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The medical and surgical management of recurrent miscarriage
Currenr Ohsrerrics & Gymecology ( 1999) 9, I3- I8 0 1999 Harcourl Brace & Co. Ltd
Mini-symposium: Recurrent abortion
The medical and surgical management of recurrent miscarriage
J. Walker Recurrent miscarriage is suffered by 1% of couples. It is extremely distressing causing stress to the woman and her family. A careful history and investigation can elicit a cause in around 50% of cases. Early pregnancy support and targeted treatments can increase the likelihood of successto approximately 80”/0in the subsequent pregnancy. Possible treatments include psychological support, aspirin, hCG injections and cervical cerclage, but these need to be considered carefully and explained fully to the couple before being tried. Extravagant claims and inappropriate, potentially dangerous therapies must be avoided. Management is best performed in specialized units with experience in this area.
INTRODUCTION
Although miscarriage is a relatively common event occurring in around 15”/0of all known pregnancies, relatively little is known about its aetiology. It is thought to be associatedwith an abnormal conceptus in at least half of the cases and is usually sporadic and non-recurring. The chance of having a second spontaneous miscarriage after only one isolated occurrence is generally considered to remain at 1520% (for clinically recognized pregnancy). If there have been two spontaneous losses in a row, there is about a 25% chance that the next pregnancy will be lost. But it is only after three spontaneous miscarriages, that the risk is significantly increased to around a 30% chance of a loss in the subsequent pregnancy. This is why the definition of recurrent miscarriage is usually used after three losses. This does not mean, however, that a woman should not get support after two miscarriages, but the investigation and management may not be as intensive.‘,?The incidence of recurrent miscarriage is relatively rare at around l%.’ Professor James Walker, Division of Obstetrics and Gynaecology, St James University Hospital, Beckett Strccl, Leeds LS9 7TF. UK
About 80% of spontaneous miscarriages occur in the first trimester of pregnancy and most off them within the first 7/8 weeks. The types of miscarriage can generally be divided into three: 1. Women who present early in gestation with a nonviable pregnancy.This is due to an early fetal death and is commonly called a blighted ovum, a missed miscarriage or an incomplete depending on the ultrasound findings. In the majority of cases,histological or biochemical examination can find evidence of a fetus that was once there. 2. Women who present at varying stages of pregnancy with a intrauterine death after an ultrasound has previously confirmed a viable pregnancy.These pregnancies present later than in the first type and into the second trimester and are similar to an intrauterine death at any gestation 3. Women who delivery an apparently normal and previously alive baby becauseof premature uterine action or incompetent cervix. This problem occurs in the second trimester and has similarities to premature labour. Although recurrent miscarriage may be due to genetic abnormality in the conceptus, most would appear to be due to problems related to immunology,
14
Current
Obstetrics
& Gvnaecolog>
Table 1 . Factors to elicit from the history of women with rccurrcnl pregnancy loss
Table 2 Investigation in casts of miscarriage (thcsc dcpcnd on the history)
Menstrual history is the cycle irregular (PCOS) Dilliculties in getting pregnant is there an associated infertility Bleeding in pregnancy is this associated with a placental separation Gestation of diagnosis is this a lirst or second-trimester loss Ultrasound findings was a fetus seen was the FH thcrc prior to the miscarriage The miscarriage was there pain and/or bleeding prior to he diagnosis in second trimcstcr casts was thcrc labour pains in second trimcstcr casts did the membranes rupture lirst
Chroniosomal analysis 0r couples for balanced translocation factor V Lcidcn abnormality Hormonal asscssmcnt delicicnt lutcal phase poor follicular dcvclopmcnt Immunological abnormalities lupus anticoagulant anticardiolipin Antibody Hystcroscopy or ultrasound examination ror utcrinc abnormality submucous fibroids ovarian morphology Cervical rcsistancc studies
coagulation, hormonal or uterine structure. It is important to remember that there may be more than one reason and other factors complicate the picture. Since the miscarriage rate rises as a woman’s age increases, and this is often associated with increasing infertility, the management may be complicated by the increasing anxiety of the couple and often requires more than one therapeutic approach with close counselling and support.
Not surprisingly, the hormonal problems found in infertility are also found in recurrent miscarriage. This does not ncccssarily imply cause. The most common abnormality is polycystic ovarian syndrome (PCO) with associated luteal phase defects, sometimes with abnormalities of luteinizing hormone (LH).” These dcfccts are the result of inadequate levels of progcsterone, sometimes associated with poor follicular development, and result in inadcquatc endometrial growth. The luteal phase is usually short. This is thought to reduce the uterine receptivity. This can be studied by looking for an abnormal LH surge, a day 21 progesterone level which is found to be low. a persistently abnormal endometrial biopsy or ultrasound investigation for polycystic ovaries. Even though some abnormality can bc found in around 50% of women with early rccurrcnt loss. successful treatments regimes have not been fully evaluated, although some women may benefit from early pregnancy hormonal support. There is no evidence that routine investigation of abnormalities of thyroid disease or diabetes is of bcnelit (Table 2)
ASSESSMENT As with all medical problems careful history taking is important with a detailed log of the couple’s prior reproductive history. Many couples blame themselves for their pregnancy losses. Although smoking and excessive alcohol intake are associated with miscarriage, this is not a significant factor in recurrent loss. Many couples are concerned about the effect of the environmental factors such as irradiation, exposure to chemical teratogens or the use of VDUs. Little evidence is available to support these fears. In general. a reduction in exposure to potentially concerning environmental factors and basic health advice is normally all that is required. The information to note from previous pregnancies is listed in Table 1. The most important factors are the association with infertility or menstrual irregularities.4 the gestation of miscarriage, whether fetal heart activity was seen prior to the loss and, in secondtrimester losses, whether contraction pains were felt and the length of the labour. Clinical examination usually reveals little of benefit except for the gross abnormalities of anatomy which should have been found before. Structural problems are not usually associated with firsttrimester losses and, if suspected, should be investigated by more direct means. INVESTIGATION Hormonal abnormalities Recurrent miscarriage is associated with menstrual abnormalities and infertility in around 30% of cases’l
Chromosomal
Spontaneous miscarriage is associated with chromosomal abnormalities in the conceptus in many instances. If material from previous miscarriages was sent for chromosomal analysis, the results should bc obtained. The couples should be tested for the presence of chromosomal abnormalities such as translocations, which are either Robertsonian or reciprocal. These abnormalities are balanced when the total amount of material is normal. The gametes can obviously contain either too much or too little genetic material, which can lead to an abnormal conceptus and miscarriage. Other abnormalities include various chromosomal structural changes such as inversions. These are rarer and can be more difficult to detect. In most clinics, genetic investigations are normal in 95% of cases.?,”If an abnormality is identified, preconception genetic counselling is required to explain the risks of further miscarriages and the role of
The medical and surgical management of recurrent miscarriage prenatal diagnosis. There are obviously no curative treatments available at the present time.
