Causes, evaluation & treatment

References for: Causes, evaluation, and treatment.

Medscape Women’s Health 1998 May;3(3):2 (ISSN: 1521-2076) Bick RL; Madden J; Heller KB; Toofanian A

Thrombosis Clinical Center, Department of Medicine (Hematology & Oncology), Presbyterian Hospital of Dallas, Tex., USA.

Table 1. Profile of 118 Women Having Recurrent Fetal Loss

Mean Age: 34 years
Mean Number of Miscarriages at Diagnosis: 3
Frequency of Defects Noted
Antiphospholipid syndrome: 50 (62.50%)
SPS: 13 (16.20%)
Protein S deficiency: 7 (8.70%)
TPA deficiency: 7 (8.70%)
APC resistance: 2 (2.50%)
PAI-1 defect: 1 (1.25%)
APC = activated protein C PAI-1 = type 1 plasminogen activator
SPS = sticky platelet syndrome TPA = tissue plasminogen activator

 

Table 2. Two-Stage Evaluation of RFL When Blood-Protein and Platelet Defects Are Suspected

Blood-Protein/Platelet Factor (Technique/Assay)
Stage I
Perform complete history and physical exam. Send serum for CBC and panel I blood protein and coagulation studies.
Panel I
  • Prothrombin time
  • Activated partial thromboplastin time
  • Anticardiolipin antibodies (solid-phase ELISA) IgG, IgA, IgM idiotypes
  • Lupus anticoagulant with phospholipid confirmation (dRVVT)
  • Functional protein S (immunologic and free)
  • C4b-binding protein (if functional protein S is low)
  • Protein C (chromogenic technique)
  • Factor XIII (immunoassay)
  • Antithrombin (chromogenic technique)
  • Sticky platelet syndrome (SPS)
  • Plasminogen (chromogenic technique)
  • Activated protein C resistance (Dahlback method16)
  • Functional fibrinogen
Stage II
Evaluate serum sample for blood protein defects more rarely associated with RFL.
Panel II
  • Plasminogen activator inhibitor type 1 (PAI-1)
  • Tissue plasminogen activator
  • Heparin cofactor II
  • Tissue factor pathway inhibitor
  • Blood and urine homocysteine

dRVVT= dilute Russel’s viper venom time; ELISA = enzyme-linked immunosorbent assay; Ig = immunoglobulin.

References for: Causes, evaluation, and treatment.

Medscape Women’s Health 1998 May;3(3):2 (ISSN: 1521-2076) Bick RL; Madden J; Heller KB; Toofanian A

Thrombosis Clinical Center, Department of Medicine (Hematology & Oncology), Presbyterian Hospital of Dallas, Tex., USA.

