Recurrent miscarriage is defined as the loss of three or more consecutive pregnancies.
Miscarriage, the most common complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation in the UK, but may be 20 weeks of gestation in other parts of the world.
- Miscarriage occurs in 15-20% of recognised pregnancies.
- 1% of couples trying to conceive have recurrent miscarriages.
- This is much higher than the 0.34% calculated risk of three occurring consecutively by chance alone.
- Following three consecutive miscarriages, the risk of further miscarriage is about 40%.
- A woman may develop recurrent miscarriage after a successful pregnancy.
No underlying cause is found in many of them.
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- Increasing maternal age affects ovarian function and increases rates of aneuploidy in association with older oocytes.
- There are a higher number of conceptions that are chromosomally abnormal and do not develop.
- As the number of miscarriages increases, the risk of chromosomal abnormalities decreases and the risk of underlying maternal cause increases.
- Genetic abnormalities:
- Recurrent miscarriage may be linked to chromosomal abnormality in 2-5% of couples.
- A balanced reciprocal or Robertsonian translocation is the most common type.
- Antiphospholipid syndrome (APS):
- This is the most important treatable cause of recurrent miscarriage.
- The antiphospholipid antibodies, lupus anticoagulant, anticardiolipin antibodies and anti-B2-glycoprotein I antibodies may be associated with recurrent miscarriage before ten weeks.
- Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage.
- APS is the only proven thrombophilia that is associated with adverse pregnancy outcomes.
- Uterine anomalies (arcuate or septate) are seen in between 10-25% of cases of recurrent miscarriage. Only 50% of pregnancies where there is a uterine structural abnormality achieve term delivery.
- Uterine fibroids are present in up to 30% of women, but the way they affect reproductive loss is unclear.
- Cervical incompetence (late miscarriage preceded by spontaneous rupture of membranes or painless cervical dilatation) may often be a cause of mid-trimester recurrent miscarriage.
Second-trimester miscarriages may be linked to uterine malformations such as the presence of a uterine septum or a bicornuate uterus.
- Women with polycystic ovarian syndrome are at higher risk of miscarriage, which may be related to insulin resistance and hyperinsulinaemia.
- There is insufficient evidence to support the use of metformin during pregnancy to reduce this risk.
- Uncontrolled diabetes mellitus is a risk factors for recurrent miscarriage.
- Women with recurrent miscarriage have more natural killer cells in their uterine mucosa than controls and those with the highest levels have a correspondingly high rate of miscarriage in subsequent pregnancies.
- However, there is no association between the levels of natural killer cells in peripheral blood and in the uterine mucosa. Levels of natural killer cells in peripheral blood are not predictive of pregnancy outcome in women with unexplained recurrent miscarriage.
- Inherited thrombophilia:
- Inherited thrombophilia, such as protein C and S deficiency, may have a role in recurrent miscarriage, because of an increased risk of thrombosis in the uteroplacental circulation.
- Women with second-trimester miscarriage should be screened for inherited thrombophilia.
- Bacterial vaginosis in the first trimester is a risk factor for second-trimester miscarriage and preterm delivery.
- Antiphospholipid antibodies:
- The presence of these is associated with early miscarriages and maternal morbidity and is referred to as primary APS. There is requirement for two tests at least six weeks apart showing either lupus anticoagulant or anticardiolipin antibodies at significant levels.
- Women with recurrent first-trimester miscarriage and all women with one or more second-trimester miscarriages should be screened for antiphospholipid antibodies before pregnancy.
- Women with second-trimester miscarriage should be screened for inherited thrombophilias including factor V Leiden, factor II (prothrombin) gene mutation and protein S.
- All women with recurrent first-trimester miscarriage and all women with one or more second-trimester miscarriages should have pelvic ultrasound to assess uterine anatomy.
- If uterine anomalies are detected then further investigations, such as hysteroscopy and/or laparoscopy, may be required.
- Karyotyping of products of conception should be undertaken on the products of conception from the third (and any subsequent) miscarriages. If an unbalanced structural chromosomal abnormality is found, referral to genetics is indicated.
