36 Miscarriage and Recurrent Pregnancy Loss

Sara Seifert

Kristiina Altman

FIRST-TRIMESTER MISCARRIAGE

Miscarriage, or spontaneous abortion, is generally defined as the spontaneous loss of a fetus weighing 30 mm without cardiac activity.

Incidence and Risk

• Thirty percent to 40% of all conceptions result in miscarriage.

• The risk of preclinical miscarriage is estimated as approximately 25% to 30% in women older than age 35 years.

• Ten percent to 15% percent of clinically recognized pregnancies end in first-trimester and early second- trimester losses ((e.g., fever, malaise); tachycardia; and/or tachypnea. The infectious source is often Staphylococcus aureus. Septic miscarriage is frequently a complication of unsafe induced abortion as opposed to the sequela of spontaneous loss.

Assessment

• The differential diagnosis for early pregnancy bleeding includes the following:

• Physiologic

• Ectopic pregnancy

• Gestational trophoblastic disease

• Anatomic pathology of the vagina, cervix, or uterus

• The gold standard for diagnosis is imaging, usually with transvaginal ultrasound. This modality is especially useful in differentiating intrauterine and ectopic pregnancies.

• Viability can be determined through the appearance of a gestational and/or yolk sac and with measurement of the CRL. A gestational sac should be visible at β-hCG levels of 1,000 to 2,000 mIU/mL (~5 weeks of gestation) depending on ultrasound equipment and radiologist, but the detection level may be higher in patients with difficult anatomy (e.g., morbid obesity, multiple fibroids, deeply retroflexed uterus). Newer research is elucidating the lowest discriminatory levels with modern ultrasound equipment and the 99% probability levels for visualizing a gestational sac (390 to 3,510 mIU/mL), a yolk sac (1,094 to 17,716 mIU/mL), and a fetal pole (1,394 to 47,685 mIU/mL).

• In diagnosing a missed clinical miscarriage, the operator can use several sonographic criteria: (a) absence of fetal cardiac activity with a CRL >5 mm and/or (b) absence of a fetal pole in the presence of a mean sac diameter of >18 mm transvaginally or >25 mm transabdominally.

• The early presence of fetal cardiac activity in women of AMA is not necessarily reassuring. One series demonstrated an increased risk of miscarriage from 4% in women younger than age 35 years to 29% in women older than age 40 years.

• Evaluation also includes a complete blood, a type and screen, serum progesterone, and serial quantitative β- hCG measurements. The last is most useful in conjunction with imaging. In normal pregnancies, β-hCG levels usually rise 55% to 66% in 48 hours. The measurements should be done in the same laboratory due to intraassay variations. Occasionally, a slower rise may be seen in normal pregnancies.

Management and Complications

• If bleeding is minimal or symptoms have resolved, a threatened miscarriage can be managed expectantly. Bed rest or progesterone treatment does not prevent miscarriage.

• Similarly, complete abortions often require no intervention other than evaluation of passed tissue to confirm POCs. In such cases or with expectant management, patients should be advised to bring the POC to the hospital for evaluation.

• Miscarriage has a 1.5% to 2% risk of alloimmunization. Given the minimal risks of anti-D immune globulin (RhoGAM) administration compared to the potential benefits, any Rh (D)-negative woman who experiences a spontaneous loss or has a threatened miscarriage should receive it.

• Incomplete, inevitable, or missed miscarriages can be managed expectantly, medically, or surgically. These three outcomes have been extensively studied. Selecting an option is based on a combination of patient wishes, stability, and stage of miscarriage.

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Expectant Management

• Expectant management is an ideal option for women who present during the first trimester, are clinically stable, and would prefer no intervention.

• The success is greatest in incomplete (91%) compared to missed (76%) or preclinical (66%) miscarriages. The average time to miscarriage completion is 2 to 4 weeks.

• Surgical or medical intervention is indicated if expectant management fails.

Medical Management

• Medical management is an effective method for women who decline surgery or expectant management (Table 36-2).

• The World Health Organization recommends either 800 μg vaginal or 600 μg sublingual misoprostol, to be repeated after 3 days. This results in a completion rate of 79% by 7 days and 87% by 30 days. Cramping and bleeding typically occur within 2 to 6 hours of administration. Pretreatment with Tylenol and NSAIDs is helpful. Of note, the oral route tends to cause more undesirable side effects, such as uterine cramping and gastrointestinal symptoms.

