, chest radiograph, and panels for coagulation and disseminated intravascular coagulation in acutely ill women
  • Acquire cervicouterine cultures; Gram stain may provide rapid preliminary analysis 
• Recurrent pregnancy loss
  • Initiate diagnostic evaluation after 2 failed clinical pregnancies 
    • 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 
    • 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 
    • Evaluate uterine cavity 
      • Recommended to assess for uterine abnormalities, although role in first trimester loss is debatable 
      • Additional imaging studies may include hysterosalpingogram, saline sonohysterogram, 3-dimensional ultrasonography, hysteroscopy, or MRI
    • Perform parental karyotype to determine if any balanced structural chromosomal abnormalities exist 
      • Balanced reciprocal translocations and Robertsonian translocations are observed in 2% to 5% of couples with recurrent miscarriage 
  • More controversial studies for the work up of an underlying cause can include: 
    • 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
    • Imaging options include hysterosalpingogram, sonohysterography, 3-dimensional transvaginal ultrasonography, MRI, and hysteroscopy 
      • Diagnostic hysteroscopy is the gold standard for uterine cavity evaluation but more invasive than hysterosalpingogram or sonohysterography 
        • Sonohysterography is a sensitive, specific, and accurate screening tool for assessing abnormalities of uterine cavity; avoids radiation 
      • MRI and 3-dimensional ultrasonography can better characterize congenital anomalies as they provide full view of uterus 
    • Intrauterine adhesions may be noted on hysterosalpingogram or sonohysterography; diagnosis best confirmed by hysteroscopy 
    • No absolute test for definitive diagnosis of cervical incompetence 
      • 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 
  • 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 because of significant inter- and intraobserver variability 
      • Thyroid disease can be initially screened with TSH levels 
        • 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
      • Prolactin levels may be measured to detect hyperprolactinemia
      •  (Related: Gestational diabetes)Diabetes is diagnosed with laboratory assessment of glycemia; short-term glycemic status can be evaluated by testing hemoglobin A1C
    • 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: 
        • 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 because of 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 women with personal or family history of celiac disease or gluten intolerance and miscarriage for antigliadin and antiendomysial antibodies 
    • Inherited thrombophilias
      • Routine testing for inherited thrombophilias is not recommended in women with recurrent pregnancy loss; no clear evidence of association and treatment (eg, heparin) benefit 
      • 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 
    • Infection
      • Routine testing for infectious agents in women with recurrent pregnancy loss is not recommended owing to lack of prospective studies linking any agent with loss 
        • Some clinicians test women with recurrent pregnancy loss for common pathogens (eg, Mycoplasma, Ureaplasma, Chlamydia) owing to association with sporadic pregnancy losses and ease of diagnosis 

How is Recurrent Pregnancy Loss diagnosed

• 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 
    • 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 
  • 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 
  • Thyroperoxidase antibodies (TPOAb) 
    • Elevated (positive) thyroperoxidase antibody status is associated with increased likelihood to develop hypothyroidism in gestation 
  • 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: 
      • 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 
  • Prolactin
    • Elevated levels (hyperprolactinemia) are associated with increased risk of miscarriage 
    • If elevated levels are found, pursue further testing to determine underlying cause (Related: Hyperprolactinemia)

Imaging

• Transvaginal ultrasonography
  • Primary imaging modality in evaluating first trimester vaginal bleeding 
  • Pregnancy evaluation
    • Gestational sac is first sonographic evidence of intrauterine pregnancy 
      • Small, spherical fluid collection with hyperechoic rim located within endometrium 
        • 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 
          • 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) 
        • 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) traditionally accepted as level at which transvaginal ultrasonography should reveal intrauterine gestational sac; use of this data point is under discussion 
            • These values may be too low to exclude a normal intrauterine pregnancy 
            • 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 
    • Yolk sac is first sonographic feature confirming intrauterine pregnancy 
      • 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 
      • Typically seen by 6 weeks of gestational and by the time gestational sac has reached 16 mm mean sac diameter; 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 
        • 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 
      • Initial fetal heart rate should be in 80 to 100 beats-per-minute range; 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 
    • 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: 
      • 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) 
      • 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 
      • 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 
  • Cervical evaluation
    • Typical cervical length is about 3.5 cm or greater 
      • Cervical shortening is a marker of preterm birth rather than cervical insufficiency; however, cerclage may be beneficial in women with short cervix 

