Aetiology

It is common to divide the associations of recurrent miscarriage into the following categories:

  • Genetic

  • Anatomical

  • Immunological

  • Thrombophilic

  • Endocrinological

  • Infective

  • Male factor

  • Environmental

  • Unexplained.

Genetic

Parental chromosomal abnormalities

These account for about 3% to 5% of patients with recurrent miscarriage and are most commonly balanced reciprocal or Robertsonian translocations.[14] Robertsonian translocation is a common form of chromosomal rearrangement involving chromosomes 13, 14, 15, 21, or 22. It is balanced and results in no excess or deficit of genetic material, thus causing no health difficulties. If these abnormalities are detected, a referral to a clinical geneticist is indicated. Patients with an unbalanced translocation have a 5% to 10% chance of a pregnancy that may result in a child with disabilities, and are therefore entitled to antenatal diagnosis. However, patients with balanced translocation have a 50% to 70% chance of a healthy live birth if they are closely monitored, evaluated for other treatable causes, and offered supportive care.[15][16]

Chromosomal abnormality of the fetus

  • This is the most common cause of miscarriage. It accounts for up to 70% of early miscarriages but only 20% of miscarriages that occur between 13 and 20 weeks' gestation.[17] Therefore, the gestational age at which a miscarriage occurs may help to identify its cause. Defects are commonly trisomy, polyploidy, or monosomy. The risk of having a fetus with chromosomal abnormality is higher in mothers older than age 35 years, confirming the association of advancing maternal age and aneuploidy. However, the underlying mechanism for this is uncertain.[17]

  • In the context of recurrent miscarriage, the frequency of fetal chromosomal abnormality significantly decreases with increasing number of previous miscarriages.[13] Thus, an abnormal fetal karyotype in a miscarriage is an important prognostic factor and suggests a successful outcome of about 75% in the next pregnancy.[13][17]

Other genetic causes

Molecular genetic abnormality such as highly skewed X-chromosome inactivation has been suggested as a potential cause of recurrent miscarriage in some small studies. However, larger studies have failed to confirm this association.[18][19]

Anatomical or structural

The exact contribution of congenital uterine anomaly in causing recurrent miscarriage is difficult to assess, due to the vast difference in criteria and techniques for diagnosing abnormal uterine morphology. The prevalence of uterine anomalies such as septate, bicornuate, or arcuate uterus in the general population is 5.5%, and it seems to be higher in patients with a history of miscarriage (13.3%).[20] However, a direct causative link is difficult to establish. Limited evidence from non-randomised trials shows an improvement in pregnancy outcomes if these anomalies are surgically corrected.[21][22] In the UK, the National Institute for Health and Care Excellence has published guidelines recommending hysteroscopic resection for patients with a uterine septum and history of recurrent pregnancy loss or preterm delivery.[23]

Cervical incompetence is a structural abnormality associated with recurrent miscarriage, more commonly in the second trimester. Unfortunately, there are no objective tests that can consistently identify women with cervical weakness when they are not pregnant. Thus, the diagnosis is often based on a history of painless dilatation of the cervix or spontaneous rupture of membranes, followed by a second-trimester miscarriage. The exact mechanism of how this condition causes second-trimester miscarriage is still uncertain. The cervix probably plays more than just a mechanistic role. Treatment with prophylactic insertion of cervical suture has not been confirmed to improve pregnancy outcomes.[24]

Immunological

Antiphospholipid syndrome (APS) is found in about 15% of patients with recurrent miscarriage.[25] Screening for APS is recommended for all women with recurrent miscarriage, because they may benefit from treatment.[26]​​[27][28][1]

APS diagnosis

The presence of at least one clinical and one laboratory component from the following criteria is often used as a guide for APS diagnosis:[29]

Clinical criteria include:

  • Vascular (arterial or venous) thrombosis in any tissue or organ

  • 3 or more consecutive miscarriages before 10 weeks' gestation

  • 1 or more unexplained deaths of a morphologically normal fetus at 10 weeks' gestation or older

  • 1 or more premature births of a morphologically normal fetus before 34 weeks' gestation associated with severe pre-eclampsia or placental insufficiency.

Laboratory criteria include:

  • Medium or high titres of IgG and/or IgM anticardiolipin (aCL) antibodies in 2 or more tests at least 12 weeks apart

  • Presence of lupus anticoagulant (LA) in 2 or more tests at least 12 weeks apart

  • High titres of IgG and/or IgM anti-beta-2 glycoprotein-1 antibodies in 2 or more tests at least 12 weeks apart.

The American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) have produced high-specificity classification criteria intended for APS research.[30]

Other immunological states

Dysregulated natural killer cells (either in the peripheral blood or in the endometrium) have been associated with recurrent miscarriage and recurrent implantation failure.[31][32]​ Further research is warranted.