• Several trials have included the combination of a progesterone antagonist (mifepristone) and misoprostol. The U.S. Food and Drug Administration-approved regimen includes 600 mg mifepristone and 48 hours later 400 μg misoprostol orally, with 92% efficacy. An alternative recommendation (200 mg mifepristone orally with 800 μg misoprostol per vagina) appears to have greater efficacy (95% to 99%) as well as fewer side effects and lower cost.

Follow-Up

• A follow-up ultrasound should show the absence of POCs, and serum β-hCG level should drop 80% 1 week following the passage of tissue. It is prudent to follow β-hCG levels to zero if an intrauterine pregnancy (IUP) was not documented.

Surgical Management

• Surgical management via dilation (or dilatation) and curettage (D&C) or dilation and evacuation (D&E) is the traditional approach in both first- and early second-trimester losses.

P.489 where the location of pregnancy is unknown. In that situation, histologic finding of chorionic villi confirms an IUP.

• Surgical management carries an increased risk of uterine perforation, cervical trauma, and anesthesia complications. Optional preoperative misoprostol treatment with 400 to 600 μg of misoprostol 4 to 6 hours before the procedure or the night before softens the cervix and makes cervical dilation easier.

• Preoperative doxycycline 100 mg PO one hour prior to the procedure or 100 mg IV thirty minutes prior to the procedure may be given. Postoperatively the patient may receive 200 mg PO once 12 hours after the procedure for prevention of infection.

• After a D&C, the serum β-hCG levels are expected to decrease by more than 20% during the following 24 hours.

• The management of septic abortions involves a combination of medical and surgical interventions. The patient must be stabilized, cultures (blood and endometrial) are obtained, and broad-spectrum antibiotics are then administered. Finally, uterine contents are removed via surgical evacuation.

SECOND-TRIMESTER MISCARRIAGE

Incidence and Risk

• Second-trimester losses (13 to 27 weeks of gestation) are less common and are often mistakenly grouped with early miscarriages. One percent to 5% of pregnancies result in miscarriage between 13 and 19 weeks' gestation, whereas only 0.3% spontaneously end between 20 and 27 weeks of gestation.

• “Stillbirth” is the customary term of pregnancy loss after 20 weeks of gestation.

• Compared to first- and early second-trimester losses, later second-trimester losses have similar etiologies, such as chromosomal abnormalities, maternal medical conditions, and teratogenic exposures.

• Causative factors more specific to second-trimester miscarriage include cervical insufficiency, thrombophilia, maternal infection or exposures, and placental abruption.

Presentation, Assessment, and Management

• History should include the following: maternal symptoms of pregnancy loss, obstetric history, past medical and gynecologic history, family history, teratogenic exposures, drug use, and trauma.

• Initial assessment should also include a review of the pregnancy development, such as sequential vital signs, weight progression, sonographic data, and antenatal testing.

• There are several clinical scenarios associated with second-trimester loss:

• Cervical insufficiency is the inability of the cervix to retain a pregnancy in the second trimester and presents as painless cervical dilation without contractions or labor. An ultrasound finding of a short cervix is not sufficient to make this diagnosis. See Chapter 9.

• Placental abruption may present with vaginal bleeding and uterine contractions but can also be occult. Early delivery is recommended and may be performed by cesarean section. Ultrasound does not necessarily diagnose abruption, as a retroplacental clot can be obscured by the placenta itself.

• Preterm premature rupture of membranes is a significant contributor to secondtrimester loss. See Chapter 9.

• Discharge instructions and care after a miscarriage are vital components of the treatment. Patients should be instructed to rest the pelvis with nothing placed in the

P.490 vagina for at least 2 weeks. They should also be advised to call a doctor for heavy bleeding, fever, or persistent abdominal pain.

• There is no evidence to suggest restrictions on contraceptive use or to recommend delaying future conception following miscarriage.

• Patients should be counseled on their risk of recurrence. These risks are a function of the underlying etiology.

• Acknowledgement of parental grief with provision of emotional support and professional counseling is encouraged.

RECURRENT PREGNANCY LOSS

Recurrent pregnancy loss (RPL) (Table 36-3) has traditionally been defined as three or more consecutive losses of clinically recognized pregnancies ultrasound and magnetic resonance imaging are also promising tools to aid in displaying uterine morphology in women with RPL. Three-dimensional ultrasound seems to be the most accurate imaging modality for the exterior contour of the uterus, which can help differentiate septate and bicornuate uteri.

