Recurrent spontaneous abortion: evaluation and management

Recurrent spontaneous abortion: evaluation and management

Scott E. Rand

Spontaneous abortion occurs in 12 to 15 percent of all pregnancies.[1] A subset of patients habitually abort in the first or second trimester. Studies have shown that the risk of recurrent spontaneous abortion is much higher in this subset.[2,3] Family physicians are likely to encounter the problem of recurrent spontaneous abortion and must address both the medical and psychosocial implications. This article reviews the literature and offers an approach to the management of patients with recurrent spontaneous abortion.

Epidemiology

The incidence of spontaneous abortion may be much greater than is clinically recognized. A prospective study published in 1988 showed that the actual incidence of spontaneous abortion is 31 percent[3]; 22 percent of these abortions occurred before the pregnancy was clinically apparent.

The risk of recurrent spontaneous abortion increases with each successive fetal loss. A study[4] of 407 pregnancies showed that the risk of spontaneous abortion is nearly five times greater in women with only unsuccessful pregnancies than in primiparous women and women with only term deliveries. A review of 10 retrospective, cohort and prospective studies showed that the risk of aborting a pregnancy after two consecutive losses is 17 to 25 percent and the risk of aborting a fourth pregnancy after three consecutive losses is between 25 and 46 percent.[2]

Etiology

A number of factors are associated with habitual abortion, but no etiology has proved to be consistent (Table 1). The association of recurrent abortion with some factors, however, is so strong that it cannot be dismissed.

TABLE 1

Factors Associated

with Recurrent Abortion

Genetic

Aneuploidy

Polyploidy

Translocation

Anatomic

Mullerian fusion defect

Uterine synechiae

Leiomyomas

Cervical incompetence

Infectious

Toxoplasma

Chlamydia

Cytomegalovirus

Listeria

Herpesvirus

Immunologic

Antinuclear antibody

Lupus anticoagulant

Anticardiolipin antibody

HLA homozygosity

Endocrine

Luteal phase defect

Hyperprolactinemia, hypoprolactinemia

Hyperthyroidism, hypothyroidism

Diabetes mellitus

Environmental

Occupational chemical exposure

Stress

GENETIC CAUSES

The most common cause of sporadic spontaneous abortion is a chromosomal abnormality of the fetus.[5] More than 60 percent of first-trimester fetal losses show some type of cytogenetic abnormality. The most common abnormality is aneuploidy (an abnormal chromosomal composition), with autosomal trisomy accounting for more than 50 percent of chromosomally abnormal abortuses. Other common types of aneuploidy include XO, XXX, XXY and XYY. Polyploidy accounts for approximately 22 percent of chromosomally abnormal abortuses. Triploidy (3n = 69 chromosomes) is approximately three times more common than tetraploidy (4n = 92 chromosomes).

Parental genetic abnormalities are a much less common cause of habitual abortion, accounting for only 2.6 percent of cases in one series.[1] A retrospective study[6] published in 1988 examined the karyotypes of 1,142 couples with recurrent spontaneous abortion and found that the frequency of genetic abnormalities was 4.8 percent. The most common abnormalities were translocations, which occurred at a greater rate than in the general population. These patients were preselected, however; all had been screened for uterine malformation, metabolic problems and infection.

In another study,[5] the frequency of major genetic abnormalities in women with recurrent spontaneous abortion was found to be 2.9 percent. This number increased to 3.7 percent when there was a history of abortion, stillbirth or genetically abnormal offspring.

ANATOMIC CAUSES

Maternal anatomic abnormalities associated with recurrent spontaneous abortion include cervical incompetence and congenital and acquired defects of the uterus.[7] Congenital malformations include incomplete mullerian fusion leading to unicorn, bicornate, septate and didelphys, or double, uterus. The acquired defects most commonly associated with recurrent spontaneous abortion include uterine synechiae (adhesions) and leiomyomas.

INFECTION AND IMMUNOLOGIC CAUSES

Occult or subclinical intrauterine infection has been associated with recurrent fetal wastage.[8] The organisms most commonly cited include Chlamydia, Ureaplasma, Mycoplasma, Cytomegalovirus, Listeria monocytogenes and Toxoplasma gondii.

