Spontaneous abortion, or miscarriage, is defined as the loss of a clinically recognized pregnancy that occurs before 20 weeks of gestation; early miscarriage occurs prior to week 12 while late spontaneous abortion occurs between weeks 12 and 20. Spontaneous abortions are classified as threatened (bleeding or cramping in the first 20 weeks of gestation), inevitable (bleeding that threatens the pregnant woman's health), incomplete (partial expulsion of the products of conception), or complete. Missed abortion refers to a fetus that has died in utero, which can be confirmed by ultrasonography. Habitual spontaneous abortion is defined as three or more consecutive miscarriages. Twenty-two to thirty-three percent of spontaneous abortions occur before clinical recognition as a pregnancy; an additional 9% to 14% of spontaneous abortions occur after pregnancy has been clinically recognized. Therefore, overall rate of loss following implantation is estimated to be one-third to one-half of all pregnancies.

Chromosomal abnormalities:

• Up to 60% of spontaneous abortions
• Balanced parental translocation—phenotypically normal parents, but abortuses show chromosomal duplications or deficiencies
• Aneuploidy—numerical chromosomal abnormalities; trisomies, then monosomy X, most common
• Triploidy—early abortions
• Inversions—order of genes is reversed

Anatomic: 

• Congenital distortion of uterine cavity – e.g. mullerian fusion defects—septate uteri or small T-shaped uteri; secondary to diethylstilbestrol (DES) exposure; generally a second trimester miscarriage
• Acquired abnormalities: Asherman's Syndrome (intrauterine adhesions from surgery and/or curettage); leiomyomas (rare); adenomyosis; endometriosis; endometritis, which may also cause synechiae; 15% to 30% of those with intrauterine adhesions have repeated spontaneous abortions
• Incompetent internal cervical os—DES exposed as well
• Placental abnormalities—rare

Endocrine:

• Hyperandrogen disorders—including polycystic ovary syndrome
• Hyperthyroidism, hypothyroidism—antithyroid antibodies higher in women experiencing repeated fetal loss
• Diabetes mellitus—only if poorly controlled
• Hyperprolactinemia
• Luteal phase defects (LPD)—inhospitable endometrium possibly from deficient progesterone production; LPD may be associated with hyperprolactinemia; although clinically plausible, currently considered an uncommon even unlikely cause as LPD also exists in fertile women who carry to term and treatment for LPD with progesterone suppositories remains unproven

Infection:

• Directly via bacterial, viral, parasitic, or fungal infection
• Indirectly via fever causing elevated core temperature
• Chlamydia trachomatis commonly associated with endometritis and salpingitis
• Ureaplasma urealyticum and Mycoplasma hominis – relationship to spontaneous abortion somewhat controversial
• Herpes simplex may be associated with increased risk for spontaneous abortion
• Human papillomavirus (HPV) more prevalent in spontaneously aborted tissue compared to electively terminated pregnancies
• Septic abortion – infected uterine contents occurring before, during, or after an abortion; generally, the woman is acutely ill with chills, high fever, leukocytosis, and signs of septicemia and/or peritonitis; causative agents include E. coli, Enterobacter aerogenes, Proteus vulgaris, hemolytic streptococci, staphylococci, and anaerobic organisms; incidence dramatically reduced with legalization of elective abortions

Autoimmunity:

• Antiphospholipid antibodies (APLA) with high-titer IgG or IgM—possibly abnormal when directed against negatively charged phospholipids (e.g., lupus anticoagulant, anticardiolipin)

Anti-Fetal Antibodies:

• Rh-negative (D-negative) women with anti-D antibodies
• Anti-P antibodies in mother rejects Pp fetus early in gestation

Alloimmune:

• Excessive sharing of HLA antigens between mother and father

Other Causes:

• Time of implantation—preovulatory oocyte aging and postovulatory gamete aging; conceptus that implants after days 8 to 10 is at increased risk
• Defective spermatozoa
• Stress—possibly a psychocytokine mechanism – controversial