• Resection of uterine septa (septoplasty), hysteroscopic lysis of adhesions, myomectomy, polypectomy, and cervical cerclage placement are all treatments for congenital and acquired uterine abnormalities.

Endocrine/Metabolic Dysfunction

• Endocrine and metabolic factors are implicated in 15% to 60% of RM cases.

• Poorly controlled diabetes mellitus (A1C >8%) and obesity have been associated with increased risk of miscarriages. See Chapter 13. Strict glycemic control should be reinforced prior to conception to decrease fetal anomalies. Pregnancy loss is increased in obese women, possibly due to insulin resistance. Weight loss prior to pregnancy improves pregnancy outcome.

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• Luteal phase deficiency:

• Functional corpus luteum defects or abnormal endometrial progesterone receptors are thought to contribute to the RPL rate, especially embryonic losses. Currently, there is no reliable means to diagnose luteal phase deficiency using either serum progesterone measurements or serial endometrial biopsies.

• Progestational agents are available in various preparations, including oral, vaginal, and intramuscular (IM) formulations.

• Oral supplementation has proven to be the most convenient but less efficacious due to its rapid metabolism and inability to bolster the progestational effect at the level of the uterus.

• There are no differences in efficacy of IM versus vaginal routes of progestational agents with regard to pregnancy or miscarriage rates.

• However, given the side effect profile of IM progesterone agents (e.g., pain, risk of bleeding and abscess formation, oil allergy, inconvenience), trials are underway to compare several vaginal options (usually 25 to 100 μg twice daily), including gel (for instance Prometrium R or Crinone R) and micronized insert (Endometrin R).

• Although studies have shown no statistically significant difference in the miscarriage rate between those receiving progesterone and those receiving placebo, there is a significant difference when stratified for obstetric history (i.e., three or more previous consecutive losses).

Polycystic Ovarian Syndrome

• A 20% risk of miscarriage has been noted in this population of women.

• Proposed mechanisms for explanation of the increased risk of miscarriage with polycystic ovarian syndrome (PCOS) include hyperandrogenism, elevated luteinizing hormone levels, obesity, hyperinsulinemia, premature or delayed ovulation, metabolic derangements of prostaglandins, growth factors, and elevated cytokines.

• Metformin has been shown to decrease miscarriage rate in women with PCOS in some studies, but randomized controlled trials offer no definitive evidence.

• Existing prospective studies show no evidence of teratogenicity or developmental problems in the first 18 months of life in the infants of mothers who used metformin in early pregnancy. Some studies advocate using metformin 500 to 2,500 mg by mouth daily through the first trimester in affected women.

Thyroid Dysfunction

• Clinical and subclinical hypo- and hyperthyroidism are thought to have an association with RPL, interfering with implantation, but causation has not been demonstrated. Thyroxine therapy should be initiated in hypothyroid patients prior to conception. See Chapter 13 for thyroid disorders.

• Thyroperoxidase antibodies: if present, therapy with thyroxin decreases the risk of miscarriage.

Hyperprolactinemia

• In a study of 64 hyperprolactinemic women treated with bromocriptine, there was a higher rate of pregnancy (86% vs. 52%); however, research is limited on whether this intervention leads to higher rates of pregnancies without miscarriage.

• Antiphospholipid syndrome (APS)

• Antiphospholipid antibodies (e.g., lupus anticoagulant, anticardiolipin or anti-β2 glycoprotein antibodies) are formed against vascular endothelium and platelets, eventually leading to vascular constriction and thrombosis. Thrombus may lead

P.494 to placental infarction and second-trimester fetal losses. Five percent to 15% of patients with RPL may have APS.

• Criteria for APS include at least one clinical and one laboratory data point.

ξ Clinical criteria:

ξ One or more episodes of arterial, venous, or small vessel thrombosis

ξ One or more unexplained pregnancy loss of a morphologically normal fetus of greater than or equal to 10 weeks of gestation

ξ One or more premature births of morphologically normal fetus at less than or equal to 34 weeks' GA due to pregnancy-induced hypertension or placental insufficiency

ξ Three or more consecutive miscarriages before 10 weeks of gestation excluding anatomic, hormonal, and parental genetic factors

ξ Laboratory criteria (any of the following):

ξ Two positive titers of moderate to high dilution at least 12 weeks apart of anticardiolipin or anti-β2 glycoprotein immunoglobulin (Ig) G or IgM antibodies

ξ Lupus anticoagulant (Russel viper venom test) on two occasions at least 12 weeks apart

• Studies have shown improved pregnancy outcome in women with APS who receive antithrombotic therapy.

