Recurrent miscarriage

Recurrent miscarriage is defined as three or more consecutive miscarriages before 12 weeks, and affects 1 out of 100 of all couples trying for a pregnancy. Sometimes a treatable cause can be found, and sometimes not. But in either case, most couples are more likely to have a successful pregnancy next time than to miscarry again. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages. Notwithstanding this, recurrent miscarriage takes a heavy emotional toll on the couple and their family.
Investigations and tests are usually not offered after one or two early miscarriages (12 weeks or less), as they are thought to be due to chance occurrences. Tests are offered after the third miscarriage and after two miscarriages in women in their late 30s or older and in women who have taken a long time to conceive.

MATERNAL CHARACTERISTICS

The mother’s age and number of previous miscarriages have an effect on a further miscarriage. It is higher when the woman is above 35 and her partner over 40. Although the risk of a further miscarriage increases after each successive pregnancy loss, most couples will have a live baby the next time. Being overweight also increases the risk of both spontaneous and recurrent pregnancy loss.

ANTIPHOSPHOLIPID SYNDROME (ACQUIRED THROMBOPHILIA)

Antiphospholipid syndrome is the most important treatable cause of recurrent miscarriage. Antiphospholipid syndrome is a blood clotting disorder where antiphospholipid antibodies comprising of lupus anticoagulant and anticardiolipin antibodies are associated with three or more consecutive miscarriages before 10 -12 weeks of pregnancy. These abnormal antibodies cause an inflammatory response in the developing placenta.
It is not clear why these antibodies cause miscarriage. They may stop the pregnancy embedding properly in the uterus (womb) or they may interfere with the development of the placenta leading to pregnancy loss.
Studies have shown that the effect of antiphospholipid antibodies on placental development is reversed by heparin. Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage, but in less than 2% of those without a similar history.

INHERITED CLOTTING DISORDERS (INHERITED THROMBOPHILIAS)

Conditions including activated protein C resistance (most commonly due to factor V Leiden mutation), deficiencies of protein C/S and antithrombin III, hyperhomocysteinaemia and prothrombin gene mutation have been implicated as a possible cause in recurrent miscarriage.

GENETIC CAUSES

The chromosomes in every cell of the body carry hereditary information in the form of genes. Everyone has 23 pairs of chromosomes.
A baby inherits half its chromosomes from each parent. About half of all miscarriages happen because the baby’s chromosomes are abnormal and is not usually an inherited problem, occurring after the egg is fertilised. This is more likely to occur when the partners are older.
In 2 to 5 % of couples with recurrent miscarriage, one partner carries a chromosomal defect called a ‘balanced translocation’. This doesn’t cause a problem for the parent, but it can be passed on to the baby as an ‘unbalanced translocation’ or an unbalanced rearrangement. This means that some genetic information is duplicated and some is missing. The risk of miscarriage is influenced by the size and the genetic content of the rearranged chromosomal segments.

ENDOMETRIAL POLYPS

Endometrial polyps may be found during the course of investigations into recurrent miscarriage. They can be associated with failure of the pregnancy to implant or embed, and should be removed surgically, a procedure called transcervical resection of endometrial polyp.

ABNORMALLY-SHAPED UTERUS

Some miscarriages especially late miscarriages, are thought to occur because the uterus (womb) has an abnormal shape. It may be divided down the centre – known as ‘bicornuate’ or ‘septate’ uterus; or just one half of the uterus may have developed – known as ‘unicornuate’ uterus. It is not clear how many women with recurrent miscarriage have these uterine abnormalities, and also how common these problems are in women who don’t miscarry. This makes it impossible to be sure that they cause miscarriage. The prevalence of uterine abnormalities appears to be higher in women with late miscarriages compared with women who suffer early miscarriages, but this may be related to the cervical weakness that is frequently associated with an abnormally shaped uterus.

GENERAL ILLNESSES

Uncontrolled diabetes and untreated thyroid problems can cause miscarriage. But well-controlled diabetes and treated thyroid problems do not cause recurrent miscarriage.

