Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK
1 To whom correspondence should be addressed. Email: jck4{at}le.ac.uk
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Abstract |
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Key words: one-stop clinic/recurrent miscarriage
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Introduction |
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East Midlands is a large region in England with a population of 1.5 x 106. A dedicated Recurrent Miscarriage Clinic (RMC) was started at the Leicester Royal Infirmary in 1999 to cater for couples with this complication. The clinic is run by a team consisting of a consultant, a primary nurse, a nurse counsellor, a clinic coordinator and a clinical research fellow. Only women who have had at least two consecutive miscarriages are eligible to be seen in the clinic.
The patients seen in the clinic are referred by their own General Practitioners (GPs), other gynaecologists or the Early Pregnancy Assessment Clinic (EPAC). For the first 12 months of the clinic, a number of investigations was undertaken at the initial visit and then reviewed at follow-up appointments often 35 months later. The plan of management for any ensuing pregnancy was discussed at these follow-up visit in the light of the results of the investigations. This often meant a delay of 69 months between receiving the initial referral and deciding on the management plan because of capacity and demand.
As the number of referrals to the clinic increased, its capacity was overstretched, and even further by the follow-up appointments. By the end of the first 12 months the average waiting time before the first visit to the clinic had risen from 23 to 912 months. This was unacceptable to most couples who had suffered significant distress during the waiting. A review of the processes within the clinic was therefore undertaken and the result was the establishment of the one-stop RMC. In this paper we present the processes within this one-stop clinic since its inception and the results of investigations, treatment and outcome over a 4 year period.
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Materials and methods |
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An embryonic miscarriage was defined as one where the loss was after an ultrasound scan that demonstrated a gestational sac but not a fetal pole, whereas a fetal miscarriage was one following an ultrasound scan which demonstrated a fetal pole and fetal heart activity. Products from the miscarriages, which occurred subsequent to the clinic visit, were sent for karyotyping wherever possible.
The results are presented as means and 1 SD where appropriate. Comparisons are made with 2-test with significance set at P<0.05. The review of the outcome from the clinic was considered as an audit and was approved by the unit.
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Results |
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Of the 189 women, 103 (54%) had no obvious abnormality detected from the investigations, i.e. they had unexplained recurrent miscarriages. Table III shows the identifiable putative causes of the recurrent miscarriages. The most common were thrombophilias (14%) and antiphospholipid syndrome (11%) and the least common was intrauterine adhesions or Ashermann's syndrome (totalling 0.5%). Some of the abnormal results were of uncertain significance. These included a high HbA1c associated with a normal glucose tolerance test, autoimmune (antismooth muscle, antimitochondrial and antiparietal) antibodies and raised thyroid peroxidase antibodies. Putative causes for the miscarriages were identified in 31 of the 75 (41%) couples who presented after 2 miscarriages, 37 out of 81 (45%) presenting with three miscarriages and 18 out of 33 (55%) presenting with four or more miscarriages. There was no statistically significant difference (P=0.2) in the frequency of the identifiable causes in the three groups.
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Table IV shows the relationship between the age at presentation and spontaneous pregnancy rate. The older the woman, the lower the chances of spontaneous pregnancy and the higher the risk of another miscarriage. The best pregnancy and live birth rates were in women aged <35 years. Although the pregnancy rate in the 3640 year age group was significantly lower than that for those <35 years, the live birth rate was similar to that of all the other younger age groups. The relationship between the number of miscarriages, pregnancy and live birth rates is shown in Table V. Although the pregnancy rates were not affected by previous miscarriages, the live birth rate was lowest in those with 4 miscarriages.