References

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  2. Wolf GC, Horger EO 3rd: Indications for examination of spontaneous abortion specimens: A reassessment. Am J Obstet Gynecol 173(5):1364-8, 1995.
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  4. Lippman-Hand A: Genetic counseling and human reproductive loss, in Porter IH, Hook EH (eds): Human Embryonic and Fetal Death. New York, Academic Press, 1980, p. 303.
  5. Boue A, Boue J, Gropp A: Cytogenetics of pregnancy wastage, in Harris H, Hirschhorn K (eds): Advances in Human Genetics. New York, Plenum Press, 1985, pp 30-31.
  6. Coulam CB: Unexplained recurrent pregnancy loss: Epilogue. Clin Obstet Gynecol 29(4):999-1004, 1986.
  7. Daniel A, Hook EB, Wulf G: Risks of unbalanced progeny at amniocentesis to carriers of chromosome rearrangements. Am J Med Genet 33:14-53, 1989.
  8. Hsu LYF: Prenatal diagnosis of chromosomal abnormalities through amniocentesis, in Milunsky (ed): Genetic Disorders and the Fetus, ed 3. Baltimore, Johns Hopkins University Press, 1992, p 160.
  9. Duckert F: The fibrin stabilizing factor, Factor XIII. Blut 26(3):177-179, 1973.
  10. Schved JF, Gris JC, Neveu S, et al: Factor XII congenital deficiency and early spontaneous abortion. Fertil Steril 52(2):335-336, 1989.
  11. Mammen EF: Congenital abnormalities of the fibrinogen molecule. Semin Thromb Hemost 1:184-189, 1974.
  12. Scott JR, Rote NS, Branch DW: Immunologic aspects of recurrent abortion and fetal death. Obstet Gynecol 70(4):645-656, 1987.
  13. Sartori MT, Viero M, Boeri G, et al: Thrombotic diathesis in 6 out of 14 new cases of type I plasminogen deficiency. Thromb Haemost 69:1257, 1993.
  14. Gris JC, Neveu S, Mares P, et al: Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. J Lab Clin Med 125(5):606-615, 1993.
  15. Patrassi GM, Sartori MT, Ruffatti A, et al: Fibrinolytic disorders and recurrent abortions: No relationship with antiphospholipid antibodies. Thromb Haemost 69:1271, 1993.
  16. Bick RL, Laughlin HR, Cohen BM, et al: Fetal wastage syndrome due to blood protein/platelet defects: Results of prevalence studies and treatment outcome with low-dose heparin and low-dose aspirin. Clin Appl Thromb Hemost 1:286-292, 1995.
  17. Dahlback B: Inherited thrombophilia: Resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 85(3):607-614, 1995.
  18. Bick RL, Baker WF: Antiphospholipid and thrombosis syndromes. Semin Thromb Hemost 20(1):3-15, 1994.
  19. Bick RL, Baker WF: The antiphospholipid and thrombosis syndromes. Med Clin North Am 78(3):667-684, 1994.
  20. Sher G, Feinman M, Zouves C, et al: High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum Reprod 9:2278-2283, 1994.
  21. Bick RL, Baker WF: Anticardiolipin antibodies and thrombosis. Hematol Oncol Clin North Am 6:1287-1299, 1992.
  22. Bick RL, Pegram M: Syndromes of hypercoagulability and thrombosis: A review. Semin Thromb Hemost 20:109-132, 1994.
  23. Brown HL: Antiphospholipid antibodies and recurrent pregnancy loss. Clin Obstet Gynecol 34:17-26, 1991.
  24. Perino A, Barba G, Cimino C, et al: Immunological problems in the recurrent abortion syndrome. Acta Eur Fertil 20:199-202, 1989.
  25. Many A, Pauzner R, Carp H, et al: Treatment of patients with antiphospholipid antibodies during pregnancy. Am J Reprod Immunol 28:216-218, 1992.
  26. Lubbe WF, Liggins GC: Role of lupus anticoagulant and autoimmunity in recurrent fetal loss. Semin Reprod Endocrinol 6:181, 1988.
  27. Lin QD: Investigation of the association between autoantibodies and recurrent abortions. Chinese J Obstet Gynecol 28:674-677, 1993.
  28. Cowchock FS, Reece EA, Balaban D, et al: Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 166:1318-1323, 1992.
  29. Landy HJ, Kessler C, Kelly WK, et al: Obstetric performance in patients with the lupus anticoagulant and/or anticardiolipin antibodies. Am J Perinatol 9:146-151, 1992.
  30. Semprini AE, Vucetich A, Garbo S, et al: Effect of prednisone and heparin treatment in 14 patients with poor reproductive efficiency related to lupus anticoagulant. Fetal Ther 4(suppl 1):S73-S76, 1989.
  31. Rosove MH, Tabsh K, Wasserstrum N, et al: Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 75:630-634, 1990.
  32. Kuttah WH: Heparin plus aspirin (Hep + ASA) is superior to aspirin alone (ASA) for the treatment of recurrent pregnancy loss (RPL) associated with antiphospholipid antibodies. Proceedings of the Annual Meeting of the American College Obstetricians & Gynecologists, 1994. Abstract.
  33. Parke, A: The role of IVIG in the management of patients with antiphospholipid antibodies and recurrent pregnancy losses, in Ballow M (ed): IVIG Therapy Today. Totowa, NJ, Humana Press, 1992, pp 105-118.
  34. Herbst AL, Scully RE: Adenocarcinoma of the vagina in adolescence: A report of seven cases including six clear cell carcinomas (so-called mesonephromas). Cancer 25:745-757, 1970.
  35. Zilianti M, Azuaga A, Calderon F, et al: Monitoring the effacement of the uterine cervix by transperineal sonography: A new perspective. J Ultrasound Med 14:719-724, 1995.
  36. Shirodkar VN: A method of operative treatment for habitual abortion in the second trimester of pregnancy. Antiseptic 52:299, 1955.
  37. McDonald IA: Suture of the cervix for unsuitable miscarriage. J Obstet Gynaecol Br Emp 64:346, 1957.
  38. Novy MJ: Transabdominal cervicoisthmic cerclage for the management of repetitive abortion and premature delivery. Am J Obstet Gynecol 143:44-54, 1982.
  39. Andrews MC, Jones HW Jr: Impaired reproductive performance of the unicornuate uterus: Intrauterine growth retardation, infertility, and recurrent abortion in five cases. Am J Obstet Gynecol 144:173, 1982.
  40. Daly DC, Maier D, Soto-Alber RS: Hysteroscopic metroplasty: 6 years' experience. Obstet Gynecol 73:201-205, 1989.
  41. Neuwirth RS: Hysteroscopic management of symptomatic submucous fibroids. Obstet Gynecol 62:509-511, 1983.
  42. March CM, Israel R: Gestational outcome following hysteroscopic lysis of adhesions. Fertil Steril 36:455-459, 1981.
  43. Speroff L, Glass RH, Kase NG: Clinical Gynecologic Endocrinology and Infertility, ed 5. Baltimore, Williams & Wilkins, 1994, pp 827-829.
  44. Regan L, Owen EJ, Jacobs HS: Hypersecretion of luteinizing hormone, infertility and miscarriage. Lancet 336:1141-1144, 1990.
  45. Clifford K, Rai R, Watson H, et al: Does suppressing luteinizing hormone secretion reduce the miscarriage rate? Results of a randomized controlled trial. Br Med J 312:1508-1511, 1993.