immunological
investigations
Immunological causes of recurrent pregnancy loss are poorly understood. If a wide range of autoantibodies is looked for, many are found to be positive.5 The rclcVance of many of these is questionable. There is no doubt that the greater the number of miscarriages the women has, the more likely that she possessesmeasurable autoantibodies. Whether this is cause or effect is difficult to establish. but they do appear to be associated with successful treatment regimes making these tests of particular importance.” One particular type is the anti-phospholipid syndrome (APS) which is associated with around 15% of rccurrcnt pregnancy loss.?.’Phospholipids are involved in cell membranes and various cellular functions such as prostacyclin synthesis and protein C activity. Antibodies against them are associated with many disease states including vascular endothelial disorders and early pregnancy loss. Classically, they are associated with intrauterine death, abruption, intrauterine growth restriction and a pre-eclamptic type condition. The original diagnosis was associated with abnormalities of coagulation, the so-called ‘Lupus’ anticoagulant. The diagnosis is made using the phospholipid-dependent coagulation tests, such as the kaolin clotting time, the plasma clotting time, dilute Russell viper venom time. and activated partial thromboplastin time. The main problem with these assays is that there is little standardization between centres and the percentage positive rate varies considcrably. There is a desperate need for uniformity. This is also true for the other test carried out into anti-cardiolipin antibodies. This assay uses a normal range to assess abnormality and cut-off’ levels vary between laboratories and centres. Another factor is that the levels of the antibodies vary with pregnancy. Some women who are negative when non-pregnant can have abnormal levels during the subsequent pregnant and these should be rechecked in the first trimester. Abnormalities of immune response have long been proposed as a cause of pregnancy loss. Normally an individual will reject non-self (such as fetal tissue) using the immune system. The placenta (and pregnancy) would appear to have a ‘privileged’ relationship with the pregnant woman that allows for it to escape rejection. The mechanism for this is not known. People have suggested that this may be due to a reduced immune response, an increased immune response or a mixture of both. So far, none of these theories has been generally proven or accepted. In recurrent miscarriage, immunological abnormalities have been found,s which has led people to develop several expensive and potentially-dangerous treatment options, none of which have proven universally successful.
Thrombophilic
15
abnormalities
With the interest in APS, other thrombophilias have been investigated. There is an increased prevalence of defects of antithrombin III, protein C, protein S and hyperhomocysteinaemia. Activated protein-C resistance is associated with various pregnancy pathologies. This is not always associated with Factor V Leiden but can be acquired during pregnancy. It is still unclear what relevance these abnormalities have in recurrent miscarriage but they may have an additive effect. If found they lend themselves easily to treatment with low-dose aspirin. Structural
abnormalities
The incidence of structural abnormalities of the uterus arc unknown since these defects are not readily apparent without invasive investigation. The available reports generally cite incidences of from about 1:200 to 1:600 women. Therefore, these defects are not rare. About 1:4 women with a congenital anomaly of the uterus owing to a fusion defect will have significant difficulty with reproduction, possibly including recurrent pregnancy loss, but problems are not inevitable and causation may not be linked. A septate uterus is the most common congenital problem with others including bicornuate and uterus didelphys less common. Fibroids of the uterus that encroach on the cavity may distort the uterine shape. Although implantation of an embryo onto these areas of abnormality is thought to be associated with spontaneous miscarriage, there is no good supportive evidence of first-trimester problems” with most of the complications occurring in the second trimester and premature labour. It important not to rush to surgical intervention if an abnormality has been found as the surgery is not without its complications. Cervical
problems
Maintenance of the pregnancy is dependent on the integrity of the cervix. If the cervix is weak. inappropriate dilatation can occur leading to premature labour and second-trimester miscarriage. It is not associated with first-trimester loss. It is not until 16-18 weeks’ gestation that pressure is exerted onto the internal OS and the function of the cervix challenged. If the cervix is weak, there is painless dilatation leading to bulging of the fetal membranes, often in an hourglass shape through the cervix, spontaneous rupture of the membranes and delivery of the fetus. This sort of clinical history is usually the result of an incompetent cervix. The causes of cervical incompetence can be congenital, but the majority are acquired following trauma to the cervix such as with mechanical dilatation, cervical conisation or extensive biopsy, and precipitous labours or cervical lacerations during labour and delivery. Although the history is often very suggestive of cervical incompetence, establishing the diagnosis with
16
Current Obsletrics & Gynuecology
Table 3’ Diagnostic groups Early fetal loss, no evidence of fetal heart seen ’ may be associated with hormonal abnormalities delicient luteal phase may benefit from hormonal support Fetal loss after fetal heart action seen can occur al any gestation associated with antiphospholipid syndrome may benelit from low-dose aspirin and/or heparin Structural abnormalities owing to congenital abnormality owing to libroids may not be causative of pregnancy loss second-trimester premature labour surgery of questionable value Cervical Incompetence second-trimester loss should have delinitive testing to confirm can benelit from cervical suture
certainty can be difftcult. Not all cases of cervical incompetence follow this typical history. In recent years measurement of the cervical resistance index has increased the accuracy of diagnosis.9This method uses a pressure-sensinghandle to assessthe pressure required to dilate the non-pregnant cervix to Hegar 8. Studies suggest that a measurement of 24 Newtons is the cut-off between incompetence and normality, although it is almost certainly a continuum. Women with a suggestive history and a normal cervical resistance delivered their subsequent pregnancy without use of a cervical suture. During pregnancy the integrity of the cervix can be assessedby serial ultrasound.‘“,” If the cervix is shortening or dilating, a rescue cervical suture can be inserted with varying degreesof success.‘?.” Infection
Although infection can be responsible for spontaneous miscarriage, its role in recurrent problems is unclear. Bacterial vaginosis (BV) is associated with premature labour and second-trimester loss. In the presence of persistent BV, metronidazole may be of benefit but further trials are necessary.Routine investigation for infection is not recommended.