Differential Diagnosis of Recurrent Pregnancy Loss

Most common

• Ectopic Pregnancy
• Implantation bleeding
• Hydatidiform mole
• Cervical polyps – 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

Treatment Goals

• Terminate bleeding
• Alleviate pain
• Complete evacuation of nonviable fetus
• Prevent recurrence

Admission criteria

• Women 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

Treatment Options

Recurrent Pregnancy Loss

• For patient with severe bleeding or hemodynamic instability, initiate immediate IV fluid resuscitation and/or blood transfusion; prepare for emergent surgery
• Threatened miscarriage
  • Administer Rho(D) immunoglobulin if patient is Rh-negative 
  • No medical interventions exist to improve prognosis 
  • Treat cramping with analgesics, if needed
  • Patient may be discharged with follow-up if stable and if ectopic pregnancy is excluded 
    • Timing of follow-up for ultrasonography and serial hCG levels made in conjunction with obstetrician
    • Provide patient education and support 
      • If intrauterine pregnancy has not been identified, potential for ectopic pregnancy still exists (eg, hCG level too low for sonographic identification or findings do not include fetal pole or yolk sac)
      • Discharge instructions include return instructions for significant bleeding, signs of hemodynamic instability, or severe pain
      • Moderate daily activities will not affect pregnancy
      • Avoid tampons, intercourse, and other activities that could induce uterine infection while patient is bleeding
      • Instruct patient to bring any tissue passed to provider to be examined for products of conception
      • Advise patient that miscarriage is common, grieving is normal, and counseling may be beneficial
        • Reassure patient that they have done nothing to cause miscarriage (eg, minor falls, injuries, stress)
• Diagnosed miscarriage (nonviable fetus)
  • First, confirm early pregnancy loss before initiating treatment; failure to do so may have detrimental consequences (eg, interruption of normal pregnancy, pregnancy complications, birth defects) 
  • Treatment options include expectant management, medical treatment, and surgical evacuation of uterus
    • Patient preference guides choice of intervention, established after discussion of various options
    • No single treatment option is superior to others (provided there are no associated medical complications or symptoms requiring urgent surgical evacuation) 
      • A Cochrane review concluded that medical treatment with misoprostol and expectant care are both acceptable alternatives to surgical evacuation, provided sufficient health care services are available to support all approaches 
      • All options usually result in complete evacuation of pregnancy tissue and serious complications are rare 
  • Administer Rho(D) immunoglobulin to women who are Rh-negative and not sensitized
    • Within 72 hours of diagnosis of early pregnancy loss with planned medical or expectant management 
    • Immediately after surgical management of early pregnancy loss
  • Treatment alternatives
    • Expectant management
      • Option for women without evidence of infection, hemorrhage, anemia, or bleeding disorder
        • Data suggest expectant management may be more effective in women who are symptomatic (tissue is passed, ultrasonogram shows incomplete expulsion) than in those who are asymptomatic 
      • 50% to 70% of women choose expectant management 
        • About 80% of women successfully achieve complete expulsion given adequate time (up to 8 weeks) 
          • 25% to 85% of miscarriages spontaneously resolve within 2 weeks, 37% of those within 7 days 
      • Counsel patient to expect cramping and moderate to heavy bleeding, and instruct patient on when and whom to call for excessive bleeding 
        • Suggested reference for excessive bleeding is soaking of 2 maxi pads per hour for 2 consecutive hours
