Recurrent miscarriage is pregnancy loss of three or more consecutive pregnancies before the fetus reaches viability at 20 - 24 weeks of gestation from the last menstrual period depending on the country. About 1% - 2 % of women trying to have children have recurrent miscarriage.
Miscarriage occurs in 15 - 20% of recognized pregnancies.
2% of couples trying to conceive have recurrent miscarriages.
Following three consecutive miscarriages, the risk of further miscarriage is about 40%.
A woman may develop recurrent miscarriage even after a successful pregnancy.
Increasing maternal age affects ovarian function and increases rates of aneuploidy in association with older eggs.
There are higher number of conceptions that are chromosomally abnormal and do not develop.
As the number of miscarriages increases, the risk of chromosomal abnormalities decreases and the risk of underlying maternal cause increases.
Causes of recurrent miscarriages:
A. Genetic abnormalities:
Recurrent miscarriage may be linked to chromosomal abnormality in 2 - 5% of couples.
A balanced reciprocal or Robertsonian translocation is the most common type.
Aneuploidy may be a cause of a spontaneous as well as recurrent pregnancy loss. Aneuploidy is more common with advanced reproductive age reflecting diminished egg quality.
B. Coagulation problems:
- Anti-phospholipid syndrome (APS):
This is the most important treatable cause of recurrent miscarriage.
The anti - phospholipid syndrome is an autoimmune disease which can cause frequent clotting in arteries and veins and is a common cause of recurrent pregnancy loss. 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 anti-phospholipid syndrome. Women diagnosed with anti-phospholipid syndrome generally take aspirin or heparin during their pregnancies.
The anti-phospholipid antibodies, lupus anticoagulant, anti-cardiolipin antibodies and anti-B2-glycoprotein I antibodies may be associated with recurrent miscarriage before ten weeks.
Anti-phospholipid antibodies are present in 15% of women with recurrent miscarriage.
APS is the only proven thrombophilia that is associated with adverse pregnancy outcomes.
- Inherited thrombophilia:
Inherited thrombophilia, such as protein C and S deficiency as well as Factor V Leiden and MTHFR mutations may have a role in recurrent miscarriage, because of an increased risk of thrombosis in the utero-placental circulation.
Women with second-trimester miscarriage should be screened for inherited thrombophilia. Women diagnosed with inherited thrombophilia generally take aspirin or heparin during their pregnancies.
C. Uterus malformations - Structural malformations of the uterus:
Uterine abnormalities such as arcuate uterus or septum of the uterus are seen in between 10-25% of cases of recurrent miscarriage. Only 50% of pregnancies where there is a uterine structural abnormality achieve term delivery. Second-trimester miscarriages may be linked to uterine malformations such as the presence of a uterine septum or a bicornuate uterus.
Uterine fibroids are present in up to 30% of women, but they affect reproductive loss depending on their size and place in the uterus.
D. Cervical incompetence:
Late miscarriage after a spontaneous rupture of membranes or painless cervical dilatation may often be a cause of mid-trimester recurrent miscarriage.
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
Women with hypothyroidism are at increased risk for pregnancy losses.
Women with polycystic ovarian syndrome are at higher risk of miscarriage, which may be related to insulin resistance and hyper-insulinemia or excess androgens.
There is insufficient evidence to support the use of metformin during pregnancy to reduce this risk.
Uncontrolled diabetes mellitus is a risk factor for recurrent miscarriage.
Inadequate production of progesterone in the luteal phase may cause miscarriages too.
Hyperprolactinemia may also be a factor of recurrent miscarriages
The endocrinology disorders are implicated in approximately 17% to 20% of recurrent miscarriages.
Bacterial vaginosis in the first trimester is a risk factor for second-trimester miscarriage and preterm delivery.
Infections are estimated to be responsible for 0.5 - 5% of cases with recurrent miscarriage. The main suspected pathogens are mycoplasma, urea plasma, Chlamydia Trachomatis, herpes simplex virus, cytomegalovirus, Rubella, and coxsackieviruses.
G. Immune factors:
Anti-phospholipid syndrome: The anti-phospholipid syndrome is an autoimmune disease that is a common cause of recurrent pregnancy
Thyroid antibodies: Anti-thyroid autoantibodies are associated with an increased risk of recurrent miscarriage.
Increased uterine NK cells: Natural killer cells, a type of white blood cell, are present in uterine tissue. High levels of these cells may be linked to recurrent miscarriage 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.
H. Sperm DNA Fragmentation:
High sperm DNA fragmentation is a cause of recurrent miscarriages.
The presence of these is associated with early miscarriages and maternal morbidity and is referred to as primary Anti-phospholipid syndrome (APS). There are also tests showing either lupus anticoagulant or anticardiolipin antibodies at significant levels.
Women with recurrent first-trimester miscarriage and all women with one or more second-trimester miscarriages should be screened for antiphospholipid antibodies before pregnancy.
Women with second-trimester miscarriage should be screened for inherited thrombophilia including factor V Leiden, factor II (prothrombin) gene mutation, protein S and protein C.
Uterine anatomy: All women with recurrent first-trimester miscarriage and all women with one or more second-trimester miscarriages should have pelvic ultrasound to assess uterine anatomy.
A hysterosalpingography is also recommended to check the cavity shape.
If uterine anomalies are detected then further investigations, such as hysteroscopy and/or laparoscopy, may be required.
Karyotyping of the products of conception should be done from the third (and any subsequent) miscarriages. If an unbalanced structural chromosomal abnormality is found, referral to genetics is indicated.
Parental peripheral blood karyotyping of both partners should be performed in couples with recurrent miscarriage where testing of products of conception reports an unbalanced structural chromosomal abnormality.
Reassurance should be given about the high probability of a successful outcome.
In primary Anti-phospholipid syndrome patients, heparin combined with low-dose aspirin during the pregnancy improves live birth rate to 70%.
There is some evidence suggesting that use of metformin during pregnancy is associated with a reduction in the miscarriage rate in women with polycystic ovarian syndrome.
There is also enough evidence of benefit for progesterone therapy in women with a history of recurrent miscarriage.
- Cervical cerclage is used where cervical incompetence is suspected. However the cerclage procedure also carries a risk of infection as well as stimulating uterine contractions.
Cerclage benefit increases as the cervix shortens to less than 25 mm. It has also been shown to be beneficial in those women with a shortened cervical length of less than 25 mm.
- Hysteroscopy alone or combined with laparoscopy can be used to remove a uterine septum.