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Fourteen (7%) women had activated protein C resistance (APCR) but subsequent genetic testing revealed Factor V Leiden mutation in only eight (4.2%) cases, all of which were heterozygous. There were 11 (5.8%) cases of protein S deficiency, four (2.1%) with protein C deficiency, two (1.1%) with combined protein C and S deficiencies and one with antithrombin III deficiency. None of the 26 women with thrombophilia had either a personal or family history of deep vein thrombosis or pulmonary embolism. The diagnosis of an abnormal result was based on two tests performed 3 months apart. Sixteen (61%) of the 26 women presented with three or more consecutive miscarriages and 10 (39%) with two consecutive miscarriages. Eight women in this group conceived once, four conceived twice and two conceived three times. Of the resulting 22 pregnancies, 14 (64%) were live births, three first trimester miscarriages (all fetal losses at 10 weeks), one second trimester miscarriage and one termination of pregnancy for Edward's syndrome. Three pregnancies are ongoing; currently 20, 25 and 39 weeks gestation. All these women received low molecular weight heparin during pregnancy.
Karyotyping for both partners was performed on all couples attending the clinic. Abnormalities were detected in nine (4.8%) cases; inversion on chromosome 9 [Inv (9) p1q21] was identified in four paternal and three maternal karyotypes. Other abnormalities included a maternal chromosomal translocation [46 XX t (5,9) (p13, q21)] and a paternal trisomy 21 mosaic (1% T21 of cells). Four (44.4%) of the nine couples in this group presented after two consecutive miscarriages and five (55.6%) after three or more. Five women conceived once and one conceived twice. Of the seven pregnancies, four were live births, one an embryonic first trimester miscarriage, another a miscarriage in the second trimester and one pregnancy was lost to follow-up at 16 weeks as the couple relocated to another country.
Two women had a positive thyroid peroxidase antibody: one had an elevated thyroid-stimulating hormone (TSH) and a normal free thyroxine (Free T4) whereas the other had a high TSH and a free thyroxine (Free T4) at the upper range of normal. Six women were found to have low TSH but normal free thyroxine (Free T4). Two of these subsequently developed hypothyroidism. Another three cases of hypothyroidism were diagnosed for the first time as a part of the investigations performed in the clinic and three were known to be hypothyroid before referral. Out of a total of eight women with hypothyroidism, six conceived resulting in three live births, two first trimester miscarriages (one fetal and one embryonic) and one second trimester miscarriage. All of these pregnancies were managed with thyroxine. Both women with antiperoxidase antibodies conceived and both had live births. No treatment was offered to these women.
Of the seven (3.7%) women with autoantibodies, three had anti-smooth muscle antibodies and two had antimitochondrial antibodies. Liver function tests were normal in these women. Additionally there was one case with a positive antiparietal antibody test and one with elevated rheumatoid factor. Six of these women conceived resulting in five live births and one early miscarriage (embryonic loss). They were treated empirically with low dose (75 mg/day) aspirin.
Hysteroscopy was performed on two women with hypomenorrhoea and previous evacuation of the uterus; the first revealed Ashermann's syndrome which was treated by hysteroscopic adhesiolysis, followed by an intrauterine device and estrogen stimulation; the second revealed a uterine septum which was removed hysteroscopically. Neither of these women has conceived.
Polycystic ovary syndrome (PCOS) was diagnosed in four women by a combination of symptoms: elevated LH:FSH ratio (>3:1) in the early follicular phase, low sex hormone-binding globulin and a low free androgen index. There were four pregnancies in this group (one conceiving twice) resulting in two live births, one second trimester miscarriage at 23 weeks gestation following pre-labour preterm rupture of fetal membranes and one first trimester fetal loss. These women received 5000 IU of -hCG injections weekly up to 12 weeks gestation.
Hyperhomocysteinaemia was identified in nine (4.8%) women, five with three or more consecutive miscarriages before referral and four with two. Four of these women conceived once, two conceived twice, one conceived three times and another conceived four times. There was a total of eight (53%) live births, one ongoing pregnancy (29 weeks) and six first trimester miscarriages. Four of the miscarriages were fetal at 11 weeks while the remaining two were embryonic early miscarriages at 5 weeks gestation. All of these women were treated with a combination of folic acid (5 mg/day), vitamin B12 (100 µg/day) and vitamin C (50 mg/day), commenced before pregnancy and continued throughout gestation.