Dr. Bick is Director, Thrombosis Clinical Center, Department of Medicine (Hematology & Oncology), Presbyterian Hospital of Dallas, Tex., and Professor at the University of Texas, Southwestern Medical Center, Dallas, Tex.

Dr. Madden and Dr. Toofanian are in the Department of Obstetrics/Gynecology, Presbyterian Hospital of Dallas.

Ms. Heller is Director, Genetic Counseling Associates, Dallas, Tex.

References for: Causes, evaluation, and treatment.

Medscape Women’s Health 1998 May;3(3):2 (ISSN: 1521-2076) Bick RL; Madden J; Heller KB; Toofanian A

Thrombosis Clinical Center, Department of Medicine (Hematology & Oncology), Presbyterian Hospital of Dallas, Tex., USA.

Endocrine Abnormalities

Luteal Phase Defect

There is a long history of attempts to implicate progesterone deficiency as a cause of spontaneous abortion. Endometrial biopsy and/or serum progesterone concentrations have been time-honored assessments of luteal phase ovarian function. When buildup of the endometrium during the preovulatory, or luteal, phase of the menstrual cycle lags by more than 2 days, a pathologic entity termed an inadequate corpus luteum is said by some to be present. The manifestation of this hormone-deficient state might be infertility or spontaneous abortion. It is impossible to know whether the bleeding associated with a threatened abortion occurs because the progesterone level is low or whether the hormone concentration is low because the pregnancy is not normal. Although it is not unreasonable to continue to make assessments of progesterone production or action, simple treatments with exogenous progesterone in the form of suppositories, injections, or micronized oral agents are unlikely to salvage many pregnancies.

