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Editors
Recurrent Miscarriage
Essentials
- Recurrent miscarriage is defined as the loss of at least 2-3 intrauterine pregnancies before 22 weeks of pregnancy.
- The underlying cause of recurrent miscarriage cannot be found in about 50% of the cases.
- An acquired thrombotic tendency (antiphospholipid antibodies) is the most important treatable cause.
- Recurrent miscarriages are both mentally and physically exhausting.
- The probability of a successful pregnancy and delivery after recurrent miscarriage is, however, very good, even up to 60-80%.
- Miscarriages become more common with woman's age. Despite this, 40% of even women over 40 years of age with recurrent miscarriages deliver.
Epidemiology
- Of all confirmed pregnancies, 15-25% end in miscarriage. Only 5% of women experience two miscarriages and 1-3% three or more.
- The most important risk factors are the maternal age and the number of miscarriages. Every third pregnancy in women aged over 40 years ends in miscarriage.
- 75% of miscarriages occur before 13 weeks of pregnancy.
Causes
- In about 50% of cases, the cause remains unknown. In these cases the underlying cause is probably a random abnormality associated with embryonic development and placentation.
Genetic and chromosomal causes
- The result of a chromosome analysis is abnormal in less than 5% of parents. The most common genetic abnormality is translocation. In early miscarriages, up to 60% of the foetuses have a chromosomal abnormality, most commonly an absent chromosome (monosomy) or a duplicated chromosome (trisomy).
- High sperm DNA fragmentation index (DFI) increases the risk of miscarriage. However, determining DFI is not recommended, as there is no proper clinical cut-off value.
Hormonal and metabolic causes
- Poorly controlled endocrine disease, such as diabetes and hypothyroidism increase the risk. In a woman with thyroid hormone therapy, TSH should be below 2.5 mlU/l.
- The relationship of hyperprolactinaemia and low concentrations of progesterone with miscarriage is debatable.
- Obesity increases the risk of miscarriage.
Acquired tendency for thrombosis
- 10-16% of women with recurrent miscarriages have antiphospholipid antibodies.
Uterine anomalies
- The prevalence of anatomic anomalies of the uterine cavity is 10-15%.
- A complete uterine septum is the most important treatable anomaly.
- A large intramural myoma or submucous myoma may increase the risk of miscarriage. The evidence regarding the benefit of removing the abnormalities is insufficient.
- Cervical weakness is a rare cause of late miscarriage.
Infections
- Bacteria, viruses and parasites do not play a significant part in miscarriage, and systemic screening does not have a role in the investigation of miscarriage.
Investigations
- Investigations are started using case-specific judgement, after 2 or 3 miscarriages, when the pregnancy has been established by either ultrasonography or, if the duration of pregnancy in regular menstrual cycle is at least 6 weeks, by plain pregnancy test.
History
- Age, life style (alcohol consumption, smoking), past medical history, medication, family history (developmental disorders, miscarriages, thrombotic disease)
- Details associated with previous miscarriages
- Ultrasonography
- Was it an intrauterine pregnancy (extrauterine pregnancies are not taken into account)?
- Were the foetus and heart beat visualised?
- What was the size of the foetus?
- During which week of pregnancy did the miscarriages occur?
- Results from previous investigations
Clinical examination
- General status, exclusion of underlying diseases
- Gynaecological status
- In specialised care: gynaecological ultrasound examination with, as required, fluid (hydrosonography), or hysteroscopy
Laboratory tests
- Basic blood counts with platelets, TSH, free T4 and blood glucose, as well as celiac disease antibodies if there is celiac disease in the family or a woman has symptoms that fit with celiac disease or if she has a low haemoglobin level.
- Prolactin if there are menstrual disturbances
- Antiphospholipid antibodies
- Thrombophilia screening Evaluation of Thrombophilia (factor V, APC resistance, antithrombin III, protein S, protein C), if the patient has other factors that predispose to thrombosis (e.g. family history or earlier vascular occlusion)
- Karyotyping (chromosome analysis for the spouses, both woman and man) is not beneficial if performed routinely; to be analyzed only at discretion.
- The prognosis is good even without treatment: 60-80% of future pregnancies are successful.
- Lifestyle changes should be attempted: normal weight, stopping smoking, no higher than moderate alcohol and caffeine consumption, exercise, avoidance of cannabis products.
- Folic acid supplementation (0.4-1 mg/day) is recommended for those planning a new pregnancy.
- Monitoring and mental support
- Pregnancy should be closely monitored from early on, which will reduce anxiety and feelings of uncertainty.
- Ultrasound examinations should be performed to establish whether the foetal development is normal or abnormal.
- It has been suggested that careful monitoring alone may significantly reduce the risk of miscarriages.
- If a woman has had at least 3 early miscarriages and antiphospholipid antibodies are detected, aspirin 75-100 mg should be started already before pregnancy. Once pregnancy test is positive, LMWH is added to the treatment using prophylactic dose that is based on patient's weightPrevention of Recurrent Miscarriage for Women with Antiphospholipid Antibody or Lupus Anticoagulant.
- Correctinguterine anomalies is considered on a case-by-case basis. The benefit of an intervention is best proven for the removal of uterine septum.
- Pre-implantation genetic diagnosis (PGD) performed in association with in vitro fertilisation (IVF) is useful when there are indications of a genetic abnormality causing the miscarriages (translocation, gene mutation, fetal chromosomal abnormality).
- Plain IVF is not beneficial.
- There is no established evidence in favour of adjuvant therapies (progesteroneProgestogen for Preventing Miscarriage in Women with Recurrent Miscarriage, vitamin supplementationVitamin Supplementation for Preventing Miscarriage, glucocorticoid treatment, LMWH, low-dose aspirin, immunotherapy [intravenous immunoglobulin]) as prophylactic treatment for miscarriages of unknown reason.
References
- ESHRE Early Pregnancy Guideline Development Group. Recurrent Pregnancy loss. Guideline of the European Society of Human Reproduction and Embryology. 2017
- Morley at al. Preventing recurrent miscarriage of unknown aetiology. The Obstetrician & Gynaecologists 2013;15:99-105 http://onlinelibrary.wiley.com/doi/10.1111/tog.12009/pdf
Evidence Summaries ⬆