Recurrent miscarriage

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.[8]

Aneuploidy may be a cause of a random spontaneous as well as recurrent pregnancy loss.[9] Aneuploidy is more common with advanced reproductive age reflecting decreased germ cell quality.[10][11]

Larger chromosomal disorders are generally detected on karyotype. In couples where a miscarried embryo has an abnormal karyotype, 76% of subsequent miscarried embryos have shown abnormal karyotypes as well. On the other hand, this group of couples have a better long-term live birth rate than those where miscarried embryos have normal karyotype.[6]

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.[9]

Fifteen percent of women who have experienced three or more recurring miscarriages have some anatomical reason for the inability to complete the pregnancy.[12] The structure of the uterus has an effect on the ability to carry a child to term. Anatomical differences are common and can be congenital.

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. It has been estimated that cervical insufficiency is a cause in about 8% of women with second trimester recurrent miscarriages.[16]

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).

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.[9] 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.[17] 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 49–65% of recurrent miscarriages.[18]

A common feature of immune factors in causing recurrent pregnancy loss appears to be a decreased maternal immune tolerance towards the fetus.[19]

The antiphospholipid syndrome is an autoimmune disease that is a common cause of recurrent pregnancy loss.[5][9] Around 15% of the women who have recurrent miscarriages have high levels of antiphospholipid antibodies.[5] 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.[5] Women diagnosed with antiphospholipid syndrome generally take aspirin or heparin in subsequent pregnancies, but questions remain due to the lack of high quality trials.[20][21]

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.[22]

Natural killer cells, a type of white blood cell, are present in uterine tissue. High levels of these cells may be linked to RPL but high numbers or the presence of these cells is not a predictor of pregnancy loss in women who have not have had a miscarriage.[23]

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

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.[24]

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.[9] Studies about the value of progesterone supplementation remain deficient, however, such supplementation is commonly carried out on an empirical basis.

Infections are estimated to be responsible for between 0.5 and 5% of cases with recurrent miscarriage.[25] The main suspected pathogens are mycoplasma, ureaplasma, Chlamydia trachomatis, Listeria monocytogenes, and herpes simplex virus.[25] An infectious evaluation may be warranted in people with immunodeficiency, or with signs of chronic endometritis/cervicitis on examination.[25] Otherwise, there is no evidence that routine infectious evaluation is appropriate or productive.[25]

Chronic endometritis (CE) due to common bacteria has been found to be prevalent in some women with a history of recurrent miscarriage. One study found that 71 percent of women who tested positive for this condition were successfully treated by an antibiogram-based antibiotic treatment. 78.4 percent of these women subsequently became pregnant in the year following treatment. The study concludes that "CE is frequent in women with recurrent miscarriages," and that "antibiotic treatment seems to be associated with an improved reproductive outcome." The authors also conclude, "that hysteroscopy should be a part of the diagnostic workup of infertile women complaining of unexplained recurrent miscarriage."[26] Despite challenges in diagnosing chronic endometritis, often done by identifying plasma cells within the lining of the womb, a recent study identified women with chronic endometritis were more likely to have a miscarriage than women without.[27]