• Previous spontaneous abortion
• Increased maternal age
• Cigarette smoking—presence of cotinine in urine, smoking half a pack a day significantly increases risk
• Alcohol—risk doubles with more than two drinks a day; paternal alcohol use as well
• Caffeine—see section entitled Nutrition
• Cocaine—hair tests mildly correlate to greater risk but urine tests did not; therefore, this issue is controversial; possible that long-term use is more predictive of miscarriage (as indicated by positive hair tests) than acute exposure
• Increased homocysteine levels (see section entitled Nutrition)
• Exposure to x-rays (greater than 10 rads)
• Environmental—excessive exposure to lead, mercury, ionizing radiation, organic solvents
• Intrauterine device – increased risk of septic abortion
• Serious maternal illness
• Flight attendants working more than 74 hours/month during pregnancy; possibly secondary to increased gravitational forces, circadian rhythm disruption, noise and vibration, ozone, decompression episodes, fatigue, chemical exposure, ionizing radiation exposure
• Maternal or paternal handling of anti-neoplastic agents

• Embryonic heart rate below 90 beats per minute at 6 to 8 weeks of gestation
• Bleeding
• Uterine cramping
• Cervical dilation
• Fever
• Shock
• Passage of necrotic fetal tissue

• Ectopic pregnancy
• Molar pregnancy
• Cervical or vaginal lesions
• Membranous dysmenorrhea

• Comprehensive medical, genetic, and social history of both parents
• Assessment for signs of metabolic illness and hyperandrogenism
• Pelvic examination—including assessment of uterine size and shape, evidence of DES or trauma

• Human chorionic gonadotropin (hCG)—chemical detection of pregnancy; levels >2,000 mIU/ml and lack of gestational sac indicates loss – to make the diagnosis
• Karyotyping—determines chromosomal abnormalities
• Hematocrit—to evaluate extent of bleeding

To evaluate possible etiology:

• Serum assay for thyroid-stimulating hormone (TSH)
• Lupus anticoagulant, IgG and IgM iosotopes of anticardiolipin and of antiphosphatidylserine—for immunologic assessment
• Cervical culture, Gram's staining of endometrial smears—reveals infection
• Endometrial biopsy—examines effect of progesterone on endometrium with luteal phase defects
• Serum progesterone level from mid-luteal phase—best predictor of low progesterone

Necrotic fetal debris—with or without chromosomal abnormalities; fetal death may precede miscarriage by several weeks

• Ultrasound for uterine and fetal evaluation to make diagnosis of spontaneous abortion; to assess for possible etiology – e.g. polycystic ovaries or anatomic abnormality
• Sonohysterography identifies mullerian lesions
• Sonohysterosalpingography differentiates between a bicornuate and septate uterus; reveals tubal patency
• MRI for uterine evaluation may be useful but costly

• Ultrasound-guided amniocentesis or chorionic villus sampling—for prenatal genetic diagnosis or before uterine evacuation to increase likelihood of fetal, not maternal, karyotyping
• Hysteroscopy evaluates uterine cavity
• Laparoscopy differentiates between a bicornuate and septate uterus

Genetic counseling is advised for parents with inborn chromosomal abnormalities. Necrotic uterine contents must be removed (naturally or surgically) to avoid complications. Recognizing that spontaneous abortion may be associated with a grieving process, counseling both partners during this process is essential. In vitro fertilization, embryo transfer, or artificial insemination are used with unexplained, recurrent loss and parental translocations involving homologous chromosomes.

• Anti-D immunoglobulin—if only mother is Rh-negative; 50 mcg first trimester, 300 mcg thereafter; plasmapheresis also possibly therapeutic in the case of anti-fetal antibodies
• Antibiotics—in case of chlamydia or ureaplasm, should treat both partners with doxycycline 100 mg po bid x 7 days to eradicate infection and avoid spontaneous abortion in the future; if mother is pregnant, use amoxicillin 500 mg po tid x 7 days instead; in case of endometritis, cefoxitin (2 g IV, every 6 to 8 hours) for moderately severe infection; in the case of sepsis or septic shock secondary to septic abortion, clindamycin (900 mg IV, q 8 hours), ampicillin (2 g IV, q 6 hours), and an aminoglycoside; prophylactic antibiotics should be used prior to certain surgeries or procedures such as hysterosalpingogram
• Estrogen supplementation—following intrauterine adhesion surgery; 2.5 mg/day for 30 days with 10 mg/day medroxyprogesterone during last 10 days, which stimulates endometrial growth
• Aspirin (81 mg/day) followed by low-molecular-weight heparin (2,500 or 5,000 U/day) after confirmed pregnancy for antiphospholipid syndrome
• Vaginal progesterone suppositories—for LPD 25 mg/bid starting at time of basal body temperature elevation, for 6 to 8 weeks
• Immunotherapy with paternal or third-party leukocytes or trophoblast membranes—for alloimmune disease; controversial