ξ Treatment with unfractionated heparin and low-dose acetylsalicylic acid (ASA) is more effective than ASA alone in increasing the live birth rate—80% compared to 40%, respectively.

ξ Some studies have suggested that low-molecular-weight heparin (LMWH) may be equipotent compared to the unfractionated heparin. The benefit of LMWH is that it carries a decreased risk of heparin-induced thrombocytopenia, heparininduced osteopenia, and maternal bleeding.

Hereditary Thrombophilias

• Retrospective data suggests a modest association between thrombophilias and RPL. However, prospective studies have failed to give proof to this connection. Therefore, anticoagulation is not recommended for preventing RPL.

• Miscarriage risk is highest in the second and third trimesters. It is hypothesized that thrombosis in the low-flow spiral arteries leads to inadequate perfusion and precedes a cascade of events leading to late fetal loss.

• Hyperhomocysteinemia (>15 mmol/L) is associated with increased risk of RPL and placental abruption. Mutations are autosomal recessive, placing only homozygotes at increased risk; therefore, routine testing is not recommended.

Immune Dysfunction

• Autoimmune and alloimmune factors may cause RPL similar to graft rejection or defects of the complement system.

• Celiac disease is thought to be associated with RPL and infertility and treatment appears to prevent these problems; thus women with RPL should be screened.

• Alloimmunity reflects the theory that pregnancy survival depends on maternal tolerance to foreign fetal antigens instead of maternal sensitization leading to activation of the immune response.

• Historically, attempted therapies have included leukocyte immunization, intravenous gamma immune globulin, third-party donor cell immunization, and trophoblast membrane immunization; however, these are not recommended.

• There are currently no evidence-based methods for clinical use to evaluate or treat possible immune system- related RPL.

Infection and Environmental Exposures

• Infectious agents (Listeria, Toxoplasma, cytomegalovirus, and primary herpes simplex virus) are known causes of miscarriage, but there is no proof of their role in RPL. Therefore, bacterial or viral cultures are not a part of the workup for RPL.

• Chemicals associated with RPL include formaldehyde, pesticides, lead, mercury, benzene, and anesthetic gases, such as nitrous oxide.

• Stress and exercise have not been found to increase the risk of RPL.

Management

• Stress and anxiety should be considered while caring for couples who experience RM. Consider psychosocial or spiritual support or counseling.

• Progesterone treatment empirically in patients with multiple early miscarriages of unknown etiology

• Abnormal karyotype: Referral for genetic counseling. Patient may be offered chorionic villus sampling, amniocentesis, and preimplantation genetic testing.

• Uterine abnormalities: surgical management if possible

• APS: aspirin and heparin

• Obesity: weight loss and nutrition counseling

• Correction of thyroid dysfunction

• PCOS: possibly metformin

• Hyperprolactinemia: cabergoline or bromocriptine

• Studies have shown that emotional support, close surveillance with frequent office visits, phone calls, and even serial ultrasound studies improve pregnancy outcomes.

• These strategies have been shown in controlled studies to halve the RM rate (from >50% to 25%) in the absence of any medical or surgical intervention.

• Therapies of no proven benefit:

• Thrombophilias: Anticoagulation for thrombophilias other than APS does not decrease RPL.

• Immunotherapy or steroids for allo-/autoimmunity

• Antibiotic treatment for Ureaplasma- or Mycoplasma-positive cervical cultures

SUGGESTED READINGS

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 24: management of recurrent early pregnancy loss. Int J Gynaecol Obstet 2002;78(2):179-190.

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 142: cerclage for management of cervical insufficiency. Obstet Gynecol 2014;123(2, pt 1):372-379.

American College of Obstetricians and Gynecologists Committee on Genetics. ACOG committee opinion no. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol 2013; 122(6):1374- 1377.

Jauniaux E, Farquharson RG, Christiansen OB, et al. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 2006;21 (9):2216-2222.

Michels TC, Tiu AY. Second trimester pregnancy loss. Am Fam Phys 2007;76(9): 1341-1346.

Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012:98(5):15-28.

Robinson L, Gallos ID, Conner SJ, et al. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Hum Reprod 2012:27(1):2908-2012.

Trott EA, Russell JB, Plouffe L Jr. A review of the genetics of recurrent pregnancy loss. Del Med J 1996;68(10):495.

Zhang J, Gilles JM, Barnhart K, et al. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353(8):761-769.