TREATMENT
Using history and the above investigations, a reasonable assessment of potential causes can be found in around 50% of women with recurrent miscarriage.‘4.‘5 A mixed picture is often present.15The broad subgroups are listed in Table 3. There are various treatment options available that can be targeted at these groups. Since many of these therapies are unproven and most women will be successful in the next pregnancy anyway, the first aim should be to provide psychological support and do no harm.‘,16In the absence of a definitive diagnosis, the history may suggest possible etiological causes and empirical treatments can
be used, partly to reassure the couple that something is being done, but excessiveclaims must be avoided. Site of care
Ideally, care of the woman with recurrent pregnancy loss should be in a unit that specializes in this area, not a subfertility or routine gynaecological service. This is because it should be part of an overall therapeutic package involving counselling. investigation and early pregnancy support services as well as treatment modalities.‘”There is evidence that psychological support alone reduces recurrent loss and should be part of any treatment regime.” Refusal to accept this concept not only denies the woman the support she desires, but also worsens the situation by projecting a ‘non-caring’ attitude. In St James Hospital in Leeds, the recurrent miscarriage service is integrated into the early pregnancy assessment unit allowing full access to support services.‘”Prior to pregnancy any relevant investigations should be carried out and a management plan designed so that everyone involved knows what is going to be done when pregnancy occurs. The most important factor is early referral to the unit as soon as pregnancy is suspected. If therapies are to work, early commencement is required, prior to an FH being seen on ultrasound and sometimes before conception. Hormonal manipulation
Increasing progesterone during the luteal phase may appear to be a useful approach in those women whose miscarriage appear to be associated with a poor luteal phase. This could be accomplished by progesterone supplementation using vaginal preparations, promoting increased follicular development using clomiphene citrate or luteal rescue using hCG. Studies of progesterone supplementation usually lack appropriate controls and often start after the viability of pregnancy has been established. Luteal-phase support would seem to be more logical as it would give support when the deficiencies are thought to be present. This was investigated in a study of women who have been found to have hormonal abnormalities or PCO. One hundred and six women were randomized into either receiving LH suppression with buserelin followed by low-dose ovulation induction and vaginal progesterone for 10 days in the luteal phase or no pituitary suppression or ovulation induction, but half receiving luteal-phase progesterone support and the other half placebo. There was no difference in any of the groups suggesting that neither LH suppression nor luteal-phase progesterone is of any benefit.‘” At present there is no trial evidence to support the use of progesterone supplementation at any time. Clomiphene citrate has been shown to improve the menstrual cycle of women with known hormonal abnormalities and would appear to be a reasonable
The medical and surgical management of recurrent miscarriage solution to those with a mixed infertility and early pregnancy loss pattern. It is usually given in doses of 100 mg for 5 days from the first day of menses but, as yet, has not been subjected to a proper trial. Its use should probably be restricted to those with a concomitant need for infertility treatment. Although early studies of hCG therapy in early pregnancy showed encouraging results,“’ later larger studies failed to confirm them.?” More recently, a smaller study in women with a history of oligomenorrhoea showed improved results with the use of hCG.Z’ These findings confirm that women with an abnormality of their hormonal cycle and a history of infertility might benelit from some form of hormonal manipulation. Further studies are required. immunological
treatments
Although APA is an immunological abnormality, treatment with low-dose aspirin (75 mg) +/- low-molecular-weight heparin would appear to be of benefit.” The aspirin was started after the diagnosis of pregnancy and it may be better to commence low-dose aspirin prior to pregnancy. The aspirin and heparin was continued until 34 weeks or until delivery, whichever was the sooner. The evidence suggested that heparin may not have been of any benefit after 12 weeks’ gestation. A combination of aspirin and heparin would appear to be better than aspirin alone. Other immunological treatments have been tried. Immunoglobulin (IgG) therapy, with intravenous injections of IgG, has been used with some apparent success.” It is claimed that its use can improve on the success rate of aspirin and heparin in APA.2”However, it is expensive and potentially dangerous and has not been subjected to controlled trial. The use of IgG should be targeted at those who have failed other therapies and preferably be part of controlled trialsZS Immunization therapy using paternal leucocytes” has been widely studied. However, meta-analysis has found that it is questionable whether paternal cell alloimmunization is an effective treatment for unexplained recurrent miscarriage. Any therapeutic effect appears to be small and would, at best, help a small minority of affected couples.” These reviews suggest that immunotherapy appears to have minimal benefit in a small number of couples and the side elTectsprobably outweigh these potential benclits. Surgery
In cases of uterine abnormality, there have been various claims for the benefit of surgical correction of uterine abnormality.‘* These have usually been in uncontrolled trials of women who have improved their outcome after surgery. Much of this work has been carried out in women with uterine septa. However, there is little evidence of the role of
17
Table 4 Potential treatments, which should be targeted after a detailed history and investigation Early pregnancy support services for all For early pregnancy loss associated with PC0 hCG support in early pregnancy For immunological/coagulation abnormalities low-dose aspirin low-molecular-weight heparin Cervical suture in proven (suspected) cervical resistance vaginal suture abdominal suture
structural abnormalities associated with Iirsttrimester 10ss,~although there may be an association with second-trimester problems. The treatment of an incompetent cervix is surgical and was originally described in the 1950~.‘~.” This consists of a surgical placement of a suture or Mersilene band around the cervix as near to the level of the internal OS as possible. The problem with this technique is that in many instances, the cervix is badly damaged and short, leading to difficulty in pacing the suture at a level that would do benefit. The multicentre trial of cervical cerclage did demonstrate an improved outcome in those pregnancies where a stitch was inserted,)’ but the improvement was small. In those women with a failed vaginal suture, a transabdominal cerclage may be helpful.)? 35This is inserted at approximately 12 weeks’gestation around the cervix, above the ureters and medial to the uterine arteries. Overall, the success rate in the world literature is around 90% after abdominal cerclage, although there are less than 300 published cases at the present time. Since so few cases are being carried out, referral to regional centres would seem prudent. After insertion of the abdominal suture, delivery needs to be carried out by Caesarean section. Whether the suture is removed at the time of the Caesarean section depends on whether further pregnancies are desired.