• D & C to evacuate necrotic debris
• Uteroplasty corrects mullerian fusion defects; controversial
• Resection of intrauterine septum and cervical cerclage—with DES exposure, uterine anomalies
• Lysis under hyperscopic visualization—followed by an intrauterine device to reduce reapposition for intrauterine adhesions

There is a strong association between dietary and lifestyle factors and the risk of spontaneous abortion; preconceptional counseling, therefore, should include discussion of diet and lifestyle in relation to known risk factors including avoidance of caffeine and abstinence from alcohol and recreational drugs. In addition, while there is no definitive scientific support, there are case reports suggesting the usefulness of Chinese herbal medicines in preventing recurrent spontaneous abortions secondary to autoimmune abnormalities.

Clinically, many naturopathic and other doctors recommend the use of vitamin B complex 50 mg per day with additional vitamin B₆ and folic acid 800 to 1,000 mcg per day. These practices for prevention of spontaneous abortion are supported by studies suggesting a connection between impaired methionine-homocysteine metabolism and recurrent miscarriages.

Increased homocysteine levels, caused by a dysfunctional methionine-homocysteine metabolism, have been implicated in spontaneous abortion, placental abruption, and neural tube defects. Cofactors in methionine metabolism include folic acid, vitamins B₁₂ and B₆, and betaine. The fetus, the neonate, and the pregnant woman all have increased requirements of folic acid and B₁₂; therefore, they are also more likely to be deficient in these vitamins (Miller and Kelly 1996).

Impaired methionine metabolism may negatively impact other important nutritional constituents such as coenzyme Q10 which may not be synthesized in sufficient quantity in the case of too little folic acid, cobalamin and betaine. Two studies comparing women with a threatened or completed spontaneous abortion with women who had a normal, term pregnancy suggest that CoQ10 levels are significantly decreased in women with negative pregnancy outcomes. Supplementation with cofactors for methionine metabolism (e.g., folic acid or its active form folinic acid; vitamin B₁₂ or its active form methylcobalamin together with riboflavin-5'-phosphate) may be useful in preventing spontaneous abortion (Miller and Kelly 1996).

The deleterious effects associated with elevated homocysteine levels have been illustrated in a case report of a woman with five consecutive spontaneous abortions and in a retrospective study of 100 women with recurrent early miscarriages of unknown cause. Evaluations of homocysteine levels in these women revealed significant hyperhomocysteinemia, with levels inversely correlated with serum folate and C677T homozygous genotype carrier status. The C677T mutation occurs in the 5,10-methylene tetrahydrofolate reductase (MTHFR) gene, which plays a central role in folate metabolism. Supplementation for 1 month with 15 mg daily folic acid and 500 mg daily B₆ resulted in restoration of normal homocysteine levels and successful pregnancy outcome in the single case study (Quere et al. 1998).

Although supplementation with folic acid prior to and during pregnancy particularly for prevention of neural tube defects is standard practice, it is not entirely without controversy. As one author writes, a few studies have suggested a slightly increased risk of miscarriage among users of prenatal vitamins, multivitamins, or folic acid supplements, particularly if their use began before conception. It is questionable whether supplementation actually increases risk of miscarriage or simply prolongs a pregnancy that might have miscarried earlier; it is also difficult to determine from these particular studies whether it was folate or another factor contributing to the incidence of spontaneous abortion (Windham et al. 2000).

Other nutrients with a potential role in spontaneous abortion include selenium, magnesium, glutathione, beta-carotene, and vitamins A and E. Subacute, chronic, and marginal deficits in magnesium may contribute to impaired reproductive function, including miscarriage. In one small study, six women with a history of unexplained infertility or early miscarriage, whose red blood cell (RBC) magnesium levels failed to normalize after 4 months of oral magnesium supplementation, were compared with a similar group of controls whose levels did normalize. Levels of RBC GSH-Px, a selenium-dependent, antioxidant enzyme, were found to be significantly lower in the non-normalized group, suggesting a role for selenium deficiency in magnesium depletion. Within 8 months of normalizing their RBC-magnesium levels with either magnesium or magnesium/selenium supplements, all 12 of the previously infertile women conceived and delivered normal healthy babies (Howard et al. 1994).

