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EiniNikander

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%. The younger the woman, the better the prognosis.
  • A general practitioner can identify and treat any underlying conditions the couple might have and check whether there are lifestyle changes that need to be made. See also Fertility counselling Fertility Counselling.

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. After three miscarriages, 40% of women aged 40 and 25% of women aged 45 give birth.
  • 75% of miscarriages occur before 13 weeks of pregnancy.

Causes

Unexplained/chance

  • 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.
  • The cause may vary between different miscarriages.

Genetic and chromosomal causes

  • The most common cause of recurrent miscarriage is foetal aneuploidy, i.e. an abnormality in the number of chromosomes. In early miscarriages, up to 60% of the foetuses have a chromosomal abnormality, most commonly an absent chromosome (monosomy) or a duplicated chromosome (trisomy).
  • Frequency of foetal aneuploidy increases with woman's age.
    • In young women, the majority of egg cells and embryos are normal, but in women over 40 years of age, only 1 in 4 or 5 embryos is euploid.
  • The result of chromosomal analysis is abnormal in less than 5% of parents. The most common abnormality is translocation.
  • DNA damage in spermatozoa predispose to miscarriage.
    • DNA damage is increased by, for example, age, smoking, abundant alcohol use, overweight and heavy physical exercise. DNA fragmentation index (DFI) can be used to examine the extent of DNA damage. A sperm DFI examination may be considered on a case-by-case basis when investigating the cause of miscarriages.

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 association of hyperprolactinaemia and low concentrations of progesterone with miscarriage has not been confirmed.
  • Significant overweight and underweight increase the risk of miscarriage.

Acquired tendency for thrombosis

  • Less than 1 out of 5 women with recurrent miscarriages have antiphospholipid antibodies.

Uterine anomalies

  • The prevalence of anatomic anomalies of the uterine cavity is 10-15%.
  • A large intramural myoma, a submucous myoma, uterine septum and uterine adenomyosis may increase the risk of miscarriage. According to the most recent research, however, surgical treatment is not necessarily beneficial.
  • 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.

Immunologic causes

  • Testing for HLA antibodies is rarely beneficial.
  • More research is needed on immunologic causes and their possible treatments.

Investigations

  • Investigations are started using case-specific judgement, after 2 or 3 miscarriages, when the pregnancy has been established by either ultrasonography or by plain pregnancy test. Extrauterine and molar pregnancies are not counted.

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, thyroid peroxidase antibodies
  • Blood glucose if any disturbance in glucose tolerance is suspected
  • Coeliac disease antibodies if there is any familly history of coeliac disease or if the woman has symptoms that fit with coeliac disease or if she has a low haemoglobin level.
  • Antiphospholipid antibodies after the second miscarriage
  • Investigations for hereditary thrombophiliaEvaluation of Thrombophilia and Prevention of Thrombosis (factor V, APC resistance, antithrombin III, protein S, protein C), only if the patient has other factors that predispose to thrombosis (e.g. family history or earlier vascular occlusion)
  • Serum prolactin, only if there are menstrual disturbances
  • Routine karyotyping (chromosome analysis for the spouses, both woman and man) is not beneficial; to be analyzed only at discretion. According to a European recommendation, chromosomes are only examined if the woman is under 39 years old or if there is history (either in the couple's own or their families' patient history) that warrants the examination.

Treatment Prevention of Recurrent Miscarriage for Women with Antiphospholipid Antibody or Lupus Anticoagulant, Progestogen for Preventing Miscarriage in Women with Recurrent Miscarriage, Aspirin or Anticoagulants for the Treatment of Recurrent Pregnancy Loss in Women Without Antiphospholipid Syndrome

  • The prognosis is good even without treatment: 60-80% of future pregnancies are successful.
    • The prognosis becomes worse in women over 35 years of age.
  • 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) and vitamin D supplementation are 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 at follow-up visits.
    • There is suggestive evidence 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. The treatment should be continued until the 36th week of pregnancy.
  • Correctinguterine anomalies is considered on a case-by-case basis.
  • 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 (vitamin supplementation, glucocorticoid treatment, LMWH, low-dose aspirin, immunotherapy) as prophylactic treatment for miscarriages of unknown reason.
  • Progesterone administered vaginally (e.g. 400 mg every 12 hours) may improve the probability of successful pregnancy in patients with early pregnancy bleeding and underlying miscarriages Progestogen for Preventing Miscarriage in Women with Recurrent Miscarriage. Progesterone is started when the bleeding starts and the treatment is continued until week 16 of pregnancy. This practice is not yet well established

    References

    • ESHRE Early Pregnancy Guideline Development Group. Recurrent Pregnancy loss. Guideline of the European Society of Human Reproduction and Embryology. 2023
    • Devall AJ, Papadopoulou A, Podesek M et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev 2021;4(4):CD013792. [PubMed]
    • Coomarasamy A, Devall AJ, Brosens JJ et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol 2020;223(2):167-176. [PubMed]
    • Morley et al. Preventing recurrent miscarriage of unknown aetiology. The Obstetrician & Gynaecologists 2013;15:99-105 http://onlinelibrary.wiley.com/doi/10.1111/tog.12009/pdf