CONCLUSION
The investigation and management of a couple with a history of recurrent pregnancy loss needs an individualized approach carried out by specialized units (Table 4). There needs to be a combined approach of psychological, investigative and therapeutic regimes. Care should be taken to provide unbiased advice, balanced information and appropriate therapy. However, these couples need reassurance that success is probable with the appropriate support and targeted treatments.36 REFERENCES I. Li TC. Recurrent miscarriage: principles of management. Hum Reprod 1998; 13: 478482. 2. Drakeley AJ, Quenby S, Farquharson RG. Mid-trimester lossappraisal of a screening protocol. Hum Reprod 1998; 13: 19751980. 3. Stirrat GM. Recurrent miscarriage I: detinition and epidemiology. Lancet 1990; 336: 673-675.
18 Current Obstetrics & Gynaecology 4. Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage preliminary experience of 500 consecutive eases. Human Reproduction 1994; 9: 1328-1332. 5. Roberts J, Jenkins C, Wilson R et al. Recurrent miscarriage is associated with increased numbers of cd5/20 positive lymphocytes and an increased incidence of thyroid antibodies. European Journal Of Endocrinology 1996; 134: 84-86. 6. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253-257. 7. Rai R, Regan L. Antiphospholipid antibodies, infertility and recurrent miscarriage. Current Opinion In Obstetrics & Gynecology 1997; 9: 279-282. 8. Maneschi I, Maneschi F, Parlato M, Fuca G, Incandela S. Reproductive performance in women with uterus didelphys. Acta Eur Fertil 1989; 20: 121-l 24. 9. Anthony GS, Fisher J, McManus TJ, Coutts JRT, Calder AA. Forces required for dilatation of the pregnant and non-pregnant human cervix. Br J Obstet Gynaecol 1982; 89: 913-916. IO. Flint S, Gibb DME Recurrent second trimester miscarriage. Current Opinion In Obstetrics & Gynecology 1996; 8: 449453. II. Guzman ER, Mellon C, Vintzilcos AM, Ananth CV, Walters C, Gipson K. Longitudinal assessment of endocervical canal length between I5 and 24 weeks’gestation in women at risk for pregnancy loss or preterm birth. Obstet Gynecol 1998; 92: 31-37. 12. Chasen ST, Silverman NS. Mid-trimester emergent cerclage: a ten year single institution review. J Perinatol 1998; 18: 338-342. 13. Heath VC, Souka AP Erasmus I, Gibb DM, Nicolaides KH. Cervical length at 23 weeks of gestation: the value of Shirodkar suture for the short cervix. Ultrasound Obstet Gynecol 1998; 12: 3 18-322. 14. Quenby SM. Farquharson RG. Predicting recurring miscarriage - what is important. Obstetrics And Gynecology 1993; 82: 132-138. 15. Clifford K, Rai R, Watson H, Regan I. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994; 9: 1328-1332. 16. Walker JJ, Shillito J. Early pregnancy units: service and organisational aspects. In: Grudzinskas JG, O’Brien PMS (eds) Problems in early pregnancy: advances in diagnosis and management. London: RCOG Press, 1997: l60- 173. 17. ClifTord K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent lirst trimester miscarriage. Hum Reprod 1997; 12: 387-389. 18. ClilTord K, Rai R, Watson H, Franks S, Regan L. Does suppressing luteinizing-hormone secretion reduce the miscarriage rate - results of a randomized controlled trial. British Medical Journal 1996; 312: 1508-1511. 19. Harrison RF. Miscarriage - hormonal treatment with hcg. Contraception Fertilite Sexualite 1991; 19: 373-376. 20. Harrison R. Human chorionic gonadotrophin in the management of recurretn abortion:results of a multicentre placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992; 72: 175-179.