While magnesium deficiency is conventionally managed with magnesium supplementation, these researchers suggest that normalization of magnesium depletion may require supplementation with selenium as well. Magnesium depletion appears to be secondary to increased permeability of cell membranes caused by oxidative damage. According to this explanation, the selenoenzyme GSH-Px is essential to cellular antioxidant activity, and a deficiency of selenium may compromise the integrity of cell membranes. Other possible explanations are that selenium improves magnesium absorption, or that enhanced selenium status optimizes reproductive function by some other mechanism not identified in this particular study (Howard et al. 1994).

Other studies have confirmed the association between antioxidant status and spontaneous abortion. In a preliminary study, 40 women presenting with first trimester miscarriage were matched with 40 nonpregnant healthy volunteers and 40 women in their first trimester of pregnancy. Healthy volunteers had normal blood levels of selenium with the exception of one volunteer with a marginally low level. All women in the healthy pregnant control group delivered healthy babies and had decreased selenium levels compared with nonpregnant controls. However, still lower selenium levels were found in the women who miscarried in the first trimester. The loss of antioxidant activity associated with selenium deficiency may have contributed to miscarriage in this group (Gabbe 1996). Similarly, blood samples of 40 women with habitual spontaneous abortion compared with those of 40 healthy fertile women revealed increased lipid peroxidation and lower levels of vitamins A and E and beta-carotene in the spontaneous abortion group. Levels of glutathione were significantly higher in the women with habitual abortion (Simsek et al. 1998).

Caffeine is known to cross the placenta readily; its impact on pregnancy is not entirely understood. Whereas the plasma half-life of caffeine in healthy adults is 2.5 to 4.5 hours, the half-life increases to 10.5 hours in pregnant women and 32 to 149 hours in the newborn. A prospective cohort study of 3135 pregnant women showed that moderate-to-heavy caffeine users (> 151 mg daily) were significantly more likely to experience late first- or second-trimester spontaneous abortion when compared with nonusers or light users. Light caffeine use (1 to 150 mg daily) was associated with increased risk for abortion only in women for whom there was a history of spontaneous abortion. (Note: one cup of coffee has 107 mg of caffeine, one cup of tea has 34 mg, and one glass of cola has 47 mg.) Coffee was the main source of caffeine in moderate-to-heavy users; light users were more likely to derive caffeine from tea and other sources. It is possible that some other component of coffee other than caffeine is responsible for the increased risk of spontaneous abortion (Srisuphan and Bracken 1986).

Researchers have recently reported on a marked positive dose-response relation between coffee consumption and plasma total homocysteine (Nygard et al. 1997). In view of a role for aberrant homocysteine metabolism in negative pregnancy outcomes (as discussed earlier), a coffee-homocysteine correlation may provide a mechanism for increased risk of spontaneous abortion among heavy coffee drinkers. However, further research is needed to investigate the possible connection between homocysteine levels, coffee consumption, and pregnancy.

A recent retrospective study examining the link between miscarriage and stillbirths and a high intake of persistent organochlorine compounds due to ingestion of contaminated fish found no association (Axmon et al. 2000). Examples of POCs are polychlorinated biphenyls (PCBs) and DDT (dichlorodiphenyltrichlorothane). Higher blood levels of PCBs were previously reported in women hospitalized for miscarriage as compared with women who carried full-term (Leoni et al. 1989).

Western herbs may be beneficial in resolving underlying endocrine abnormalities and may also play a role in stress reduction; however, these have not yet been explored in relation to spontaneous abortion specifically.

Autoimmune abnormalities have been successfully treated with Traditional Chinese Medicine. Twelve patients positive for antinuclear antibodies (ANA) and one or more antiphospholipid antibodies (APLA) were admitted into treatment; all had experienced recurrent spontaneous abortion during the first trimester. Preconceptional administration of Sairei-to (a modified, Japanese version of the Chinese herbal preparation Chan ling-tang) resulted in normalization of APLA values in all but one of the patients within 2 months of treatment. Sairei-to was continued throughout the prenatal course and discontinued after delivery. Corticosteroids and aspirin were not administered during this time. In 9 out of 11 patients, these levels continued to be negative throughout the course of Sairei-to. In the other two cases, levels increased and became positive. Ten patients delivered healthy babies following a normal prenatal course. Two of the patients whose APLA re-elevated or remained positive experienced recurrent miscarriage (Takakuwa et al. 1996).

There are case reports in Chinese journals of women with recurrent spontaneous abortion secondary to elevated autoantibodies and/or allo-antibodies including anti-zona pellucida, APLA, and anti-ABO blood group antibodies being treated successfully with Chinese herbal preparations (Li et al. 1997). Such reports suggest that, for the appropriate patient with a history of one or more spontaneous abortions, referral to a traditional medical practitioner is not unreasonable.

