Trip Answers

Question answered:18/06/02 Warning! this question is over two years old.

The Royal College of Obstetricians and Gynecologists hold a green top guideline for the Management of Recurrent Miscarriage, dated June 2001 (1). The College state that

"green-top guidelines are produced under the direction of the Guidelines and Audit Committee of the Royal College of Obstetricians and Gynaecologists. The recommendations are not intended to dictate an exclusive course of management or treatment. They must be evaluated with reference to individual patient needs, resources and limitations unique to the institution and variations in local populations."

Individual recommendations have been graded according to the level of evidence on which they are based using the scheme endorsed by the NHS Executive:
Grade A:	randomised controlled trials
Grade B:	other robust experimental or observational studies
Grade C:	more limited evidence but the advice relies on expert opinion and has the endorsement of respected authorities

 

The Cochrane Library holds two reviews on treatments for recurrent miscarriage. Scott et al note that there is not enough evidence to evaluate the use of human chorionic gonadotrophin during pregnancy to prevent miscarriage in women with a history of unexplained recurrent spontaneous miscarriage (2). A review on immunotherapy for recurrent miscarriage concluded that paternal cell immunization, third party donor leukocytes, trophoblast membranes and IVIG provide no significant beneficial effect over placebo in preventing further miscarriages (3). There are also two protocols listed in the Cochrane Library for other treatments which consider recurrent miscarriage. One considers miscarriage associated with antiphospholipid antibody or lupus anticoagulant (4) and one intends to evaluate progestogen for preventing miscarriage (5); the latter will consider sub group analysis of recurrent miscarriage if the data is available. When these two reviews are written they will add to the body of systematically collected evidence on recurrent miscarriage.

Bandolier recently reported on a systematic review on antiphospholipid anitbodies and pregnancy loss published by Emspon in Obstetrics & Gynecology (2002) (6). They quote numbers and percentages of pregnancy losses with different treatments:

 

Intervention	Trial Arms	Losses/Total pregnancies	Percent (95% CI)
None, usual care	4	30/80	37 (27 to 48)
Aspirin alone	6	50/129	39 (30 to 47)
Low MW heparin plus aspirin	6	36/155	23 (17 to 30)

 

They also add that use of prednisolone was associated with higher rates of premature birth and admission to neonatal intesive care units with no evidence of preventing pregnancy loss.

1. http://www.rcog.org.uk/guidelines.asp?PageID=106&GuidelineID=18

2. Scott JR, Pattison N, Human chorionic gonadotrphin for recurrent miscarriage, The Cochrane Library, last amendment July 2000.

3. Scott JR, Immunotherapy for recurrent miscarriage, The Cochrane Library, last amended May 2001.

4. Empson M et al, Therapy for miscarriage associated with antiphospholipid antibody or lupus anticoagulant [protocol], The Cochrane Library, due to be published Issue 4, 2001.

5. Oates-Whitehead RM, Carrier JAK, Progestogen for preventing miscarriage [protocol], The Cochrane Library, due to be published Issue 4 2002.

6.

 

 

http://www.jr2.ox.ac.uk/bandolier/band97/b97-2.html.

 

On investigation and treatment the guideline states:

"Genetic factors

Some 3%-5% of partners presenting with recurrent pregnancy loss carry a chromosomal abnormality, most commonly a balanced reciprocal or Robertsonian translocation.56 Peripheral blood karyotyping should be performed on all couples with recurrent miscarriage (Grade C recommendation) and the finding of an abnormality should prompt referral to a clinical geneticist. Specialist counseling offers the couple a prognosis for future pregnancies, as well as allowing for the investigation and counseling of relatives and appropriate prenatal diagnosis in ongoing pregnancies (Grade C recommendation). Although fetal chromosomal abnormalities are the commonest cause of sporadic miscarriage, they are less frequent in women with recurrent miscarriage. Nonetheless, these women are not protected from a sporadic fetal loss and karyotyping the products of conception in cases of recurrent miscarriage provides useful information for counseling and future management (Grade C recommendation).

Anatomical factors

 

It is difficult to assess the importance of uterine structural abnormalities amongst women with recurrent miscarriage. For example, when a uterine septum is identified, it is important to question whether it is causally related to the history of pregnancy loss, since the reported incidence of uterine septa in women with normal reproductive histories, is similar to that identified in women with a history of recurrent miscarriage. Open uterine surgery is associated with significant postoperative infertility and carries the risk of uterine rupture during labour. These complications are less likely after hysteroscopic surgery but no randomised studies assessing the benefits of surgical correction of uterine abnormalities in relation to pregnancy outcome have been published.

The use of hysterosalpingography as a routine investigation for recurrent miscarriage is questionable since it is associated with patient discomfort, carries a risk of pelvic infection and offers the same diagnostic sensitivity as non-invasive pelvic ultrasound assessment of the uterine cavity.