The five women with high HbA1c but normal glucose tolerance test were grouped as idiopathic with those in whom no factor was identified. Of the 103 (54%) women in this group, there was a total of 75 pregnancies; 50 women conceived once, 11 conceived twice and one conceived three times; 56 (75%) were live births, 15 (20%) first trimester miscarriages with eight embryonic losses and seven fetal losses, one termination for multiple structural abnormalities and three (4%) ongoing (>24 weeks gestation).
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Discussion |
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Although the definition of recurrent miscarriages has traditionally been three or more consecutive miscarriages (Li et al., 2002a), there is an increasing acceptance that couples should be investigated after two miscarriages (Quenby and Farquharson, 1993
; Stephenson et al., 1998
). The traditional approach is based on the assumption that the prevalence of possible causes will be significantly different in those with two compared to those with three or more miscarriages. We did not find such a difference. There is therefore no justification in denying couples investigations after two consecutive miscarriages. Whether the gestational age at which the miscarriages occur influences the prevalence of the aetiological factors remains to be seen.
A prevalence of 29.8% for the prothrombotic state was similar to the 25% reported by Li et al. (2002b). However, chromosomal (4.8%), structural uterine anomaly (1%) and endocrine (7.9%) abnormalities were less common than reported by Li et al. (2002b)
. The lower prevalence of uterine anomalies in our series could, however, be explained by the differences in the investigations for these anomalies. We did not routinely offer all our patients timed endometrial biopsies and pelvic ultrasound scans. This would have enabled us to identify not only those women with uterine myomata and other congenital malformations but those with luteal phase defects. Consequently our unexplained category of 54% was higher than that of Li et al. (2002b)
, but was within the prevalence of 1155% reported in the literature (Stray-Pedersen and Stray-Pedersen, 1984
; Coulam et al., 1995
). Hyperhomocysteinaemia reported by Nelen et al. (2000)
as a cause of recurrent miscarriages was present in 4.8% of our patients. The role of investigating for thyroid dysfunction in asymptomatic women with recurrent miscarriages, however, remains uncertain. Drakeley et al. (1998)
identified 2% of their cases with thyroid dysfunction, while we identified 4.2%. The most difficult cases were those with raised TSH and normal free thyroxine (Free T4) and those with raised thyroid peroxidase antibodies. Although these were not treated, we have been advised by the endocrinologist that these women are at a significantly increased risk of hypothyroidism and should be monitored by yearly thyroid function test (personal communications). In fact, two of our patients with raised TSH and normal free thyroxine (Free T4) (compensatory euthyroid) became overtly hypothyroid.
The live birth rate of 67% in our series is similar to that reported by others (Li et al., 2002b; Morikawa et al., 2003
). The rate was similar in women aged <40 years although the pregnancy rates were much higher in those aged <35 years compared to those aged 3540 years. Those aged >40 years were not only less likely to conceive spontaneously but were significantly more likely to miscarry. Women with two or three miscarriages had a similar live birth rate (67 versus 73%, P>0.05) whereas those with four or more miscarriages had a lower live birth rate 50%).
The idiopathic group (75%) had the highest live birth rate, similar to rates quoted in the literature (Liddell et al., 1991; Clifford et al., 1997
). Although the rate was highest in those with autoimmune antibodies (85%) the numbers in the group were small. The live birth rate was lowest in those with abnormal karyotypes (57%), hyperhomocysteinaemia (53%) and hypothyroidism (50%). The pregnancy loss rates in the couples with abnormal karyotypes is expected to be higher especially if the fetus is karyotypically abnormal; however, for the other two groups, we have been able to review our approach to their management. For example, while we were not stressing the importance of normal homocysteine levels before pregnancy after initiating treatment for the hyperhomocysteinaemias, we now make every effort to ensure that this is indeed the case. This approach appears to have improved the chances of a live birth in this group. Those with thyroid dysfunction were unfortunately not treated until much later, as they had presented with compensatory euthyroidism. Whether they should be offered thyroxine empirically or not remains to be resolved. There have been some suggestions by endocrinologists that these should be treated with an empirical dose of thyroxine (50100 µg/day) but this is yet to be adopted in our clinic. The same applies to those with raised thyroid peroxidase antibodies. We are collecting these cases and will hopefully review them when the numbers are large enough to make any meaningful conclusions.