While information regarding the use of homeopathy for prevention of recurrent spontaneous abortion was not found in the literature, a licensed and certified homeopath would evaluate each individual and determine the appropriate constitutional homeopathic treatment, which may be useful in supporting the person's overall health.

Although not necessarily recorded in the medical literature, acupuncturists report clinical success in treating women with a history of spontaneous abortion leading to future term pregnancies. The mechanism of success is possibly related to resolution of underlying endocrine abnormalities and may also play a role in stress reduction.

• Monitor until miscarriage is complete
• Postconception monitoring is critical

• Avoid known risks as described above
• Abortus karyotyping for clues to etiology and likelihood of recurrence

• Retained necrotic tissue may become infected and could possibly result in pelvic abscess, septic shock, or death
• Feelings of depression and guilt are quite common, as well as fear and concern with the next pregnancy

• Fetal chromosomal abnormality—present in 45% to 60% of first abortus and 75% of second abortuses
• Fetal chromosomal normality—second loss has 75% chance of normality
• Recurrent miscarriage—approximately 1%; risk for subsequent loss is 24% after two, 30% after three, and 40% after four consecutive losses

Axmon A, Rylander L, Stromberg U, Hagmar L. Miscarriages and stillbirths in women with a high intake of fish contaminated with persistent organochlorine compounds. Int Arch Occup Environ Health. 2000;73(3):204-208.

Barrington JW, Lindsay P, James D, Smith S, Roberts A. Selenium deficiency and miscarriage: a possible link? Br J Obstet Gynaecol. 1996;103(2):130-132.

Gabbe SG, ed. Obstretrics—Normal and Problem Pregnancies. 3rd ed. New York, NY: Churchill Livingston; 1996.

Howard JM, Davies S, Hunnisett A. Red cell magnesium and glutathione peroxidase in infertile women: effects of oral supplementation with magnesium and selenium. Magnes Res. 1994;7(1):49-57.

Klebanoff MA, Levine RJ, DerSimonian R, Clemens JD, Wilkins DG. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N Engl J Med. 1999;341(22):1639-1644.

Leoni V, Fabiani L, Marinelli G, et al. PCB and other organochlorine compounds in blood of women with or without miscarriage: a hypothesis of correlation. Ecotoxicol Environ Saf. 1989;17(1):1-11.

Li DJ, Li CJ, Zhu Y. Treatment of integrated traditional and western medicine in recurrent spontaneous abortion of immune abnormality type [in Chinese]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 1997;17(7):390-392.

Miller AL, Kelly GS. Methionine and homocysteine metabolism and the nutritional prevention of certain birth defects and complications of pregnancy. Altern Med Rev. 1996;1(4):220-235.

Ness RB, Grisso JA, Hirschinger N, et al. Cocaine and tobacco use and the risk of spontaneous abortion. N Engl J Med. 1999;340(5):333-339.

Nygard O, Refsum H, Ueland PM, et al. Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study. Am J Clin Nutr. 1997;65(1):136-143.

Quere I, Bellet H, Hoffet M, Janbon C, Mares P, Gris JC. A woman with five consecutive fetal deaths: case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages. Fertil Steril. 1998;69(1):152-154.

Rosen P, Barkin R, eds. Emergency Medicine: Concepts and Clinical Management. 4th ed. St. Louis, Mo: Mosby-Year Book; 1998.

Ryan KJ, ed. Kistner's Gynecology & Women's Health. 7th ed. St. Louis, Mo: Mosby, Inc.; 1999.

Simsek M, Naziroglu M, Simsek H, Cay M, Aksakal M, Kumru S. Blood plasma levels of lipoperoxides, glutathione peroxidase, beta carotene, vitamin A and E in women with habitual abortion. Cell Biochem Funct. 1998;16(4):227-231.

Srisuphan W, Bracken MB. Caffeine consumption during pregnancy and association with late spontaneous abortion. Am J Obstet Gynecol. 1986;154(1):14-20.

Takakuwa K, Yasuda M, Hataya I, et al. Treatment for patients with recurrent abortion with positive antiphospholipid antibodies using a traditional Chinese herbal medicine. J Perinat Med. 1996;24(5):489-494.

Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med. 1999;340(23):1796-1799.

Windham GC, Shaw GM, Todoroff K, Swan SH. Miscarriage and use of multi-vitamins or folic acid. Am J Med Genet. 2000;90(3):261-262.