Investigation of recurrent miscarriagesBMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7509.121 (Published 14 July 2005) Cite this as: BMJ 2005;331:121
- Fred Kavalier, primary care geneticist ()
Human reproduction is hopelessly inefficient. The maximum probability of conceiving during a menstrual cycle is only about 40%. One third of conceptions do not result in the delivery of a baby.1–3 But this inefficient process produces astoundingly good outcomes. The vast majority of continuing pregnancies result in the birth of a healthy human being who will, eventually, pass his or her genes on to the next generation. Miscarriages—clinically detectable pregnancies that fail to progress—are the inevitable byproduct of such a process. They are common and often remain unexplained, even after investigation. They are a source of distress for women and their partners. When a woman has had two or more miscarriages, she is likely to seek professional help, in the hope that a cause and a cure will be found.
Because 10-15% of clinically recognised pregnancies end in miscarriage, and because most women who have one, two, or even three first trimester miscarriages will nevertheless go on to have a successful pregnancy, investigations are usually done only when a woman has recurrent miscarriages.4 5 The United Kingdom's Royal College of Obstetricians and Gynaecologists, which defines recurrent miscarriage as the loss of three or more pregnancies, and the American College of Obstetricians and Gynecologists, have both published similar guidelines on the management of recurrent miscarriage.6 7 Recurrent miscarriages have a range of possible causes including genetic, anatomical, endocrine, immune, infective, thrombophilic, and unexplained.
Balanced chromosome translocations, in which sections of chromosomes change their geographical position on the chromosomal map without any loss or gain of important genetic material, are an important cause of recurrent miscarriages because they are common; one in 500 people carries a balanced translocation. When one member of a couple carries a balanced chromosome translocation, the risk of having a miscarriage is approximately doubled. In 3-5% of couples with recurrent miscarriage, one partner has a balanced translocation. Peripheral blood karyotyping of both partners is considered a mandatory investigation of couples with recurrent miscarriage but, in this week's BMJ, Franssen et al raise the question of whether other factors, such as family history of miscarriages, should be taken into consideration when deciding who should be karyotyped.8 When a balanced translocation is identified, it is useful to karyotype miscarriage products to see if they are the result of unbalanced translocations.
Congenital abnormalities of the uterus probably account for some recurrent miscarriages, but the extent of their contribution is uncertain. The guidelines from the Royal College of Obstetricians and Gynaecologists recommend an ultrasound scan of the pelvis for women with recurrent miscarriage, but this recommendation is based solely on the clinical experience of the guideline development group, rather than on published evidence. Some centres use hysterosonography (ultrasound with the introduction of an echocontract fluid into the uterus).6
It is traditional to screen for maternal endocrine disease in the investigation of recurrent miscarriage. But the prevalence of these conditions is no greater in women who miscarry than in the general population, so screening is not worth while.6
Antiphospholipid syndrome, in which anticardiolipin antibodies and lupus anticoagulant are present, is detectable in 15% of women with recurrent miscarriage. Its identification is important, because treatment with aspirin or heparin or both significantly improves the likelihood of a live birth.9 But a recent review of the management of the obstetric antiphospholipid syndrome recommended that healthy women with fewer than three early miscarriages should not be tested or treated for antiphospholipid syndrome because, for these women, there is no evidence that drug treatment during pregnancy is beneficial.10
Infections with bacteria, viruses, and other organisms such as toxoplasma and listeria can all interfere with pregnancy, but none seems to be significant causes of recurrent early miscarriage. The Royal College, on the basis of evidence obtained from experts but not from randomised controlled trials, recommends that TORCH screening for infection (looking for toxoplasma, other viruses, rubella, cytomegalovirus, herpesvirus, and sometimes HIV) should be abandoned in the investigation of recurrent miscarriage.6
There is much debate, but little evidence from prospective studies, on the importance of thrombophilic defects, such as Factor V Leiden mutation, in the aetiology of recurrent miscarriage. In the absence of convincing evidence, there is no agreed protocol for investigation of these defects.
With so many possible causes for recurrent miscarriage, it would be tempting to think that the prognosis for those women whose recurrent miscarriages are unexplained (about half) is dire.7 But three quarters of these women will go on to have a successful pregnancy if offered nothing more, and nothing less, than tender loving care and reassurance through ultrasound that nothing is abnormal. A specialised clinic for women with miscarriage may be the best place to offer this.11
Who should investigate couples with recurrent miscarriage? Although a thorough investigation will eventually require the expertise of an obstetric specialist, possibly working in a dedicated clinic, the karyotyping of both partners can, and should, be done by primary care physicians so that couples can take their karyotypes with them if they need further investigation or advice. When one partner is the carrier of a balanced translocation the couple should be referred to a clinical geneticist. Karyotyping in primary care will streamline the process. And it will be one small step towards the incorporation of genetics into mainstream medical services, one of the objectives of Our Inheritance, Our Future—realising the potential of genetics in the NHS, the UK Department of Health's white paper on genetics.12
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Competing interests None declared.