The weight of evidence suggests that most abnormalities of luteal function originate in the follicular phase of the cycle. Thus, well-documented, persistently low levels of progesterone in the luteal phase of the cycle are likely to be the consequence of abnormal folliculogenesis. This condition is more likely to be improved by low doses of clomiphene citrate in the early follicular phase of the cycle than by postovulatory administration of progesterone. A search for subtle ovulatory dysfunction, such as that related to hyperprolactinemia, should be conducted, and treatment should be administered accordingly.

Abnormal corpus luteum function may be due to a number of pathogenic factors: (1) aberrant follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion early in the cycle; (2) a miscue in the timing (too early or too late) of the midcycle LH surge; or (3) insufficient estrogen production to allow normal progesterone action at the level of the endometrium. None of these conditions would be improved by postovulatory progesterone administration.[43]


LH Hypersecretion

Perhaps a more impressive endocrine-related explanation for recurrent spontaneous abortion is the prospective study by Regan and colleagues.[44] This study indicates that midfollicular (cycle day 8) LH hypersecretion (random serum LH of 10 mIU/mL or greater) is associated with a marked increase in the incidence of spontaneous abortion. Those findings, which have since been confirmed by others, suggest that hypersecretion of LH is associated with subfertility and early pregnancy failure. To date, however, prepregnancy treatments to suppress elevated serum concentrations of LH with GnRH agonists have not improved pregnancy outcome when compared with expectant management/supportive care during early pregnancy.[45]

References for: Causes, evaluation, and treatment.

Medscape Women’s Health 1998 May;3(3):2 (ISSN: 1521-2076) Bick RL; Madden J; Heller KB; Toofanian A

Thrombosis Clinical Center, Department of Medicine (Hematology & Oncology), Presbyterian Hospital of Dallas, Tex., USA.

Anatomic Abnormalities

Diethylstilbesterol Exposure in Utero

From 1945 to 1971, diethylstilbesterol (DES), a synthetic estrogen, was prescribed for women with threatened or recurrent spontaneous abortion. The use of this agent in pregnant women was then banned in the US. The first evidence of the drug’s adverse effects, which occurred a generation removed from the time of administration, was the report by Herbst and Scully[34] in 1970, indicating an increased incidence of vaginal adenosis and clear cell adenocarcinoma of the vagina. There is often relative absence of the vaginal fornices and a "cockscomb" or "hooded" deformity of the anterior cervix. The female offspring of DES-treated women may also have a diminution in the size and capacity of the uterus. The classical appearance of the constricted endometrial cavity on hysterosalpingogram is a "T" configuration. The severity of the abnormality is variable, depending on the dose and duration of administration of the drug during embryogenesis. Women who underwent DES exposure in utero experience an increased likelihood of ectopic pregnancy as well as first- and second-trimester spontaneous fetal losses and preterm labor.

In some cases, the likelihood of second-trimester pregnancy loss resulting from cervical incompetence may be diminished with cervical cerclage. Vigilant assessment of cervical length with transvaginal sonography allows the clinician to identify patients who may benefit from cerclage.[35] When treating patients with DES-induced abnormalities, the surgeon should be liberal in the performance of cerclage. Other than cervical cerclage, surgical intervention rarely improves anatomic abnormality of the DES-affected uterus.


Cervical Incompetence

Painless cervical dilatation during the second trimester, followed by bulging or rupture of the membranes and delivery of an immature fetus, typically suggests cervical incompetence. When cervical dilatation is advanced but membranes remain intact, it may be possible to perform cerclage. In this situation, a tocolytic agent may be necessary; the intervention is technically difficult to perform and frequently fails to salvage the pregnancy.

