Identifying recurrent miscarriage

Base interventions on those proven effective in randomised controlled trials.

In unexplained recurrent miscarriage, there is a good prognosis for a future pregnancy
In unexplained recurrent miscarriage, there is a good prognosis for a future pregnancy

In western populations, recurrent miscarriage, defined as three miscarriages occurring in a row, affects 1 per cent of women of childbearing age,1 whereas 25-50 per cent of all women experience one or more sporadic miscarriages.2 Chance alone would suggest that only 0.34 per cent of women would have three miscarriages in a row.

On average, the live birth rate for women with unexplained recurrent miscarriage is 75 per cent in a subsequent pregnancy, with a miscarriage rate of 20 per cent up to nine weeks and a 5 per cent miscarriage rate after this period.3

However, prognosis varies, depending on maternal age and number of previous miscarriages. The chance of a successful subsequent pregnancy after three unexplained miscarriages varies from 54 per cent in a 45-year-old woman to 90 per cent in a 20-year-old woman.3

Aetiology
Most fetal chromosomal abnormalities are sporadic and do not recur. The exceptions are translocations. Four per cent of couples experiencing recurrent miscarriage will include one partner with a balanced translocation; 50-70 per cent of gametes and/or embryos will have an unbalanced translocation. Most of these will cause miscarriage.

Congenital uterine abnormalities, such as septate and bicornuate uterus, are thought to be relatively common in the normal population, although the exact frequency is unknown.

The benefits of surgical correction on pregnancy outcome in women with recurrent miscarriage has yet to be assessed by a randomised controlled trial.

The effect of fibroids on reproduction is unclear, although it might be supposed that submucosal fibroids could affect implantation.

Infection of the genital tract or systemic infection may be the cause of sporadic miscarriage, but is unlikely to cause recurrent miscarriage.

Poorly controlled diabetes or thyroid disease may cause miscarriage although, again, they are unlikely to cause recurrent miscarriage.

It has long been recognised that women with polycystic ovary syndrome (PCOS) have a higher rate of miscarriage. It is now thought that the underlying insulin resistance present in PCOS impairs the fibrinolytic response necessary for successful embryonic implantation.2

The current focus is on the role of natural killer (NK) cells, a subset of lymphocytes. NK cells are present in the uterine mucosa, where they are involved in the cytokine response at the maternal/fetal interface. Women with the highest levels of NK cells have an increased risk of miscarriage in another pregnancy.2

Women with high stress scores and sporadic miscarriages have a different lymphocyte response in their endometrium, raising the possibility that stress may be a factor in miscarriage.4

Antiphospholipid syndrome (APS) is an important cause of first and second trimester recurrent miscarriage.

APS, with anticardiolipin or lupus anticoagulant antibodies, is present in 15 per cent of women with recurrent first and second trimester miscarriage.5

It is unclear whether the presence of thrombophilias in either parent is related to recurrent miscarriage, although increased thrombin causes trophoblast apoptosis in vitro.

A study comparing 357 Caucasian couples with recurrent miscarriage and 68 Caucasian parous couples as controls found a similar incidence of carriage of common thrombophilic genetic mutations in both groups, however, the carriage of more than one thrombophilic allele in either partner significantly increased the risk of miscarriage in the next pregnancy.6

Investigations
Investigations (FSH; anticardiolipin antibodies and lupus anticoagulant antibodies; thrombophilia screening; parental karyotype; pelvic ultrasound, hysterosalpingogram or hysteroscopy) should be carried out after three consecutive first trimester miscarriages.

Although pregnancy tissue is routinely sent for histological analysis after an ERPC, this is mainly to exclude features suggestive of gestational trophoblastic disease and to confirm intrauterine pregnancy.

The RCOG recommends that cytogenetic analysis of the products of conception should be performed in recurrent miscarriage. If the karyotype of the miscarried pregnancy is abnormal, there is a better prognosis in the next pregnancy, suggesting they have had a sporadic loss this time.7

Women with recurrent miscarriage can also experience sporadic miscarriage, so it is important to give advice that will help them to reduce this risk.

Links between miscarriage and lifestyle factors

Lifestyle factorRisk of miscarriage

Cigarette smoking

Adverse effect on trophoblast function
Dose-dependent increase in miscarriage risk
Cocaine useIncreases risk of miscarriage
Alcohol use of
3-5 units per week or more

Increases risk of miscarriage

 

Caffeine intake more than or equal to 300mgDose dependent increase in miscarriage per day risk. Recent advice recommends<200mg (three cups of coffee) per day to reduce risk of intrauterine growth restriction later in pregnancy
ObesityIncreases risk of miscarriage

A miscarriage is quite likely to be followed by a successful pregnancy, so it is important to base interventions on those proven to be effective in randomised controlled trials. Agents given at this crucial time in fetal development have the potential to harm, as well as help.

Only one treatment has been proven effective in recurrent miscarriage. Heparin plus low-dose aspirin significantly improves the live birth rate in women with APS; rates of >70 per cent can be achieved.8

In unexplained recurrent miscarriage, there is a good prognosis for a future pregnancy without intervention. Psychological support should be offered at an early pregnancy assessment unit or dedicated recurrent miscarriage clinic.7

After a miscarriage, couples must decide for themselves when to begin trying for another pregnancy. They are usually recommended to wait for the first period after the miscarriage and begin trying after that.

- Dr Duckitt is consultant obstetrician and gynaecologist at the Milton Keynes Hospital NHS Foundation Trust

- This article originally appeared in MIMS Women's Health. To subscribe visit www.healthcarerepublic.com/wh

- The MIMS Women's Health Conference will be held on 17 September 2009 in Manchester. For more information visit www.mimswomenshealthconference.com

References

1. Stirrat G. Recurrent miscarriage. Lancet 1990; 336: 673-5.

2. Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-11.

3. Brigham S, Conlon C, Farquharson R. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod 1999; 14: 2,868-71.

4. Arck P, Rose M, Hertwig K et al. Stress and immune mediators in miscarriage. Hum Reprod 2001; 16: 1,505-11.

5. Rai R S, Regan L, Clifford K et al. Antiphospholipid antibodies and beta2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod 1995; 10: 2,001-5.

6. Jivraj S, Rai R, Underwood J, Regan L. Genetic thrombophilic mutations among couples with recurrent miscarriage. Hum Reprod 2006; 21: 1,161-5.

7. Royal College of Obstetricians and Gynaecologists. The investigation and treatment of couples with recurrent miscarriage. Green Top Guidelines 17. RCOG, London, 2003.

8. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005. Issue 2. Art No: CD002859. DOI: 10.1002/14651858.CD002859.pub2.

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