Cervical incompetence

 

Cervical incompetence is often over-diagnosed as a cause of mid-trimester miscarriage. Cervical cerclage should only be considered when the history of miscarriage is preceded by spontaneous rupture of membranes or painless cervical dilatation. The MAC/RCOG trial of the use of cervical cerclage reported a small decrease in preterm birth, but no significant improvement in fetal survival (Grade B recommendation). Transabdominal cerclage performed preconceptually has been advocated as a treatment for second trimester miscarriage and the prevention of early preterm labour. The reported improvement in pregnancy outcome is difficult to assess in the absence of a control group.

Infective factors

 

Any severe maternal infection which leads to bacteraemia or viraemia can cause sporadic miscarriage. The role of infection in the aetiology of recurrent miscarriage is unclear. For an infective organism to be implicated in the aetiology of recurrent episodes of pregnancy loss, it must be capable of persisting in the genital tract and avoiding detection, or cause insufficient symptoms to disturb the woman. Toxoplasmosis, rubella, cytomegalovirus, herpes and listeria infections do not fulfil these criteria and the performance of TORCH screening is invariably uninformative (Grade C recommendation). The presence of Bacterial Vaginosis (BV) in the first trimester of pregnancy has been reported as a risk factor for preterm delivery and second trimester miscarriage, but an association with first trimester miscarriage has not been shown. Treatment with metronidazole for pregnant women with bacterial vaginosis has recently been reported to reduce the risk of preterm delivery, but the benefit was only noted in those women with a history of previous preterm delivery. Further pregnancy outcome studies are required.

Endocrine factors

 

Inadequate secretion of progesterone during the luteal phase of the menstrual cycle and in the early weeks of pregnancy has been presumed to be a causative factor in many cases of recurrent miscarriage. A review of pregnancy rates following hormonal treatments for luteal phase deficiency concluded that the benefits are uncertain, and a meta-analysis of six trials has reported that exogenous progesterone supplementation after conception does not improve pregnancy outcome (Grade A recommendation) Low progesterone levels in early pregnancy appear to reflect a pregnancy that has already failed.

 

A multicentre placebo controlled trial of early pregnancy human chorionic gonadotrophin (hCG) supplementation failed to show any benefit in pregnancy outcome. However, a further small randomised study has suggested that hCG improves pregnancy outcome in a small subgroup (n=23) of recurrent miscarriers with oligomenorrhoea and a history of recurrent miscarriage. This finding has prompted proposals for a further multicentre study of hCG treatment in this particular subgroup of recurrent miscarriers. Since pregnancies recruited to a study between six and eight weeks of gestation are destined to be successful in 98% of cases, analysis of these data will need careful interpretation. hCG supplementation should only be used in the context of ongoing randomised controlled trials.

Systemic maternal endocrine disorders such as diabetes mellitus and thyroid disease have been

associated with miscarriage. Diabetic women with high haemoglobin Alc levels in the first trimester are at significantly higher risk for miscarriage and fetal malformation. However' well controlled diabetes mellitus is not a risk factor for recurrent miscarriage, nor is treated thyroid dysfunction. Routine screening for occult diabetes and thyroid disease with oral glucose tolerance and thyroid function tests should not be performed in asymptomatic women presenting with recurrent miscarriage. (Grade C recommendation)

The prevalence of polycystic ovaries (PCO) identified using pelvic ultrasound criteria is significantly higher among women with recurrent early miscarriage (56%) when compared to the general population (22%). Many of these women hypersecrete luteinising hormone (LH), which has been reported as a risk factor for both infertility and recurrent pregnancy loss. However, a recent randomised trial has shown that pre-pregnancy suppression of LH does not improve the live birth rate amongst ovulatory women with PCO who hypersecrete LH (Grade A recommendation).

A history of subfertility, particularly ovulatory defects is present in 25%-30% of women with recurrent miscarriage and confers a poor prognosis for future pregnancy outcome. Raised follicle stimulating hormone (FSH) levels are found in a small percentage of these women (1%-2%) but when persistent, require counselling for the implications of premature ovarian failure (Grade C recommendation) .

The routine performance of a pelvic ultrasound scan to establish ovarian (and uterine) morphology is a useful tool to identify women with risk factors for pregnancy loss (Grade C recommendation) .

At the present time there are no treatments of proven benefit for specific endocrine defects in women with recurrent pregnancy loss. This lack of evidence is probably a reflection of poor understanding of these endocrine events.

2.6 Autoimmune factors

The primary antiphospholipid syndrome (PAPS) refers to the association between antiphospholipid antibodies (aPL) with recurrent miscarriage or thrombosis. Thrombocytopenia is sometimes present. It is now recognised that aPL are implicated in the pathogenesis of a wider range of obstetric, vascular and neurological conditions. Pregnancy loss has traditionally been ascribed to thrombosis of the uteroplacental vasculature and subsequent placental infarction. It is unlikely that this is the only explanation since aPL are also reported to impair trophoblast function via mechanisms unrelated to thrombosis.