Often effective, therapeutic leverage may be applied during a subsequent pregnancy. Plans should be made to perform the cerclage by the tenth week of gestation or soon thereafter. Various techniques have been used to close the cervix at the level of the internal os. The most common surgical techniques for cerclage are minor variations of those described by Shirodkar[36] and McDonald.[37] The stitch should be removed by week 37 or upon active labor, to avoid amputation of the cervix. When vaginal fornices are absent and a secure transvaginal cerclage is impossible, a transabdominal cerclage should be considered.[38]


Congenital Müllerian Duct Malformations

The anatomic variations of the müllerian duct malformation are legion. The classic abnormality associated with recurrent second-trimester fetal loss is the septate uterus. The vertical septum extends a variable length from the fundus toward the cervix. The septum may be thick or thin, entirely fibrous or vascular, and partially covered by a layer of endometrium. In addition, the "compartments" into which the uterine cavity is divided by the septum may not be symmetrical. These anatomic variants, as well as the site of embryo implantation, dictate whether the septum might cause first- or second-trimester spontaneous abortion or preterm labor, or whether it will not present a problem.

Symptoms other than fetal loss seldom lead to the detection of müllerian duct malformation. Hysterosalpingogram and sonography usually establish the diagnosis, although on occasion there is difficulty in distinguishing the septate from the bicornuate uterus. Historically, clinicians required that a patient have 2 or 3 miscarriages before offering surgical intervention. In that era, laparotomy was required, and the septum was excised according to the techniques described by Jones or by Tompkins.[39] Both of these surgical procedures necessitated bivalving the uterus. Customary postoperative recommendations included deferring conception for at least several months to ensure complete healing of the uterine incision. It was also suggested that the subsequent delivery be performed by cesarean section.

Today, the management of this malformation is simple incision of the septum with a scissors at hysteroscopy.[40] Routinely, the hysteroscopy is accompanied by laparoscopy to distinguish definitively septate from bicornuate uteri and to ensure that the dissection of the septum is not overzealous. The bicornuate uterus would rarely require surgical intervention to improve obstetric outcome.

In addition to the aforementioned duct malformations, unicornuate and hypoplastic uteri are common. Magnetic resonance imaging (MRI) is most useful in delineating the malformation when the abnormality cannot be precisely discerned by sonogram and hysterosalpingogram.


Leiomyoma

Many women with fibroids (if not the majority) have normal fertility and pregnancies that are without complication. Spontaneous abortion related to a leiomoyoma is the consequence of either the size or strategic location of the lesion. Submucous intracavitary fibroids are the most likely to interfere with successful progression of an early pregnancy. Large intramural lesions that compress the endometrial cavity, thereby altering the blood supply to the implantation site, may also cause early termination of pregnancy. Even very large subserous fibroids are unlikely to cause early disruption of pregnancy in the absence of an unusual event (acute degeneration resulting in an increase in myometrial contractions). Submucous lesions are almost always associated with a history of menorrhagia.

The hysterosalpingogram has been a traditional test to assess compromise of the endometrial cavity by fibroids. Sonography and, in selected instances, hysterosonography are helpful in determining the relevance of fibroids to pregnancy wastage. In exceptional instances, pelvic MRI may be required to define the pathology. Pretreatment with a gonadotropin-releasing hormone (GnRH) agonist is frequently used to reduce the size of the fibroid before surgical intervention; such treatment also may diminish intraoperative blood loss. Large intramural leiomyomas necessitate myomectomy through laparotomy or laparoscopy, depending on the size/location of the tumor and the operative skills/experience of the surgeon. Submucous fibroids are usually best managed with a resectoscope at hysteroscopy.[41]


Intrauterine Synechiae

Intrauterine synechiae are an infrequent cause of spontaneous abortion. Diagnosis is made by hysterosalpingogram or hysterosonography, and lysis of the intracavitary adhesions may be performed under direct vision during hysteroscopy.[42]

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