      • Provide adequate analgesia 
      • Compared to surgical treatment, expectant management has higher risk of incomplete miscarriage, bleeding, and need for unplanned (or additional) surgical evacuation of uterus and for transfusion; similar psychological outcomes and risk of infection 
        • Counsel patient that surgery may be indicated if complete expulsion is not achieved 
    • Medical therapy
      • Consider for eligible women who wish to shorten time to complete expulsion and avoid surgical evacuation 
        • Must be without known or suspected infection, hemorrhage, severe anemia, or bleeding disorder
      • Medications
        • Misoprostol (prostaglandin E1 analogue)
          • Typically administered vaginally to expedite expulsion of products of conception
          • Reduces need for uterine curettage and shortens time to complete expulsion compared to placebo 
          • Most women (80%-90%) completely expel a first trimester loss after 1 or 2 doses 
            • 71% of patients expel loss by day 3 after single vaginal dose; 84% after second dose of 800 mcg of vaginal misoprostol 
            • Older gestational age is associated with a higher likelihood of medical management failure 
        • Mifepristone (synthetic steroid)
          • Consider adding oral dose of mifepristone 24 hours before administering misoprostol (if available) 
          • May improve treatment efficacy; pretreatment with mifepristone before misoprostol was found to be superior to misoprostol alone in managing early pregnancy loss 
      • Counsel patient to expect cramping (potentially severe) and moderate to heavy bleeding, and instruct patient on when and whom to call for excessive bleeding; inform patient that surgery may be indicated if complete expulsion is not achieved 
      • Provide adequate analgesia
      • Administer Rho(D) immunoglobulin to women who are Rh-negative and not sensitized within 72 hours of first misoprostol dose 
      • If misoprostol fails, patient may choose expectant management (in consultation with gynecologist to determine timing) or suction curettage 
    • Surgical evacuation of uterus
      • Treat women with hemorrhage, hemodynamic instability, or signs of infection urgently with surgical uterine evacuation 
      • May be preferable in other situations, such as medical comorbidities (eg, severe anemia, bleeding disorders, cardiovascular disease); may also be preferred by women who desire an immediate completion with less follow-up 
      • Results in faster and more predictable complete evacuation than expectant or medical management; success rate approaches 99% 
      • Suction curettage is superior to sharp curettage alone 
        • Sharp curettage adds little once complete suction evacuation of uterus has been performed, and is generally avoided completely owing to lack of any demonstrative benefits and potential for harms (eg, perforations, adhesions)
        • May be performed in outpatient setting using local anesthesia with or without additional sedation
      • Administer single preoperative dose of doxycycline to prevent infection 
      • If contraception with intrauterine device is desired after miscarriage, it may be placed immediately after surgical treatment (provided septic abortion is not suspected)
• After complete passage of pregnancy tissue, recommend patient abstain from vaginal intercourse for 1 to 2 weeks to reduce risk of infection 
• Evaluation of conceptus
  • Offer cytogenic evaluation of conceptus with recurrent pregnancy loss (3 or more) 
    • Miscarriage of aneuploid fetus is more likely to be a random event; may preclude unnecessary further evaluation and suggest greater likelihood of success in future pregnancy
• Septic abortion
  • Initiate broad-spectrum IV antibiotics 
  • Perform evacuation of uterus within 2 hours of initiation of antibiotics 
  • Consider hysterectomy in women with severe sepsis or if uterus cannot be evacuated through cervix 