21. Quenby S, Farquharson RG. Human chorionic gonadotrophin supplementation in recurring pregnancy loss. A controlled trial. Fertil Steril 1994; 62: 708- 710. 22. Rai R, Cohen H, Dave M. Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253-257. 23. Harris EN, Pierangeli SS. Utilization of intravenous immunoglobulin therapy to treat recurrent pregnancy loss in the antiphospholipid syndrome: a review. Stand J Rheumatol Suppl 1998; 107: 97-102. 24. Sher G, Matzner W, Feinman M et al. The selective use of heparinlaspirin therapy, alone or in combination with intravenous immunoglobulin G. in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization. Am J Reprod Immunol 1998; 40: 74-82. 25. Christiansen OB. Intravenous immunoglobulin in the prevention of recurrent spontaneous abortion: the European experience. Am J Reprod Immunol 1998; 39: 77-8 I. 26. Maejima M, Fujii T, Yamashita T et al. Immunotherapy before and during pregnancy improves pregnancy outcome in women who sulTer from recurrent abortion and did not benefit from immunotherapy before pregnancy. Am J Reprod Immunol 1998; 39: 12-15. 27. Jeng GT, Scott JR, Burmeister LF. A comparison of metaanalytic results using literature vs individual patient data - paternal cell immunization for recurrent miscarriage. Journal Of The American Medical Association 1995; 274: 830-836. 28. March CM, Israel R. Hysteroscopic management of rccurrcnt abortion caused by scptate uterus. Am J Obstet Gynecol 1987; 156: 834-842. 29. Shirodkar VN. A new method of operative treatment for habitual abortion in the second trimester of pregnancy. Antiseptic 1955; 52: 299-300. 30. McDonald IA. Suture of the cervix for inevitable miscarriage. J Obstet Gynaecol Br Emp 1957; 64: 346-353. 31. Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage. MRC/RCOG Working Party on Cervical Cerclaae. Br J Obstet Gvnaecol 1993: 100: 516-523. 32. Gibb DMF, Salaria DA. Transabdominal cervicoisthmic cerclage in the management of recurrent Znd-trimester miscarriage and preterm delivery. Br J Obstet Gynaecol 1995; 102: 802-806. 33. Anthony GS, Walker RG, Cameron AD, Price JL, Walker JJ, Calder AA. Transabdominal cervico-isthmic cerclage in the management of cervical incompetence. Eur J Obstet Gynecol Reprod Biol 1997; 72: 127-l 30. 34. Novy MJ, Transabdominal cervicoisthmic cerclage: a reappraisal 25 years after its introduction. Am J Obstet Gynecol 1991; 164: 163551641. 35. Novy MJ. Transabdominal cervicoisthmic cerclage for the management of repetitive abortion and premature delivery. Am J Obstet Gynecol 1982; 143: 44-54. 36. Clifford K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent lirst trimester miscarriage. Human Reproduction 1997; 12: 387-389.
Mini-symposium: Recurrent abortion
The medical and surgical management of recurrent miscarriage
J. Walker Recurrent miscarriage is suffered by 1% of couples. It is extremely distressing causing stress to the woman and her family. A careful history and investigation can elicit a cause in around 50% of cases. Early pregnancy support and targeted treatments can increase the likelihood of successto approximately 80”/0in the subsequent pregnancy. Possible treatments include psychological support, aspirin, hCG injections and cervical cerclage, but these need to be considered carefully and explained fully to the couple before being tried. Extravagant claims and inappropriate, potentially dangerous therapies must be avoided. Management is best performed in specialized units with experience in this area.
INTRODUCTION
Although miscarriage is a relatively common event occurring in around 15”/0of all known pregnancies, relatively little is known about its aetiology. It is thought to be associatedwith an abnormal conceptus in at least half of the cases and is usually sporadic and non-recurring. The chance of having a second spontaneous miscarriage after only one isolated occurrence is generally considered to remain at 1520% (for clinically recognized pregnancy). If there have been two spontaneous losses in a row, there is about a 25% chance that the next pregnancy will be lost. But it is only after three spontaneous miscarriages, that the risk is significantly increased to around a 30% chance of a loss in the subsequent pregnancy. This is why the definition of recurrent miscarriage is usually used after three losses. This does not mean, however, that a woman should not get support after two miscarriages, but the investigation and management may not be as intensive.‘,?The incidence of recurrent miscarriage is relatively rare at around l%.’ Professor James Walker, Division of Obstetrics and Gynaecology, St James University Hospital, Beckett Strccl, Leeds LS9 7TF. UK
About 80% of spontaneous miscarriages occur in the first trimester of pregnancy and most off them within the first 7/8 weeks. The types of miscarriage can generally be divided into three: 1. Women who present early in gestation with a nonviable pregnancy.This is due to an early fetal death and is commonly called a blighted ovum, a missed miscarriage or an incomplete depending on the ultrasound findings. In the majority of cases,histological or biochemical examination can find evidence of a fetus that was once there. 2. Women who present at varying stages of pregnancy with a intrauterine death after an ultrasound has previously confirmed a viable pregnancy.These pregnancies present later than in the first type and into the second trimester and are similar to an intrauterine death at any gestation 3. Women who delivery an apparently normal and previously alive baby becauseof premature uterine action or incompetent cervix. This problem occurs in the second trimester and has similarities to premature labour. Although recurrent miscarriage may be due to genetic abnormality in the conceptus, most would appear to be due to problems related to immunology,
14
Current
Obstetrics
& Gvnaecolog>
Table 1 . Factors to elicit from the history of women with rccurrcnl pregnancy loss
Table 2 Investigation in casts of miscarriage (thcsc dcpcnd on the history)
Menstrual history is the cycle irregular (PCOS) Dilliculties in getting pregnant is there an associated infertility Bleeding in pregnancy is this associated with a placental separation Gestation of diagnosis is this a lirst or second-trimester loss Ultrasound findings was a fetus seen was the FH thcrc prior to the miscarriage The miscarriage was there pain and/or bleeding prior to he diagnosis in second trimcstcr casts was thcrc labour pains in second trimcstcr casts did the membranes rupture lirst
Chroniosomal analysis 0r couples for balanced translocation factor V Lcidcn abnormality Hormonal asscssmcnt delicicnt lutcal phase poor follicular dcvclopmcnt Immunological abnormalities lupus anticoagulant anticardiolipin Antibody Hystcroscopy or ultrasound examination ror utcrinc abnormality submucous fibroids ovarian morphology Cervical rcsistancc studies
coagulation, hormonal or uterine structure. It is important to remember that there may be more than one reason and other factors complicate the picture. Since the miscarriage rate rises as a woman’s age increases, and this is often associated with increasing infertility, the management may be complicated by the increasing anxiety of the couple and often requires more than one therapeutic approach with close counselling and support.
