Recurrent miscarriage

Recurrent miscarriage
Classification and external resources
Specialty urology
ICD-10 N96
ICD-9-CM 629.81
eMedicine article/260495

Recurrent miscarriage, habitual abortion, or recurrent pregnancy loss (RPL) is a disease distinct from infertility, defined by three or more consecutive pregnancy losses. When the cause is unknown, each pregnancy loss merits careful review to determine whether specific evaluation may be appropriate. After three or more losses, a thorough evaluation is warranted.[1] About 1% of couples trying to have children are affected by recurrent miscarriage.[2][3]

Causes

There are various causes for recurrent miscarriage, and some are treatable. Some couples never have a cause identified, often after extensive investigations.[4] About 50-75% of cases of Recurrent Miscarriage are unexplained.[1]

Anatomical conditions

Uterine conditions

A uterine malformation is considered to cause about 15% of recurrent miscarriages. The most common abnormality is a uterine septum, a partition of the uterine cavity. The diagnosis is made by MRI or a combined laparoscopy hysteroscopy of the uterus. Also uterine leiomyomata could result in pregnancy loss.

Cervical conditions

In the second trimester a weak cervix can become a recurrent problem. Such cervical incompetence leads to premature pregnancy loss resulting in miscarriages or preterm deliveries.

Chromosomal disorders

Translocations

A balanced translocation or Robertsonian translocation in one of the partners leads to unviable fetuses that are miscarried. This explains why a karyogram is often performed in both partners if a woman has experienced repeated miscarriages. About 3% of the time a chromosomal problem of one or both partners can lead to recurrent pregnancy loss. Although patients with such a chromosomal problem are more likely to miscarry, they may also deliver normal or abnormal babies.

Aneuploidy

Aneuploidy may be a cause of a random spontaneous as well as recurrent pregnancy loss.[5] Aneuploidy is more common with advanced reproductive age reflecting decreased germ cell quality.

Endocrine disorders

Women with hypothyroidism are at increased risk for pregnancy losses. Unrecognized or poorly treated diabetes mellitus leads to increased miscarriages. Women with polycystic ovary syndrome also have higher loss rates possibly related to hyperinsulinemia or excess androgens. Inadequate production of progesterone in the luteal phase may set the stage for RPL (see below).

Thrombophilia

An important example is the possible increased risk of miscarriage in women with thrombophilia (propensity for blood clots). The most common problem is the factor V Leiden and prothrombin G20210A mutation.[5] Some preliminary studies suggest that anticoagulant medication may improve the chances of carrying pregnancy to term but these studies need to be confirmed before they are adopted in clinical practice.[6] Note that many women with thrombophilia go through one or more pregnancies with no difficulties, while others may have pregnancy complications. Thrombophilia may explain up to 15% of recurrent miscarriages.

Immune factors

A common feature of immune factors in causing recurrent pregnancy loss appears to be a decreased maternal immune tolerance towards the fetus.[7]

Antiphospholipid syndrome

The antiphospholipid syndrome is an autoimmune disease that is a common cause of recurrent pregnancy loss.[3][5] Around 15% of the women who have recurrent miscarriages have high levels of antiphospholipid antibodies.[3] Women who have had more than one miscarriage in the first trimester, or a miscarriage in the second trimester, may have their blood tested for antibodies, to determine if they have antiphospholipid syndrome.[3] Women diagnosed with antiphospholid syndrome generally take aspirin or heparin in subsequent pregnancies, but questions remain due to the lack of high quality trials.[8][9]

Thyroid antibodies

Anti-thyroid autoantibodies are associated with an increased risk of recurrent miscarriage with an odds ratio of 2.3 with a 95% confidence interval of 1.5–3.5.[10]

Increased uterine NK cells

A controversial area is the presence of increased natural killer cells in the uterus. It is poorly understood whether these cells actually inhibit the formation of a placenta, and it has been noted that they might be essential for this process. A 2004 paper (Moffett et al.) warned that determination of NK cells in peripheral blood does not predict uterine NK cell numbers, because they are a different class of lymphocytes, and state that immunosuppressive treatments are not warranted.[5]

Parental HLA sharing

Earlier studies that perhaps paternal sharing of HLA genes would be associated with increased pregnancy loss have not been confirmed.