The outcome for those with antiphospholipid syndrome (53%) was much poorer than that for other groups (7077%) (Kutteh, 1996; Granger and Farquharson, 1997
; Rai et al., 1997
; Li et al., 2002b
). However, if we include the one patient who relocated and the three with ongoing pregnancies beyond 24 weeks gestation, this value will rise to 73%, which is in keeping with the value of 7077%. We treated these patients with a combination of both aspirin and Dalteparin (Fragmin) throughout pregnancy. Although Rai et al. (1997)
recommended stopping the anticoagulant therapy at 34 weeks, others have suggested continuing with treatment throughout pregnancy (Farquharson et al., 2002
; Li et al., 2002a
), the rationale for this being that the risk of thrombosis does not diminish with gestation and therefore the thromboprophylactic value should remain. However, the findings from randomized controlled trials that the outcome of pregnancies in placebo- and aspirin-treated groups (Pattison et al., 2000
) and aspirin- and aspirin and heparin-treated groups Farquharson et al., 2002
) were similar questions the rationale for intervention in these women. Since the numbers in these studies are small, the consensus is to continue the present approach. There is emerging evidence that antiphospholipid syndrome may in fact cause recurrent pregnancy losses by interfering with trophoblast development and differentiation (Chamley et al., 1998
). If this is indeed the case, then there may well be a strong reason for starting treatment earlier, but there is as yet no evidence to support this approach.
Although inheritable thrombophilias as a cause of recurrent miscarriage is controversial, with some studies suggesting an increased risk (Grandone et al., 1997; Younis et al., 2000
; Vossen et al., 2004
) and other studies not (Rai et al., 2001
), we found a prevalence of 14% in our population. The most common, that for factor V Leiden, had a prevalence of 4.2%, which is similar to the 34% for the general UK population (Li et al., 2002a
). Perhaps in such a highly selected group, this would have been expected to be higher. For the other thrombophilias, while the population prevalence is low (Li et al., 2002a
) we had a higher prevalence of 5.8% for protein S deficiency, 2.1% for protein C deficiency, 1.1% for combined protein C and S deficiencies and 0.5% for antithrombin III deficiency. All these women were treated with Dalteparin (Fragmin) as recommended by Brenner et al. (2000)
and the live birth rate in the group was 64% which is in keeping with that of Brenner et al. (2000)
but significantly higher than the 20% in an untreated group (Brenner et al., 2000
). Li et al. (2002a)
on the other hand suggest that routine treatment with low molecular weight heparin or heparin in this group is not indicated. In the absence of randomized controlled trials, we feel this will remain contentious.
We offered three of the women with PCOS and oligomenorrhoea, treatment with hCG on the basis of the randomized controlled trial of Quenby and Farquharson (1994) but have stopped this practice since the publication of the Royal College of Obstetricians and Gynaecologists' guidelines (2003)
, without affecting pregnancy outcome, although the numbers are still too small for statistical judgement.
In conclusion, a one-stop RMC significantly reduced the interval and increased the throughput in the clinic. Although we did not routinely offer all our patients investigations for endometrial abnormalities, the live birth rate was similar to that from other units, including those units where such screening is offered. This will confirm the observations that supportive therapy is probably the single most effective therapy for couples with recurrent miscarriages irrespective of the putative aetiological factor.
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Submitted on June 21, 2004; accepted on August 26, 2004.