Immunologic or autoimmune markers that are significantly associated with recurrent spontaneous abortion include antinuclear antibody,[9] lupus anticoagulant and anticardiolipin antibody.[10] These markers may be present despite the absence of overt signs of clinical disease. HLA homozygosity between the parents is also under investigation as a cause of recurrent spontaneous abortion.

ENDOCRINE CAUSES

Occult thyroid abnormalities and diabetes mellitus are infrequent but treatable causes of recurrent spontaneous abortion. Luteal phase deficiency or defect has been strongly associated with recurrent fetal loss. Normal corpus luteum function is essential for providing hormonal support for implantation, as well as maintenance of early pregnancy.

Abnormalities of luteinizing hormone and follicle-stimulating hormone concentration, ovarian steroid production and uterine sensitivity to progesterone may lead to luteal phase deficiency. Abnormal prolactin levels, both low and high, have been proposed as another mechanism of luteal phase defect, although prospective studies have failed to confirm this theory.[11]

OTHER CAUSES

Sporadic miscarriage and preterm delivery have been reported in association with intrauterine diethylstilbestrol exposure, but recurrent spontaneous abortion has not been reported.[12] Smoking and alcohol use are cited as risk factors for recurrent spontaneous abortion, but two studies[4,13] have failed to show any statistical influence. Organohalide pesticides and organic solvents have both been implicated anecdotally in recurrent spontaneous abortion. The subject of occupational chemical exposure is explored in depth in an article published in 1988.[14]

Evaluation and Management

Developing a comprehensive and efficient plan for evaluating the patient with recurrent spontaneous abortion is difficult, given the multifactorial nature of the problem. The chance of finding any of the previously listed abnormalities is low unless three consecutive abortions have occurred. However, because of the emotional stress caused by spontaneous abortion, some physicians begin an evaluation after two consecutive fetal losses.

Any evaluation should be guided by findings from the history and physical examination (Table 2). A strong family history of habitual abortion or genetic anomaly suggests a parental karyotypic abnormality, and a chromosomal analysis of the affected partner is a appropriate in the primary evaluation. If an abnormality is found, referral for genetic counseling is indicated. Cervical incompetence should be suspected if there is a history of recurrent midtrimester losses, especially if the patient describes painless cervical dilatation. First-trimester loss caused by anatomic abnormalities is suggested by a history of pelvic infection or previous instrumentation (i.e., synechiae).

[TABULAR DATA OMITTED]

Important physical findings include a double cervix, a midline uterine depression indicating a mullerian fusion defect, and uterine enlargement, suggesting leiomyomas. Mullerian fusion defect predisposes women to habitual abortion secondary to poor blood supply to the endometrium and placenta. Uterine synechiae and leiomyomas interfere with implantation of the embryo and normal growth and expansion of the uterus.[8]

Initial evaluation of anatomic abnormalities includes either hysteroscopy or hysterosalpingogram, with referral for surgical evaluation and treatment as indicated. Incompetent cervix is diagnosed by frequent cervical examinations between 12 and 20 weeks of gestation. Early referral for cervical cerclage should be considered.

Active infectious causes of habitual abortion are uncommon. Cervical and endometrial cultures and viral titers should be pursued in the evaluation only after other possible causes have been investigated. To date, studies have not determined whether treatment of these infections improves pregnancy outcome. One author[15] has suggested that past infection with either Chlamydia or Listeria may induce an alteration in the immune status of the mother that predisposes her to recurrent spontaneous abortion.

Possible effects of immunologic abnormalities include placental infarction (vessel thrombosis), deficiency of maternal “blocking antibodies” and autoimmune rejection of the fetus. Any history of immunologic disease (e.g., Raynaud’s phenomenon, lupus erythematosus, rheumatoid arthritis) or of idiopathic deep venous thrombosis suggests the presence of abnormal antibodies.[16] These antibodies often exist, however, without historical or physical evidence of disease. The screening evaluation for these abnormalities includes measurement of activated partial thromboplastin time (APTT) and antinuclear antibody and anticardiolipin antibody titers. A prolonged APTT suggests the possible presence of lupus anticoagulant.