Male-specific minor histocompatibility

Immunization of mothers against male-specific minor histocompatibility (H-Y) antigens has a pathogenic role in many cases of secondary recurrent miscarriage, that is, recurrent miscarriage in pregnancies succeeding a previous live birth. An example of this effect is that the male:female ratio of children born prior and subsequent to secondary recurrent miscarriage is 1.49 and 0.76 respectively.[11]

Ovarian factors

Reduced ovarian reserve

The risk for miscarriage increases with age, and women in the advanced reproductive age who have a reduced ovarian reserve are prone to higher risk of repeated miscarriages. Such miscarriages are due to decreased egg quality .

Luteal phase defect

The issue of a luteal phase defect is complex. The theory behind the concept suggests that an inadequate amount of progesterone is produced by the corpus luteum to maintain the early pregnancy. Assessment of this situation was traditionally carried out by an endometrial biopsy, however recent studies have not confirmed that such assessment is valid.[5] Studies about the value of progesterone supplementation remain deficient, however, such supplementation is commonly carried out on an empirical basis.

Lifestyle factors

While lifestyle factors have been associated with increased risk for miscarriage in general, and are usually not listed as specific causes for RPL, every effort should be made to address these issues in patients with RPL. Of specific concern are chronic exposures to toxins including smoking, alcohol, and drugs.[5]

Infection

A number of maternal infections can lead to a single pregnancy loss, including listeriosis, toxoplasmosis, and certain viral infections (rubella, herpes simplex, measles, cytomegalo virus, coxsackie virus). However, there are no confirmed studies to suggest that specific infections will lead to recurrent pregnancy loss in humans. Malaria, syphilis and brucellosis can also cause recurrent miscarriage.[5]

Assessment

Transvaginal ultrasonography has become the primary method of assessment of the health of an early pregnancy.

In non-pregnant patients who are evaluated for recurrent pregnancy loss the following tests are usually performed. Parental chromosome testing (karyogram) is generally recommended after 2 or 3 pregnancy losses. Blood tests for thrombophilia, ovarian function, thyroid function and diabetes are performed.

Treatment

If the likely cause of recurrent pregnancy loss can be determined treatment is to be directed accordingly. In pregnant women with a history of recurrent miscarriage, anticoagulants seem to increase the live birth rate among those with antiphospholipid syndrome and perhaps those with congenital thrombophilia but not in those with unexplained recurrent miscarriage.[12]

There are currently no treatments for women with unexplained recurrent pregnancy loss. The majority of patients are counseled to try to conceive again, and chances are about 60% that the next pregnancy is successful without treatment.[5] However, each additional loss worsens the prognostic for a successful pregnancy and increases the psychological and physical risks to the mother. Aspirin has no effect in preventing recurrent miscarriage in women with unexplained recurrent pregnancy loss.[13] Immunotherapy has not been found to help.[14] There is currently one drug in development, NT100, which is in clinical trials for the treatment of unexplained recurrent miscarriage. The study investigates the role of NT100 in improving maternal-fetal tolerance for women with unexplained recurrent miscarriage [15]

In certain chromosomal situations, while treatment may not be available, in vitro fertilization with preimplantation genetic diagnosis may be able to identify embryos with a reduced risk of another pregnancy loss which then would be transferred. However, in vitro fertilization does not improve maternal-fetal tolerance imbalances.

Close surveillance during pregnancy is generally recommended for pregnant patients with a history of recurrent pregnancy loss. Even with appropriate and correct treatment another pregnancy loss may occur as each pregnancy develops its own risks and problems.

Psychological effects of miscarriages

There is significant, and often unrecognized, psychological and psychiatric trauma for the mother – for many, miscarriage represents the loss of a future child, of motherhood, and engenders doubts regarding her ability to procreate.[16] Studies have shown that a significant percentage of women experience grief, depression, and anxiety, and that there is an increased risk of major depressive disorder following a miscarriage. The psychological effects can persist for 6 months to 3 years and tend to deepen with additional miscarriages.