Recurrent pregnancy loss

• Treatment is based on cause, if identified, and should be corrected before attempting subsequent pregnancy 
  • Treatment of uterine anomalies
    • Septate uterus
      • Hysteroscopic septoplasty is treatment of choice; laparotomy reserved for exceptional and complicated anomalies 
    • Bicornuate uterus
      • Transfundal metroplasty technique may achieve unification 
      • Cervical cerclage (placement of a suture to support and partially occlude cervix) is effective in bicornuate uterus to prevent preterm delivery; also helpful in unicornuate uterus 
    • Incompetent cervix
      • Serial transvaginal ultrasonographic monitoring from 16 weeks of gestation until end of 24 weeks for women with risk of cervical insufficiency; can avoid placement of history-indicated cerclage in more than one-half of patients 
      • Cervical cerclage reduces risk for preterm labor due to cervical insufficiency
    • Leiomyomas (fibroids)
      • Abdominal myomectomy can significantly reduce rate of spontaneous abortion; best indicated for women with recurrent miscarriage than a single loss 
    • Uterine polyps 
      • Treated using hysteroscopic polypectomy
    • Intrauterine adhesions
      • Hysteroscopic lysis of adhesions; after lysis, a mechanical barrier (eg, balloon catheter) is often placed in cavity for 10 days 
        • Postoperative administration of high-dose estrogen can promote reepithelialization and reduce risk of recurrent adhesions
  • Treatment of medical conditions
    • Endocrine issues
      • Progesterone deficiency
        • Insufficient evidence exists to support routine use of progesterone to prevent miscarriage in early to midpregnancy; however, there is some evidence that supplementation with progestogen may prevent miscarriage in subsequent pregnancies in women with history of unexplained miscarriages 
        • No benefit to initiating progesterone when patient develops symptoms of threatened abortion; in early gestation (before 7 weeks), low progesterone levels are a result of, not cause of, the abortion 
      • Hypothyroidism
        • Before conception, treat hypothyroidism with oral levothyroxine and adjust dosage to achieve TSH level within reference range (reference ranges are laboratory specific) 
        • To reduce risk of loss during pregnancy, it is reasonable to adjust levothyroxine dose to target lower half of trimester-specific range for TSH values; requires escalating doses throughout pregnancy under the guidance of endocrinologist 
      • Hyperprolactinemia
        • Very limited data suggest that a trial of bromocriptine can normalize prolactin levels before pregnancy in women with history of 2 or more pregnancy losses, which may improve rate of successful pregnancy 
      • Abnormal glucose metabolism 
        • Optimize glycemic control
        • Treatment with metformin can reduce risk of recurrent miscarriage
    • Immunologic factors
      • Alloimmune disorders
        • There are no current immunotherapies available for women with recurrent miscarriages 
          • A Cochrane review concluded that paternal cell immunization, third-party donor leukocytes, trophoblast membranes, and IV immunoglobulin provide no significant beneficial effect over placebo in improving live birth rate 
      • Antiphospholipid syndrome
        • Treat women with documented antiphospholipid syndrome with daily low-dose aspirin (81 mg) and prophylactic unfractionated heparin; initiate with positive pregnancy test result 
          • Decreases pregnancy loss and increases live birth rate
          • Low-molecular-weight heparin has not shown comparable efficacy in reducing pregnancy loss in these patients
        • Continue for minimum of 6 weeks postpartum (to minimize risk of maternal thromboembolism) 
      • Celiac disease 
        • Gluten-free diet can decrease miscarriage rate in women with celiac disease and recurrent pregnancy loss
    • Inherited thrombophilias 
      • Antepartum prophylactic use of anticoagulants, aspirin, or both has not been proved to reduce risk of early pregnancy loss; however, low-molecular-weight heparin is often used to prevent complications, owing to the absence of other effective treatments 
    • Infection
      • Empiric antibiotic treatment for infectious agents in women with recurrent pregnancy loss is not indicated, owing to lack of prospective studies linking any agent with recurrent loss 
      • If acute infection is identified, initiate appropriate antibiotic therapy in both parents 
  • Parental chromosomal abnormalities
    • Refer patient to genetic counselor 
      • Several options are available to detect genetic abnormality in offspring when 1 partner carries a structural genetic abnormality: 
        • Chorionic villus sampling
        • Amniocentesis
        • In vitro fertilization with preimplantation genetic testing 
          • Allows for diagnosis of specific translocations and transfer of only unaffected embryos; success rate of live births compared to natural conception and observation remain lower
          • Routine preimplantation genetic testing is not currently recommended for couples with recurrent pregnancy loss and structural genetic abnormality (eg, deletions, duplications, translocations)
  • No identifiable cause
    • Accounts for about 50% of women with recurrent pregnancy loss 
    • Consider administration of exogenous progesterone in early pregnancy to women with 3 or more unexplained consecutive miscarriages; not recommended in women with sporadic miscarriage 
    • Counseling and emotional support during early pregnancy has been shown to increase live birth rate in couples with unexplained recurrent miscarriage 