Not surprisingly, the hormonal problems found in infertility are also found in recurrent miscarriage. This does not ncccssarily imply cause. The most common abnormality is polycystic ovarian syndrome (PCO) with associated luteal phase defects, sometimes with abnormalities of luteinizing hormone (LH).” These dcfccts are the result of inadequate levels of progcsterone, sometimes associated with poor follicular development, and result in inadcquatc endometrial growth. The luteal phase is usually short. This is thought to reduce the uterine receptivity. This can be studied by looking for an abnormal LH surge, a day 21 progesterone level which is found to be low. a persistently abnormal endometrial biopsy or ultrasound investigation for polycystic ovaries. Even though some abnormality can bc found in around 50% of women with early rccurrcnt loss. successful treatments regimes have not been fully evaluated, although some women may benefit from early pregnancy hormonal support. There is no evidence that routine investigation of abnormalities of thyroid disease or diabetes is of bcnelit (Table 2)
ASSESSMENT As with all medical problems careful history taking is important with a detailed log of the couple’s prior reproductive history. Many couples blame themselves for their pregnancy losses. Although smoking and excessive alcohol intake are associated with miscarriage, this is not a significant factor in recurrent loss. Many couples are concerned about the effect of the environmental factors such as irradiation, exposure to chemical teratogens or the use of VDUs. Little evidence is available to support these fears. In general. a reduction in exposure to potentially concerning environmental factors and basic health advice is normally all that is required. The information to note from previous pregnancies is listed in Table 1. The most important factors are the association with infertility or menstrual irregularities.4 the gestation of miscarriage, whether fetal heart activity was seen prior to the loss and, in secondtrimester losses, whether contraction pains were felt and the length of the labour. Clinical examination usually reveals little of benefit except for the gross abnormalities of anatomy which should have been found before. Structural problems are not usually associated with firsttrimester losses and, if suspected, should be investigated by more direct means. INVESTIGATION Hormonal abnormalities Recurrent miscarriage is associated with menstrual abnormalities and infertility in around 30% of cases’l
Chromosomal
Spontaneous miscarriage is associated with chromosomal abnormalities in the conceptus in many instances. If material from previous miscarriages was sent for chromosomal analysis, the results should bc obtained. The couples should be tested for the presence of chromosomal abnormalities such as translocations, which are either Robertsonian or reciprocal. These abnormalities are balanced when the total amount of material is normal. The gametes can obviously contain either too much or too little genetic material, which can lead to an abnormal conceptus and miscarriage. Other abnormalities include various chromosomal structural changes such as inversions. These are rarer and can be more difficult to detect. In most clinics, genetic investigations are normal in 95% of cases.?,”If an abnormality is identified, preconception genetic counselling is required to explain the risks of further miscarriages and the role of
The medical and surgical management of recurrent miscarriage prenatal diagnosis. There are obviously no curative treatments available at the present time.
immunological
investigations
Immunological causes of recurrent pregnancy loss are poorly understood. If a wide range of autoantibodies is looked for, many are found to be positive.5 The rclcVance of many of these is questionable. There is no doubt that the greater the number of miscarriages the women has, the more likely that she possessesmeasurable autoantibodies. Whether this is cause or effect is difficult to establish. but they do appear to be associated with successful treatment regimes making these tests of particular importance.” One particular type is the anti-phospholipid syndrome (APS) which is associated with around 15% of rccurrcnt pregnancy loss.?.’Phospholipids are involved in cell membranes and various cellular functions such as prostacyclin synthesis and protein C activity. Antibodies against them are associated with many disease states including vascular endothelial disorders and early pregnancy loss. Classically, they are associated with intrauterine death, abruption, intrauterine growth restriction and a pre-eclamptic type condition. The original diagnosis was associated with abnormalities of coagulation, the so-called ‘Lupus’ anticoagulant. The diagnosis is made using the phospholipid-dependent coagulation tests, such as the kaolin clotting time, the plasma clotting time, dilute Russell viper venom time. and activated partial thromboplastin time. The main problem with these assays is that there is little standardization between centres and the percentage positive rate varies considcrably. There is a desperate need for uniformity. This is also true for the other test carried out into anti-cardiolipin antibodies. This assay uses a normal range to assess abnormality and cut-off’ levels vary between laboratories and centres. Another factor is that the levels of the antibodies vary with pregnancy. Some women who are negative when non-pregnant can have abnormal levels during the subsequent pregnant and these should be rechecked in the first trimester. Abnormalities of immune response have long been proposed as a cause of pregnancy loss. Normally an individual will reject non-self (such as fetal tissue) using the immune system. The placenta (and pregnancy) would appear to have a ‘privileged’ relationship with the pregnant woman that allows for it to escape rejection. The mechanism for this is not known. People have suggested that this may be due to a reduced immune response, an increased immune response or a mixture of both. So far, none of these theories has been generally proven or accepted. In recurrent miscarriage, immunological abnormalities have been found,s which has led people to develop several expensive and potentially-dangerous treatment options, none of which have proven universally successful.