Association with later disease

Recurrent miscarriage in itself is associated with later development of coronary artery disease with an odds ratio of approximately 2,[17] increased risk of ovarian cancer,[18] increased risk of cardiovascular complications,[19] and an increased risk of all-cause mortality of 44%, 86%, and 150% for women with a history of 1, 2, or 3 miscarriages, respectively.[20]

Women with a history of recurrent miscarriage are at risk of developing preeclampsia in later pregnancies.[21]

References

  1. 1 2 https://www.asrm.org/FACTSHEET_Recurrent_Pregnancy_Loss/
  2. ↑ American College of Obstetricians and Gynecologists (ACOG) Repeated Miscarriage FAQ 100 http://www.acog.org/-/media/For-Patients/faq100.pdf?dmc=1&ts=20150820T1255284207
  3. 1 2 3 4 Royal College of Obstetricians and Gynaecologists (RCOG) (April 2011). "The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage" (PDF). Green-top Guideline No. 17. Royal College of Obstetricians and Gynaecologists (RCOG). Retrieved 2 July 2013.
  4. ↑ "The Investigation and Treatment of Couples with Recurrent Miscarriage: Guideline No 17" (PDF). Royal College of Obstetricians and Gynaecologists.
  5. 1 2 3 4 5 6 7 8 "Management of Early Pregnancy Loss". ACOG Practice Bulletin (American College of Obstetricians and Gynecologists) 24 (February). 2001.
  6. ↑ Rodger MA, Paidas M, McLintock C, et al. (August 2008). "Inherited thrombophilia and pregnancy complications revisited". Obstet Gynecol 112 (2 Pt 1): 320–4. doi:10.1097/AOG.0b013e31817e8acc. PMID 18669729.
  7. ↑ Williams, Zev (Sep 2012). "Inducing Tolerance to Pregnancy". New England Journal of Medicine 367 (12): 1159–61. doi:10.1056/NEJMcibr1207279. PMC 3644969. PMID 22992082.
  8. ↑ Empson, M; Lassere, M; Craig, J; Scott, J (Apr 18, 2005). "Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant.". Cochrane database of systematic reviews (Online) (2): CD002859. doi:10.1002/14651858.CD002859.pub2. PMID 15846641.
  9. ↑ Patient’s Fact Sheet: Recurrent Pregnancy Lost. American Society for Reproductive Medicine, 8/2008
  10. ↑ Van Den Boogaard, E.; Vissenberg, R.; Land, J. A.; Van Wely, M.; Van Der Post, J. A. M.; Goddijn, M.; Bisschop, P. H. (2011). "Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: A systematic review". Human Reproduction Update 17 (5): 605–619. doi:10.1093/humupd/dmr024. PMID 21622978.
  11. ↑ Nielsen, H. S. (2011). "Secondary recurrent miscarriage and H-Y immunity". Human Reproduction Update. doi:10.1093/humupd/dmr005.
  12. ↑ De Jong, P. G.; Goddijn, M.; Middeldorp, S. (2013). "Antithrombotic therapy for pregnancy loss". Human Reproduction Update 19 (6): 656–673. doi:10.1093/humupd/dmt019. PMID 23766357.
  13. ↑ Kaandorp, S. P.; Goddijn, M. T.; Van Der Post, J. A. M.; Hutten, B. A.; Verhoeve, H. R.; Hamulyák, K.; Mol, B. W.; Folkeringa, N.; Nahuis, M.; Papatsonis, D. N. M.; Büller, H. R.; Van Der Veen, F.; Middeldorp, S. (2010). "Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage". New England Journal of Medicine 362 (17): 1586–1596. doi:10.1056/NEJMoa1000641. PMID 20335572.
  14. ↑ Wong, LF; Porter, TF; Scott, JR (Oct 21, 2014). "Immunotherapy for recurrent miscarriage.". The Cochrane database of systematic reviews 10: CD000112. doi:10.1002/14651858.CD000112.pub3. PMID 25331518.
  15. ↑ http://www.noratherapeutics.com
  16. ↑ Lok, I. Psychological Morbidity Following Miscarriage
  17. ↑ Oliver-Williams, C. T.; Heydon, E. E.; Smith, G. C. S.; Wood, A. M. (2013). "Miscarriage and future maternal cardiovascular disease: A systematic review and meta-analysis". Heart 99 (22): 1636–1644. doi:10.1136/heartjnl-2012-303237. PMC 3812894. PMID 23539554.
  18. ↑ Braem, Multiple Miscarriages and Risk of Ovarian Cancer
  19. ↑ Kessous, RPL: A Risk Factor for maternal atherosclorosis
  20. ↑ Coleman, Reproductive history patterns and long-term mortality
  21. ↑ Trogstad, L; Magnus, P; Moffett, A; Stoltenberg, C (2009). "The effect of recurrent miscarriage and infertility on the risk of pre-eclampsia". BJOG 116 (1): 108–13. doi:10.1111/j.1471-0528.2008.01978.x. PMID 19087081.

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