Antiphospholipid antibodies - lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) of the IgG or IgM class - are present in 15% of women with recurrent miscarriage. By comparison, the prevalence of aPL in women with a low risk obstetric history is less than 2%. In women with recurrent miscarriage associated with aPL the livebirth rate in pregnancies with no pharmacological intervention may be as low as 10%. Treatment with corticosteroids in pregnancy does not improve the live birth rate and since it is associated with significant maternal and fetal morbidity should be abandoned (Grade C recommendation). A recently published prospective randomised study has reported that the live birth rate in recurrent miscarriers with aPL treated with low dose aspirin alone (75mg acetylsalicylic acid daily) is 40% and significantly improved to 70% when they are treated with low dose aspirin together with low dose heparin (5,000 iu subcutaneously 12 hourly) (Grade A recommendation). In this trial, aspirin was commenced at the time of a positive urinary pregnancy test and the heparin once fetal heart activity was seen on ultrasound scan. Treatment with aspirin and/or heparin was discontinued at 34 weeks' gestation. However, the results of this trial and the observational study conducted in the USA do not exclude the possibility of a placebo effect from heparin treatment. Efficacy and other issues, including optimum duration of treatment, is the subject of current research, and clearly this recommendation may be reviewed when more evidence becomes available.

Detection of aPL is subject to considerable inter-laboratory variation. This is due to:

• temporal fluctuations of aPL titres in individual patients;
• transient positivity secondary to viral and other infections present at the time of sampling;
• suboptimal sample collection and preparation of platelet poor plasma;
• lack of standardisation of laboratory tests for their detection.

Before a diagnosis of PAPS can be made it is mandatory that the patient should have two positive tests at least six weeks apart. The dilute Russell's viper venom time (RVVT) test is more sensitive than the kaolin cephalin time (KCT) or activated partial thromboplastin time (APTT) tests to detect LA. Anticardiolipin antibodies are detected using a standardised ELISA. A recent study has reported that testing for aPL other than LA and aCL in women with recurrent miscarriage is of no clinical value (Grade C recommendation) .

Thrombophilic defects

Retrospective studies have reported an increased prevalence of the natural inhibitors of coagulation - antithrombin m, protein C and protein S - as well as hyperhomocysteinaemia in women with recurrent miscarriage. Activated protein C resistance (APCR) has been reported in a variable proportion of women with recurrent miscarriage. The vast majority of cases of APCR are congenital, secondary to a mutation in the factor V (Leiden) gene. Factor V Leiden is the most prevalent familial thrombophilic condition. Acquired APCR is rare outwith pregnancy when the recently developed coagulation assays are employed. Thrombophilic defects in women presenting with recurrent miscarriage is a promising avenue of research. However the efficacy of thromboprophylaxis during pregnancy in recurrent miscarriers found to have thrombophilic defects, but who are otherwise asymptomatic, has not been established.

Alloimmune factors

There is no clear evidence to support the concept of partner specific miscarriage or the hypothesis that some women miscarry because they are unable to mount an appropriate protective immune response to prevent rejection of their genetically dissimilar fetus. Meta-analysis has suggested that the marginal benefit which has been claimed with paternal white cell infusions should be balanced against the potential complications of immunotherapy, including transfusion reaction, anaphylactic shock and hepatitis. Routine tests for HLA type, anti-paternal cytotoxic antibody and the use of immunotherapy cannot be recommended (Grade B recommendation).

Unexplained recurrent miscarriage

In a proportion of women the recurrent episodes of pregnancy loss will remain unexplained despite careful investigation. The importance of identifying this group is significant, since they can be reassured that the prognosis for future pregnancy with supportive care alone is in the region of 75%. The value of psychological support in improving pregnancy outcome has not been tested in the form of a randomised controlled trial. However, data from several non-randomised studies have suggested that attendance at a dedicated early pregnancy assessment clinic has a beneficial effect although the mechanism is unclear. These data suggest that the use of empirical therapy in women with no recognisable aetiological factors for their miscarriages is unnecessary and should be resisted (Grade C recommendation). Further, clinical evaluation of future treatments for recurrent miscarriage should only be performed in the context of randomised trials.

Recommendations

It is recommended that the investigation of recurrent miscarriage should include:

• peripheral blood karyotyping in both partners
• karyotyping of all fetal products
• a pelvic ultrasound scan to assess ovarian morphology and the uterine cavity
• screening tests for antiphospholipid antibodies (both the lupus anticoagulant and anticardiolipin antibodies) performed on two separate occasions at least six weeks apart. Discordant results should prompt the performance of a third test.

The place of all other investigations including a search for newly described thrombophilic defects is unproven and such tests should only be performed in the context of research studies.

It is further recommended that in women with recurrent miscarriage who have undergone the above investigations

• those with karyotypic abnormalities should be seen by a clinical geneticist
• that women with persistently positive tests for antiphospholipid antibodies are offered treatment with low dose aspirin together with low dose heparin during pregnancy (also the subject of on-going research).
• that treatments of unproven benefit should be abandoned
• that all future treatment options are evaluated in randomised controlled trials.

 

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