Although the mechanisms are poorly understood, corticosteroids, low-dose aspirin, and mini- and full-dose subcutaneous heparinization for patients with lupus anticoagulant and anticardiolipin antibody have shown statistically significant efficacy.[16,17] An infusion of paternal leukocytes has been studied for HLA homozygosity and other abnormalities.”[18] This patient may be referred to a tertiary care center for HLA typing and possible inclusion in ongoing study protocols.

Screening for occult diabetes mellitus and thyroid abnormalities with a 50-g glucose challenge, and thyroxine and thyroid-stimulating hormone determinations should be considered in the primary evaluation.[8] Treatment of these disorders has shown statistically significant efficacy.

LUTEAL PHASE DEFECT

The diagnosis of luteal phase defect is made by dating two consecutive endometrial biopsies from the late luteal phase that are two or more days out of phase with the menstrual cycle. Other, less invasive, tests have been used to establish a diagnosis. The simplest of these is the basal body temperature chart (Figure 1).

In this method, the patient records her temperature each morning at approximately the same time, before rising or drinking anything. Ovulation, and the beginning of the luteal phase, is signaled by a temperature elevation of 0.5 to 1.0 [degrees] F. A short luteal phase is considered as one that lasts less than 11 days; when this situation is coupled with a midcycle progesterone level of less than 10 ng per mL (32 nmol per L), luteal phase defect is diagnosed.[19]

It has been suggested that greater sensitivity and specificity may be achieved by measuring progesterone levels on day 25 or day 26 of the menstrual cycle.[20] The significance of this diagnosis is questionable, however, since luteal phase defect is known to exist in normally fertile women in up to 50 percent of cycles.[21] An algorithm outlining one method of diagnosing luteal phase defect is shown in Figure 2.

Abnormal prolactin levels, both low and high, have been proposed as another mechanism of luteal phase defect. Prospective studies have failed to confirm this mechanism, however.” Measurement of serum prolactin levels is not recommended in a normally menstruating woman.

Treatment of luteal phase defect is even more controversial than its diagnosis. Common treatments include progesterone vaginal suppositories and oral clomiphene (Clomid, Serophene). Controlled studies to date have neither proved nor disproved the efficacy of either of these methods. Both Daya[22] and Goldstein and colleagues[23] have performed a meta-analysis of the controlled trials done to date. While neither of these analyses showed overwhelming evidence of benefit from treatment, one was able to prove statistically significant improvement in outcome (although one of the studies[24] evaluated, which found treatment to be efficacious, had no controls and defined success as any pregnancy lasting longer than 13 weeks). Large, randomized, double-blind cotrolled studies are needed to examine both luteal phase defect and its treatment. Routine use of progesterone or clomiphene is not recommended in the absence of data from controlled trials.

Evaluation of the male partner is indicated only when his karyotype is in question. No studies have implicated male genital tract infections in habitual abortion. The male HLA phenotype plays an equal role in HLA homozygosity, but the significance of this factor is questionable and is the subject of current research.

Even with exhaustive medical evaluation, a possible etiology can be defined in only about half of cases of recurrent spontaneous abortion.[1] In patients with the diagnosis of “unexplained infertility,” a psychotherapeutic approach has shown significant benefit.[1,8,12] The reason for this is unclear, but evidence suggests that a supportive, therapeutic environment should be part of any treatment protocol. In fact, these studies concluded that concerned, attentive care alone produces as good an outcome as any of the other interventions.

Therefore, positive reinforcement should be given to the patient at every step of the evaluation. Because of the emotional distress caused by recurrent spontaneous abortion, it is important to emphasize to patients that there is no absolute evidence that anything they did or did not do caused the abortion. Lifestyle modification and stress reduction should be emphasized by pointing out that a healthier lifestyle, free from tobacco, alcohol, illicit drugs and undue stress, cannot hurt and may significantly improve the couple’s chances for a successful pregnancy. Unless an untreatable etiology is found, a successful pregnancy is still possible. A recommendation to pursue adoption is a clinical decision that must take into account the results of the evaluation and the personal needs of the patient.

Final Comment

Recurrent spontaneous abortion affects a small but significant proportion of the patients of family physicians. Its causes are multifactorial, and the evaluation requires a systematic, thorough and supportive approach. Family physicians can complete most of the evaluation and should guide their patients through referral for subspecialty evaluation and treatment.