Drug therapy

• Misoprostol
  • For medical treatment of early pregnancy loss
  • Administered either orally or vaginally 
    • 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 
  • Consider as an option to treat pregnancy loss; however, not yet universally adopted
  • Mifepristone Oral tablet; Adult 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 mg buccally; the patient should place two 200 mg misoprostol tablets in each cheek pouch for 30 minutes and then swallow any remnants with water or another liquid. Discuss an appropriate location for the patient to be when she takes misoprostol; expulsion typically occurs within 2 to 24 hours. Patients should be given emergency contact numbers for healthcare providers and instructed what to do if significant discomfort, excessive bleeding, or other adverse events occur. Follow-up assessment to confirm complete pregnancy termination and evaluate bleeding should occur approximately 7 to 14 days after mifepristone administration. If complete expulsion has not occurred, but the pregnancy is not ongoing, women may be treated with another dose of misoprostol 800 mg buccally; a follow-up visit approximately 7 days later should occur to assess for complete termination.
• Doxycycline
  • For prophylaxis of infection resulting from surgical management
  • Doxycycline Hyclate Oral tablet; Adults: Administer a single dose of 200 mg PO 1 hour before the procedure. 
• Rho(D) immunoglobulin
  • For loss of pregnancy during first trimester (12 weeks of gestation or less) 
    • 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.
      • NOTE: 300 mcg dose is acceptable if 50 mcg dose unavailable. 
  • For loss of pregnancy after first trimester 
    • Rho(D) Immune Globulin (Human) Solution for injection; Adult and adolescent females: 300 mcg (1500 international units) IM as soon as possible and within 72 hours of the event.
• Progesterone
  • Consider in women who have had 3 or more consecutive miscarriages 
  • Available as vaginal suppository (50-100 mg twice daily) to begin 3 days after ovulation and continued throughout first trimester 
  • Vaginal suppository
    • Progesterone Vaginal insert; Adult females: 100 mg PV 2 to 3 times per day starting the day after oocyte retrieval; continue for up to 10 weeks. Efficacy in women >= 35 years has not been established.
• Unfractionated heparin
  • 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. 
• Levothyroxine replacement
  • For treatment of hypothyroidism
    • Administer levothyroxine replacement to maintain TSH level between 1 and 2.5 milliunits/L in first trimester 
      • If overt hypothyroidism is diagnosed during pregnancy, aim to normalize thyroid function test results as rapidly as possible 
      • Consider referral to endocrinologist for assistance with management
      • For TSH levels between 2.5 and 10 milliunits/mL, starting dose of at least 50 mcg/day oral levothyroxine is suggested 
  • For known prepartum hypothyroidism, adjust preconception levothyroxine dose to reach prepartum TSH level (not higher than 2.5 milliunits/L)
    • Dose usually needs to be incremented by 4 to 6 weeks of gestation and may require a 30% or more increase in prepartum dosage 
• Bromocriptine
  • For normalization of prolactin levels before pregnancy in women with history of 2 or more pregnancy losses 
  • 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 women 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 
  • If contraception is desired and appropriate, hormone-based contraception may be initiated immediately after completion of early miscarriage 
• Advise adoption of lifestyle modifications
  • Encourage women to stop smoking and refrain from drinking alcohol during pregnancy
  • Recommend limiting caffeine intake to women who become pregnant 
  • 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 
  • Recommend weight reduction in obese women
  • 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 
    • 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 women feel the loss was something they caused by some action they performed; reassure that exercise, intercourse, and dietary indiscretions do not cause miscarriage 
    • Grieving and depression: grieving may cause physical symptoms of depression (eg, fatigue, anorexia, sleeplessness, headache, back pain); depression can affect up to 30% of women after miscarriage 
      • 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

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

Procedures

Suction curettage

General explanation

• Can be performed with electric vacuum source or manual vacuum aspirator, typically with local anesthesia with or without additional sedation 
  • Manual vacuum aspiration can be performed up to 10 weeks of gestation, sometimes later 
  • Electric vacuum aspiration is more effective after 10 weeks of gestation; similar efficacy as manual vacuum aspiration in early gestation 
• Often requires cervical dilation