- Parental peripheral blood karyotyping of both partners should be performed in couples with recurrent miscarriage where testing of products of conception reports an unbalanced structural chromosomal abnormality.
Note: the Royal College of Obstetricians and Gynaecologists (RCOG) does not recommend routine screening for diabetes, inherited coagulopathies, thyroid disease, serum prolactin, or toxoplasmosis, rubella, cytomegalovirus and herpes simplex (TORCH).
Reassurance should be given about the high probability of a successful outcome. In a large trial that included women with 4.2 consecutive miscarriages and an average age of 32.7 years, the placebo group was shown to have a live birth rate of 65%.
- In primary APS patients, heparin combined with low-dose aspirin improves live birth rate to 70%. There ARE only limited data supporting the use of heparin in women without APS.
- There is some evidence suggesting that use of metformin during pregnancy is associated with a reduction in the miscarriage rate in women with polycystic ovarian syndrome.
- However, the RCOG DOES NOT recommend its use in pregnancy at present until further randomised prospective study results are available to provide adequate evidence of safety and efficacy of its use.
- A Cochrane review found evidence of benefit for progestogen therapy in women with a history of recurrent miscarriage. There was no statistically significant difference in rates of adverse effects.
- However, there is currently a large randomised, double-blind, placebo-controlled multicentre trial underway - the Progesterone in recurrent miscarriage (PROMISE) study - which aims to provide a definitive answer regarding progesterone use in women with recurrent miscarriages.
- Cervical cerclage (a Shirodkar or McDonald suture) is used where cervical incompetence is suspected. However, it is overdiagnosed as a cause of second-trimester miscarriage. The cerclage procedure also carries a risk of stimulating uterine contractions.
- Cerclage benefit increases as the cervix shortens to less than 25 mm. It has also been shown to be beneficial in those women with a shortened cervical length of less than 25 mm.
Further reading & references
- Rai R, Regan L; Recurrent miscarriage. Lancet. 2006 Aug 12;368(9535):601-11.
- Branch DW, Gibson M, Silver RM; Clinical practice. Recurrent miscarriage. N Engl J Med. 2010 Oct 28;363(18):1740-7.
- McNamee K, Dawood F, Farquharson R; Recurrent miscarriage and thrombophilia: an update. Curr Opin Obstet Gynecol. 2012 Aug;24(4):229-34. doi: 10.1097/GCO.0b013e32835585dc.
- The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage, Royal College of Obstetricians and Gynaecologists (April 2011)
- Ziakas PD, Pavlou M, Voulgarelis M; Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a Obstet Gynecol. 2010 Jun;115(6):1256-62.
- Bennett SA, Bagot CN, Arya R; Pregnancy loss and thrombophilia: the elusive link. Br J Haematol. 2012 Jun;157(5):529-42. doi: 10.1111/j.1365-2141.2012.09112.x. Epub 2012 Mar 26.
- De Leo V, Musacchio MC, Piomboni P, et al; The administration of metformin during pregnancy reduces polycystic ovary Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):63-6. Epub 2011 May 6.
- Long-term consequences of polycystic ovary syndrome, Royal College of Obstetricians and Gynaecologists (2007)
- Haas DM, Ramsey PS; Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003511.
- Coomarasamy A, Truchanowicz EG, Rai R; Does first trimester progesterone prophylaxis increase the live birth rate in women with unexplained recurrent miscarriages? BMJ. 2011 Apr 18;342:d1914. doi: 10.1136/bmj.d1914.
- Owen J, Mancuso M; Cervical cerclage for the prevention of preterm birth. Obstet Gynecol Clin North Am. 2012 Mar;39(1):25-33. doi: 10.1016/j.ogc.2011.12.001. Epub 2012 Jan 4.
|Original Author: Dr Hayley Willacy||Current Version: Dr Louise Newson||Peer Reviewer: Dr John Cox|
|Last Checked: 11/02/2013||Document ID: 2707 Version: 23||© EMIS|
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