REFERENCES

[1.] Stray-Pedersen B, Stray-Pedersen S. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol 1984;148:140-6. [2.] Stirrat GM. Recurrent miscarriage. I. Definition and epidemiology. Lancet 1990;336:673-5. [3.] Hertz-Picciotto I, Samuels SJ. Incidence of early loss of pregnancy [Letter]. N Engl J Med 1988;319:1483-4. [4.] Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. BMJ 1989;299:541-5 [Published erratum appears in BMJ 1989;299:1082]. [5.] Tharapel AT, Tharapel SA, Bannerman RM. Recurrent pregnancy losses and parental chromosome abnormalities: a review. Br J Obstet Gynaecol 1985;92:899-914. [6.] Portnoi MF, Joye N, van den Akker J, Morlier G, Taillemite JL. Karyotypes of 1142, couples with recurrent abortion. Obstet Gynecol 1988;72:31-4. [7.] Golan A, Barnan S, Wexler S, Langer R, Bukovsky I, David MP. Incompetence of the uterine cervix. Obstet Gynecol Surv 1989;44:96-107. [8.] Rock JA, Zacur HA. The clinical management of repeated early pregnancy wastage. Fertil Steril 1983;39:123-40. [9.] Harger JH, Rabin BS, Marchese SG. The prognostic value of antinuclear antibodies in women with recurrent pregnancy losses: a prospective controlled study. Obstet Gynecol 1989;73(3 Pt 1):419-24. [10.] Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC. The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 1989;161:369-73. [11.] Glazener CM, Kelly NJ, Hull MG. Prolactin measurement in the investigation of infertility in women with a normal menstrual cycle. Br J Obstet Gynaecol 1987;94:535-8. [12.] Stirrat GM. Recurrent miscarriage. II. Clinical associations, causes, and management. Lancet 1990;336:728-33. [13.] Strobino B, Fox HE, Kline J, Stein Z, Susser M, Warburton D. Characteristics of women with recurrent spontaneous abortions and women with favorable reproductive histories. Am J Public Health 1986;76:986-91. [14.] Paul M, Himmelstein J. Reproductive hazards in the workplace: what the practitioner needs to know about chemical exposures. Obstet Gynecol 1988;71(6 Pt 1):921-38. [15.] Quinn PA, Petric M, Barkin M, Butany J, Derzko C, Gysler M, et al. Prevalence of antibody to Chlamydia trachomatis in spontaneous abortion and infertility. Am J Obstet Gynecol 1987;156:291-6. [16.] Out HJ, Derksen RH, Christiaens GC. Systemic lupus erythematosus and pregnancy. Obstet Gynecol Surv 1989;44:585-91. [17.] Rosove MH, Tabsh K, Wasserstrum N, Howard P, Hahn BH, Kalunian KC. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 1990;75:630-4. [18.] Smith JB, Cowchock FS, Hankinson B, Iftekhar A. Association of HLA-DR5 with recurrent spontaneous abortion in women treated with paternal leukocytes. Possible subclinical autoimmune disease. Arth Rheum 1989;32:1572-6. [19.] McNeely MJ, Soules MR. The diagnosis of luteal phase deficiency: a critical review. Fertil Steril 1988;50:1-15. [20.] Daya S. Optimal time in the menstrual cycle for serum progesterone measurement to diagnose luteal phase defects. Am J Obstet Gynecol 1989;161:1009-11. [21.] Davis OK, Berkeley AS, Naus GJ, Cholst IN, Freedman KS. The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsies. Fertil Steril 1989;51:582-6. [22.] Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials. Br J Obstet Gynaecol 1989;96:275-80. [23.] Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol 1989;96:265-74. [24.] Daya S, Ward S, Burrows E. Progesterone profiles in luteal phase defect cycles and outcome of progesterone treatment in patients with recurrent spontaneous abortion. Am J Obstet Gynecol 1988;158:225-32.

SCOTT E. RAND, LT, MC, USNR is currently a staff family physician at the U.S. Naval Hospital, Keflavik, Iceland. Dr. Rand graduated from the University of South Dakota School of Medicine, Vermillion, and completed a residency in family practice at the Naval Hospital, Pensacola, Fla.

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