Indication 

• Treatment of early pregnancy loss or retained products of conception
• Urgent treatment of women presenting with hemorrhage, hemodynamic instability, or signs of infection
• May be preferable to expectant and medical management for women who:
  • Have certain conditions, such as cardiovascular disease, bleeding disorders, or severe anemia
  • Prefer more immediate endpoint to process with less follow-up management

Contraindications

• Viable intrauterine pregnancy

Complications

• Uterine perforation (most common)
• Intrauterine adhesion formation (rare)

Interpretation of results

• After procedure, examine tissue to determine that gestational sac, placenta, and any fetal parts have been removed 
  • If products of conception cannot be visualized, ultrasonogram can identify retained tissue
  • Serial hCG evaluation or repeat ultrasonography in 1 week can ensure termination of pregnancy

Cervical cerclage

General explanation

• Perform ultrasonographic examination before cerclage placement to document presence of normal gestation
• Concentric, nonabsorbable suture is placed as close to level of internal os as possible 
• Externally placed sutures are usually removed at 36 to 37 weeks of gestation to allow vaginal delivery to occur 
  • If suture is buried, consider elective cesarean delivery at or beyond 39 weeks

Indication

• History-indicated cerclage 
  • History of second trimester pregnancy loss without contractions or labor and absence of other clear cause (eg, bleeding, infection, ruptured membranes)
    • Elective placement at 12 to 14 weeks of gestation is recommended
    • Consider in women with singleton pregnancy, history of spontaneous preterm birth at less than 34 weeks of gestation, and cervical length less than 25 mm before 24 weeks of gestation
• Examination-indicated cerclage (emergency or rescue cerclage) 
  • Cervical dilation found on digital or speculum examination at less than 24 weeks of gestation

Contraindications 

• Absolute
  • Nonviable pregnancy
  • Undiagnosed vaginal bleeding
  • Ruptured membranes
  • Acute cervical or intrauterine infection
• Relative
  • Known or suspected abnormal pregnancy
  • Prolapse of fetal membranes through external cervical os (risk for rupture)

Complications 

• Rupture of membranes
• Infection
• Cervical scarring
• Pregnancy loss
• Increased contractions
• Cervical lacerations with hemorrhage, if labor occurs

Interpretation of results

• Fetal survival rates increase from 20% to 80% with cerclage when strict criteria are used to diagnose cervical incompetence (only slight increase if criteria are less certain) 

Hysteroscopy

General explanation 

• Direct visualization of endometrial cavity via cervix using endoscope and light source
• Procedure may be done for both diagnostic and treatment purposes

Indication 

• Evaluation of recurrent miscarriage, uterine synechiae, abnormal hysterosalpingography or sonohysterography, and infertility
• Operative procedures include submucous myoma resection, synechiae lysis, uterine septal incision, and endometrial polyp removal

Contraindications 

• Absolute
  • Acute pelvic or vaginal infections (including genital herpes)
  • Cervical and uterine cancers may be absolute contraindications (risk of endometrial dissemination); remains under debate
  • Pregnancy is a contraindication, as is recent uterine perforation
• Relative
  • Active bleeding
  • Extensive adhesions
  • Leiomyomata that are largely intramyometrial (greater than 50%), as opposed to submucosal

Complications 

• Rare (less than 2% of procedures); can include:
  • Uterine perforation (major complication)
  • Pelvic infection
  • Bleeding
  • Fluid overload
  • Bladder or bowel injury