POLYCYSTIC OVARIES

Polycystic ovary syndrome (PCOS) has been linked to an increased risk of miscarriage but the exact mechanism remains unclear. The increased risk of miscarriage in women with PCOS is related to insulin resistance, increased insulin levels and increased levels of male hormones.

Immune factors

Natural killer (NK) cells are found in circulating blood and in the uterine mucosa. NK cells in the circulating blood are different from NK cells in the uterus (uNK). It is thought that uterine NK cells may be associated with placental development and the mother’s response. But there is no clear evidence that increased NK cells in the circulating blood are related to recurrent miscarriage.

FOR ANTIPHOSPHOLIPID SYNDROME

All women with recurrent early miscarriages and all women with one or more late miscarriages should be offered a test for antiphospholipid antibodies before a further pregnancy. For a diagnosis of antiphospholipid syndrome, there has be two positive tests at least 12 weeks apart for either lupus anticoagulant or anticardiolipin antibodies.

FOR INHERITED THROMBOPHILIAS

Women with late miscarriages are offered blood tests to check for factor V Leiden, factor II (prothrombin) gene mutation and protein S.

CHROMOSOME CHECK

A chromosome check is offered on tissues from the miscarriage of the third and subsequent consecutive miscarriage(s). If tests on the miscarriage tissue show chromosomal abnormalities, that usually means that this is a ‘one-off’ problem and there is very a good chance of a successful pregnancy next time. If the results show an ‘unbalanced translocation’ chromosomal abnormality, then both parents would be offered to identify the ‘balanced translocation’.

ABNORMAL UTERINE SHAPE

All women with recurrent early miscarriage and all women with one or more late miscarriage are offered an ultrasound to check for any uterine abnormality. If the uterus looks abnormal on the scan, further investigations can help arrive at a diagnosis. Hysteroscopy will assess the cavity of the uterus and identify any septum. Laparoscopy will assess the outer surface of the uterus. Sometimes a 3-D ultrasound scan may help with more details than available in the ordinary scans.

ANTIPHOSPHOLIPID SYNDROME

Pregnant women with antiphospholipid syndrome are offered treatment with low-dose aspirin (75mg) and heparin (Clexane or Fragmin injections) to prevent further miscarriage. This combination has been shown to significantly reduce the miscarriage rate by 54 % and increase live birth rates among women with antiphospholipid syndrome. Use of corticosteroids or intravenous immunoglobulin therapy have not been convincingly shown to improve outcomes.

INHERITED THROMBOPHILIA

A number of studies have shown that use of heparin in women with inherited thrombophilia and recurrent early miscarriages are associated with improved live birth outcomes.

CHROMOSOMAL PROBLEMS

If either partner is found to carry a balanced translocation, they are offered special genetic counselling about future pregnancy options.

ENDOMETRIAL POLYPS

Upon a diagnosis of an endometrial polyp during investigations for recurrent miscarriage or spontaneous miscarriage (less than 3 miscarriages), the polyp is best removed surgically (transcervical resection of endometrial polyp) to reduce risks of a further pregnancy loss.

UTERINE ABNORMALITIES

Abnormalities of the uterus such as resection of a septum can be done, but there is no good evidence that this improves the chances of a successful pregnancy.

PROGESTERONE SUPPLEMENTATION

Progesterone is necessary for successful implantation and the maintenance of pregnancy, and progesterone supplementation during pregnancy is widely used to reduce risks of miscarriage.

METFORMIN SUPPLEMENTATION

The increased risk of miscarriage in women with PCOS has been attributed to insulin resistance and increased insulin levels. Some studies have shown that use of metformin during pregnancy is associated with a reduction in the miscarriage rate in women with recurrent miscarriage and PCOS.

TREATMENT WITH STEROIDS

Steroid treatment may reduce the risk of miscarriage in some women. A small pilot trial suggested that steroids might benefit women who have raised uterine NK cells. However larger studies are needed to see if those results are confirmed or not.

A significant proportion of cases of recurrent miscarriage remain unexplained despite detailed investigations. However, they can be reassured that the prognosis for a successful future pregnancy with supportive care alone is in the region of 75%. Aspirin alone or in combination with heparin is being prescribed for women with unexplained recurrent miscarriage, with the aim of improving pregnancy outcome.