Thrombophilic
15
abnormalities
With the interest in APS, other thrombophilias have been investigated. There is an increased prevalence of defects of antithrombin III, protein C, protein S and hyperhomocysteinaemia. Activated protein-C resistance is associated with various pregnancy pathologies. This is not always associated with Factor V Leiden but can be acquired during pregnancy. It is still unclear what relevance these abnormalities have in recurrent miscarriage but they may have an additive effect. If found they lend themselves easily to treatment with low-dose aspirin. Structural
abnormalities
The incidence of structural abnormalities of the uterus arc unknown since these defects are not readily apparent without invasive investigation. The available reports generally cite incidences of from about 1:200 to 1:600 women. Therefore, these defects are not rare. About 1:4 women with a congenital anomaly of the uterus owing to a fusion defect will have significant difficulty with reproduction, possibly including recurrent pregnancy loss, but problems are not inevitable and causation may not be linked. A septate uterus is the most common congenital problem with others including bicornuate and uterus didelphys less common. Fibroids of the uterus that encroach on the cavity may distort the uterine shape. Although implantation of an embryo onto these areas of abnormality is thought to be associated with spontaneous miscarriage, there is no good supportive evidence of first-trimester problems” with most of the complications occurring in the second trimester and premature labour. It important not to rush to surgical intervention if an abnormality has been found as the surgery is not without its complications. Cervical
problems
Maintenance of the pregnancy is dependent on the integrity of the cervix. If the cervix is weak. inappropriate dilatation can occur leading to premature labour and second-trimester miscarriage. It is not associated with first-trimester loss. It is not until 16-18 weeks’ gestation that pressure is exerted onto the internal OS and the function of the cervix challenged. If the cervix is weak, there is painless dilatation leading to bulging of the fetal membranes, often in an hourglass shape through the cervix, spontaneous rupture of the membranes and delivery of the fetus. This sort of clinical history is usually the result of an incompetent cervix. The causes of cervical incompetence can be congenital, but the majority are acquired following trauma to the cervix such as with mechanical dilatation, cervical conisation or extensive biopsy, and precipitous labours or cervical lacerations during labour and delivery. Although the history is often very suggestive of cervical incompetence, establishing the diagnosis with
16
Current Obsletrics & Gynuecology
Table 3’ Diagnostic groups Early fetal loss, no evidence of fetal heart seen ’ may be associated with hormonal abnormalities delicient luteal phase may benefit from hormonal support Fetal loss after fetal heart action seen can occur al any gestation associated with antiphospholipid syndrome may benelit from low-dose aspirin and/or heparin Structural abnormalities owing to congenital abnormality owing to libroids may not be causative of pregnancy loss second-trimester premature labour surgery of questionable value Cervical Incompetence second-trimester loss should have delinitive testing to confirm can benelit from cervical suture
certainty can be difftcult. Not all cases of cervical incompetence follow this typical history. In recent years measurement of the cervical resistance index has increased the accuracy of diagnosis.9This method uses a pressure-sensinghandle to assessthe pressure required to dilate the non-pregnant cervix to Hegar 8. Studies suggest that a measurement of 24 Newtons is the cut-off between incompetence and normality, although it is almost certainly a continuum. Women with a suggestive history and a normal cervical resistance delivered their subsequent pregnancy without use of a cervical suture. During pregnancy the integrity of the cervix can be assessedby serial ultrasound.‘“,” If the cervix is shortening or dilating, a rescue cervical suture can be inserted with varying degreesof success.‘?.” Infection
Although infection can be responsible for spontaneous miscarriage, its role in recurrent problems is unclear. Bacterial vaginosis (BV) is associated with premature labour and second-trimester loss. In the presence of persistent BV, metronidazole may be of benefit but further trials are necessary.Routine investigation for infection is not recommended.
TREATMENT
Using history and the above investigations, a reasonable assessment of potential causes can be found in around 50% of women with recurrent miscarriage.‘4.‘5 A mixed picture is often present.15The broad subgroups are listed in Table 3. There are various treatment options available that can be targeted at these groups. Since many of these therapies are unproven and most women will be successful in the next pregnancy anyway, the first aim should be to provide psychological support and do no harm.‘,16In the absence of a definitive diagnosis, the history may suggest possible etiological causes and empirical treatments can
be used, partly to reassure the couple that something is being done, but excessiveclaims must be avoided. Site of care
Ideally, care of the woman with recurrent pregnancy loss should be in a unit that specializes in this area, not a subfertility or routine gynaecological service. This is because it should be part of an overall therapeutic package involving counselling. investigation and early pregnancy support services as well as treatment modalities.‘”There is evidence that psychological support alone reduces recurrent loss and should be part of any treatment regime.” Refusal to accept this concept not only denies the woman the support she desires, but also worsens the situation by projecting a ‘non-caring’ attitude. In St James Hospital in Leeds, the recurrent miscarriage service is integrated into the early pregnancy assessment unit allowing full access to support services.‘”Prior to pregnancy any relevant investigations should be carried out and a management plan designed so that everyone involved knows what is going to be done when pregnancy occurs. The most important factor is early referral to the unit as soon as pregnancy is suspected. If therapies are to work, early commencement is required, prior to an FH being seen on ultrasound and sometimes before conception. Hormonal manipulation
Increasing progesterone during the luteal phase may appear to be a useful approach in those women whose miscarriage appear to be associated with a poor luteal phase. This could be accomplished by progesterone supplementation using vaginal preparations, promoting increased follicular development using clomiphene citrate or luteal rescue using hCG. Studies of progesterone supplementation usually lack appropriate controls and often start after the viability of pregnancy has been established. Luteal-phase support would seem to be more logical as it would give support when the deficiencies are thought to be present. This was investigated in a study of women who have been found to have hormonal abnormalities or PCO. One hundred and six women were randomized into either receiving LH suppression with buserelin followed by low-dose ovulation induction and vaginal progesterone for 10 days in the luteal phase or no pituitary suppression or ovulation induction, but half receiving luteal-phase progesterone support and the other half placebo. There was no difference in any of the groups suggesting that neither LH suppression nor luteal-phase progesterone is of any benefit.‘” At present there is no trial evidence to support the use of progesterone supplementation at any time. Clomiphene citrate has been shown to improve the menstrual cycle of women with known hormonal abnormalities and would appear to be a reasonable