Monitoring

• Follow-up depends on diagnosis and specific approach to management taken
• Monitor women at risk for cervical insufficiency with serial ultrasonographic examination from 16 weeks of gestation to end of 24 weeks 
• Women treated with expectant or medical management for miscarriage require follow-up within 1 to 2 weeks to establish that passage of tissue is complete 
  • Ultrasonography is typically used to document absence of (and presumed passage of) gestational sac previously seen
    • Endometrial thickness less than 30 mm is also a commonly used criterion to indicate complete expulsion of pregnancy tissue; however, in asymptomatic women, there is no evidence of increased morbidity if endometrium is thicker 
      • Surgical intervention is not required in asymptomatic women with thickened endometrial stripe after treatment of early pregnancy loss
  • Consider patient-reported symptoms, such as passage of tissue and resolution of vaginal bleeding and pelvic cramping, as well
  • Standardized follow-up phone calls, urine pregnancy tests, or serial quantitative β-hCG values may also be useful, especially for women with limited access to ultrasonographic evaluations 
    • Reversion to negative pregnancy test result may take several weeks 
    • Insufficient studies exist to provide meaningful guidance for using these approaches
• For women treated for hypothyroidism during pregnancy, obtain thyroid function tests 30 to 40 days after initial normalization of TSH level (to less than 2.5 milliunits/L), then every 4 to 6 weeks after 
  • In women with thyroid autoimmunity who are euthyroid in early pregnancy, monitor every 4 to 6 weeks for TSH level elevation owing to higher risk for developing hypothyroidism 

Complications

• Physical
  • Uterine retention of aborted fetus beyond 5 weeks can be associated with consumptive coagulability and hypofibrinogenemia 
  • Transient thyroid disease
    • 5% to 20% of women may develop thyroiditis after miscarriage; these patients incur a risk of thyroid disease over next 5 years 
  • Complications of miscarriage management options (expectant, medical, or surgical)
    • Serious complications are rare
    • Hemorrhage and infection can occur with all treatment approaches
      • Similar rates of hemorrhage-related hospitalization (0.5%-1%), with or without transfusion 
      • Overall rates of infection are low (1%-2%) 
• Emotional/psychological
  • Often associated with emotional and psychological morbidity (eg, grief, guilt, anger, depression, anxiety)
    • Couples experiencing miscarriage have increased risk for relationship failure compared to couples with live births 

Prognosis

• Miscarriage
  • Bleeding may occur in 30% to 40% of pregnancies during the first 20 weeks of gestation; about 50% of these will ultimately result in miscarriage 
    • Women who do not miscarry are slightly more apt to deliver preterm or have fetal anomalies
  • About two-thirds of women with bleeding will have live fetus on ultrasonographic examination; nearly 85% of these women go on to deliver live-born infant 
  • Rate of loss by fetal development on ultrasonogram 
    • Gestational sac visualized: 11.5%
    • Embryonic cardiac activity at 6 weeks: 6% to 8%
    • Cardiac activity persistent at 8 to 12 weeks: 2% to 3%
  • Septic abortion fatality rate is 0.4 to 0.6 per 100,000 spontaneous abortions 
  • Most patients will have successful pregnancy after a miscarriage, even without intervention 
    • 90% of pregnancy losses are not recurrent 
• Recurrent pregnancy loss
  • If no cause for recurrent loss is identified after complete evaluation, 65% of patients have successful subsequent pregnancy 
  • Patients with recurrent losses who seek treatment have good prognosis; over 80% of women younger than 30 years and 60% to 70% of women aged 31 to 40 years achieve successful pregnancy within 5 years of first visit to physician 

Prevention

• There are no effective interventions to prevent early pregnancy loss 
  • Bed rest, pelvic rest, vitamin supplementation, uterine relaxants, and β-hCG have not been proved to prevent miscarriage
  • Women who have experienced 3 or more prior pregnancy losses may benefit from progesterone therapy in first trimester 
• Decreasing risk for miscarriage
  • Treatment is based on cause, if identified, and should be corrected before attempting subsequent pregnancy, for example: 
    • Treat maternal hypothyroidism 
    • Maintain euglycemia in women with diabetes
    • Administer low-dose aspirin and prophylactic unfractionated heparin to women with documented antiphospholipid syndrome
    • Strive for a healthy, normal-range BMI 

Summary

• The most common cause of recurrent pregnancy loss is an abnormal number of chromosomes in the developing baby (fetus).
• Most of the time, recurrent pregnancy loss happens by chance.
• Talk to your health care provider if you are trying to get pregnant and have a history of recurrent pregnancy loss.

Sources

Practice Committee of American Society for Reproductive Medicine: Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 99(1):63, 2013 Reference