The medical and surgical management of recurrent miscarriage solution to those with a mixed infertility and early pregnancy loss pattern. It is usually given in doses of 100 mg for 5 days from the first day of menses but, as yet, has not been subjected to a proper trial. Its use should probably be restricted to those with a concomitant need for infertility treatment. Although early studies of hCG therapy in early pregnancy showed encouraging results,“’ later larger studies failed to confirm them.?” More recently, a smaller study in women with a history of oligomenorrhoea showed improved results with the use of hCG.Z’ These findings confirm that women with an abnormality of their hormonal cycle and a history of infertility might benelit from some form of hormonal manipulation. Further studies are required. immunological
treatments
Although APA is an immunological abnormality, treatment with low-dose aspirin (75 mg) +/- low-molecular-weight heparin would appear to be of benefit.” The aspirin was started after the diagnosis of pregnancy and it may be better to commence low-dose aspirin prior to pregnancy. The aspirin and heparin was continued until 34 weeks or until delivery, whichever was the sooner. The evidence suggested that heparin may not have been of any benefit after 12 weeks’ gestation. A combination of aspirin and heparin would appear to be better than aspirin alone. Other immunological treatments have been tried. Immunoglobulin (IgG) therapy, with intravenous injections of IgG, has been used with some apparent success.” It is claimed that its use can improve on the success rate of aspirin and heparin in APA.2”However, it is expensive and potentially dangerous and has not been subjected to controlled trial. The use of IgG should be targeted at those who have failed other therapies and preferably be part of controlled trialsZS Immunization therapy using paternal leucocytes” has been widely studied. However, meta-analysis has found that it is questionable whether paternal cell alloimmunization is an effective treatment for unexplained recurrent miscarriage. Any therapeutic effect appears to be small and would, at best, help a small minority of affected couples.” These reviews suggest that immunotherapy appears to have minimal benefit in a small number of couples and the side elTectsprobably outweigh these potential benclits. Surgery
In cases of uterine abnormality, there have been various claims for the benefit of surgical correction of uterine abnormality.‘* These have usually been in uncontrolled trials of women who have improved their outcome after surgery. Much of this work has been carried out in women with uterine septa. However, there is little evidence of the role of
17
Table 4 Potential treatments, which should be targeted after a detailed history and investigation Early pregnancy support services for all For early pregnancy loss associated with PC0 hCG support in early pregnancy For immunological/coagulation abnormalities low-dose aspirin low-molecular-weight heparin Cervical suture in proven (suspected) cervical resistance vaginal suture abdominal suture
structural abnormalities associated with Iirsttrimester 10ss,~although there may be an association with second-trimester problems. The treatment of an incompetent cervix is surgical and was originally described in the 1950~.‘~.” This consists of a surgical placement of a suture or Mersilene band around the cervix as near to the level of the internal OS as possible. The problem with this technique is that in many instances, the cervix is badly damaged and short, leading to difficulty in pacing the suture at a level that would do benefit. The multicentre trial of cervical cerclage did demonstrate an improved outcome in those pregnancies where a stitch was inserted,)’ but the improvement was small. In those women with a failed vaginal suture, a transabdominal cerclage may be helpful.)? 35This is inserted at approximately 12 weeks’gestation around the cervix, above the ureters and medial to the uterine arteries. Overall, the success rate in the world literature is around 90% after abdominal cerclage, although there are less than 300 published cases at the present time. Since so few cases are being carried out, referral to regional centres would seem prudent. After insertion of the abdominal suture, delivery needs to be carried out by Caesarean section. Whether the suture is removed at the time of the Caesarean section depends on whether further pregnancies are desired.
CONCLUSION
The investigation and management of a couple with a history of recurrent pregnancy loss needs an individualized approach carried out by specialized units (Table 4). There needs to be a combined approach of psychological, investigative and therapeutic regimes. Care should be taken to provide unbiased advice, balanced information and appropriate therapy. However, these couples need reassurance that success is probable with the appropriate support and targeted treatments.36 REFERENCES I. Li TC. Recurrent miscarriage: principles of management. Hum Reprod 1998; 13: 478482. 2. Drakeley AJ, Quenby S, Farquharson RG. Mid-trimester lossappraisal of a screening protocol. Hum Reprod 1998; 13: 19751980. 3. Stirrat GM. Recurrent miscarriage I: detinition and epidemiology. Lancet 1990; 336: 673-675.
18 Current Obstetrics & Gynaecology 4. Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage preliminary experience of 500 consecutive eases. Human Reproduction 1994; 9: 1328-1332. 5. Roberts J, Jenkins C, Wilson R et al. Recurrent miscarriage is associated with increased numbers of cd5/20 positive lymphocytes and an increased incidence of thyroid antibodies. European Journal Of Endocrinology 1996; 134: 84-86. 6. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253-257. 7. Rai R, Regan L. Antiphospholipid antibodies, infertility and recurrent miscarriage. Current Opinion In Obstetrics & Gynecology 1997; 9: 279-282. 8. Maneschi I, Maneschi F, Parlato M, Fuca G, Incandela S. Reproductive performance in women with uterus didelphys. Acta Eur Fertil 1989; 20: 121-l 24. 9. Anthony GS, Fisher J, McManus TJ, Coutts JRT, Calder AA. Forces required for dilatation of the pregnant and non-pregnant human cervix. Br J Obstet Gynaecol 1982; 89: 913-916. IO. Flint S, Gibb DME Recurrent second trimester miscarriage. Current Opinion In Obstetrics & Gynecology 1996; 8: 449453. II. Guzman ER, Mellon C, Vintzilcos AM, Ananth CV, Walters C, Gipson K. Longitudinal assessment of endocervical canal length between I5 and 24 weeks’gestation in women at risk for pregnancy loss or preterm birth. Obstet Gynecol 1998; 92: 31-37. 12. Chasen ST, Silverman NS. Mid-trimester emergent cerclage: a ten year single institution review. J Perinatol 1998; 18: 338-342. 13. Heath VC, Souka AP Erasmus I, Gibb DM, Nicolaides KH. Cervical length at 23 weeks of gestation: the value of Shirodkar suture for the short cervix. Ultrasound Obstet Gynecol 1998; 12: 3 18-322. 14. Quenby SM. Farquharson RG. Predicting recurring miscarriage - what is important. Obstetrics And Gynecology 1993; 82: 132-138. 15. Clifford K, Rai R, Watson H, Regan I. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994; 9: 1328-1332. 16. Walker JJ, Shillito J. Early pregnancy units: service and organisational aspects. In: Grudzinskas JG, O’Brien PMS (eds) Problems in early pregnancy: advances in diagnosis and management. London: RCOG Press, 1997: l60- 173. 17. ClifTord K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent lirst trimester miscarriage. Hum Reprod 1997; 12: 387-389. 18. ClilTord K, Rai R, Watson H, Franks S, Regan L. Does suppressing luteinizing-hormone secretion reduce the miscarriage rate - results of a randomized controlled trial. British Medical Journal 1996; 312: 1508-1511. 19. Harrison RF. Miscarriage - hormonal treatment with hcg. Contraception Fertilite Sexualite 1991; 19: 373-376. 20. Harrison R. Human chorionic gonadotrophin in the management of recurretn abortion:results of a multicentre placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992; 72: 175-179.
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