Additional immunological risk factors implicated in recurrent miscarriage include antinuclear antibodies, thyroid antibodies, IgA antibodies against transglutaminase (tTG-IgA), regulatory T-cells (Tregs), HLA-sharing and HLA associations, and cytokine polymorphisms.[26][33][34]​ There is, however, an absence of high-level evidence to support the association between many of these immunological factors and recurrent miscarriage.[33] One systematic review of 20 trials of various immunotherapies such as paternal cell immunisation, third-party donor cell immunisation, trophoblast membrane infusion, and intravenous immunoglobulin showed no significant beneficial effect over placebo in improving live-birth rates.[35]

Thrombophilia

Women with recurrent miscarriage should be offered testing for acquired thrombophilia, particularly for lupus anticoagulant and anticardiolipin antibodies.[26][1]

Inherited thrombophilia

Meta-analyses report that FVL mutation (associated with activated protein C resistance) and prothrombin gene mutation are associated with recurrent miscarriage and adverse pregnancy outcomes.[36][37]

Two systematic reviews have concluded that the prevalence of inherited thrombophilia in women with recurrent miscarriage is similar to that in the general population.[38][39]​ The UK and US guidelines recommend against routine heritable thrombophilia screening in women with recurrent miscarriage or a history of fetal loss, respectively.[40][41] Targeted assessment for inherited thrombophilia may be considered in specific clinical circumstances.[41]

Endocrinological

Polycystic ovarian syndrome

  • The prevalence of polycystic ovarian syndrome (PCOS) in recurrent miscarriage ranges from 4.8% to 82% as there was a huge variation in criteria for diagnosing PCOS before the availability of the Rotterdam diagnostic criteria.[42][43] Thus, reappraisal of the prevalence of PCOS in recurrent miscarriage using the Rotterdam criteria is needed.

  • The most likely possible mechanisms by which PCOS could cause recurrent miscarriage are hyperandrogenism, obesity, and insulin resistance, although further work is needed to assess this.[42][44] Patients with PCOS with abnormal ovarian morphology on ultrasound scan, elevated luteinising hormone (LH), and elevated testosterone have been found to have similar live-birth rates to women without PCOS.[45] 

Luteal phase problems

These disorders are diagnosed when there are low progesterone levels and the histological date of the endometrium lags behind menstrual dating for 2 or more days in a minimum of 2 menstrual cycles. Association of luteal phase problems with recurrent miscarriage is controversial, but it is believed to be related to either decreased progesterone production by the corpus luteum, abnormal LH secretion, or poor response of the endometrium to available progesterone.[46] Although a systematic review of progestogen treatment showed no significant difference in the risk of miscarriage, a subgroup analysis of trials involving women who had recurrent miscarriages showed a significant decrease in miscarriage rate.[47] [ Cochrane Clinical Answers logo ] ​​ One large RCT found that there was no benefit from giving progesterone supplementation in women with unexplained recurrent pregnancy loss.[48] However, a recent re-evaluation of the results of this trial and another trial involving progesterone supplementation of women with bleeding in pregnancy shows a trend of increasing benefit of progesterone supplementation with increasing number of miscarriages.[49]

Hyperprolactinaemia

The role of hyperprolactinaemia in recurrent miscarriage is debated.[46] Furthermore, a randomised controlled trial that found an improved pregnancy success when recurrent miscarriage patients with hyperprolactinaemia were treated has been criticised for its methodology.[50] Thus, the relationship is still uncertain.

Undiagnosed and untreated thyroid disorders

These disorders are associated with miscarriages, but when women are euthyroid on treatment, thyroid disorders are not risk factors for recurrent miscarriage, and these pregnancies can go to term with minimal complications.[51] The presence of thyroid antibodies has been found to be associated with a higher miscarriage rate.[52] However, the presence of association does not mean causation and could be explained by mechanisms such as an underlying autoimmune state or mild thyroid failure.[52] Although there is no treatment available for autoimmunity against the fetal allograft, screening for subclinical hypothyroidism could be done, as patients may be treated and have better pregnancy outcomes.[51]

Diabetes mellitus

When uncontrolled, diabetes mellitus is known to cause miscarriages and congenital malformations. However, when well managed, diabetes mellitus alone is not a risk factor for miscarriage and thus should not cause recurrent miscarriage.[53]

Infective

Severe infections have been associated with spontaneous miscarriages. However, for infection to be considered a cause for recurrent miscarriage, the bacteria or virus must be capable of persisting in the genital tract (to facilitate an infectious carrier state), or be able to repeatedly cause placental infection.[26]​​[54]​ The presence of bacterial vaginosis is a recognised risk factor for late miscarriage and preterm birth if found in early pregnancy.[55]

There is no evidence that other bacterial or viral infections such as Chlamydia, Ureaplasma, Mycoplasma, cytomegalovirus, adeno-associated virus, human papillomavirus, toxoplasmosis, rubella, herpes virus, and listeria are associated with recurrent miscarriages in the first trimester.[54][56] Herpes simplex virus carriers are not known to be more susceptible to recurrent miscarriages.

There is growing evidence that women with recurrent pregnancy loss have an increased incidence of chronic endometritis (29.67%) as diagnosed by hysteroscopic visualisation, histological assessment, and/or CD138 staining of endometrial biopsy. Chronic endometritis can be treated successfully with antibiotics; however, it is unclear whether this leads to an increase in live birth rate.[57]

Male factor

There has been interest in investigating male factor causes of recurrent pregnancy loss, specifically sperm DNA fragmentation. Meta-analyses have found an association between increased sperm DNA fragmentation in male partners and unexplained recurrent miscarriages.[58][59] Tests to assess sperm DNA fragmentation measure single and/or double stranded DNA breaks in sperm directly or indirectly.

The European Society of Human Reproduction and Embryology (ESHRE) recommends consideration of sperm DNA fragmentation tests for explanatory purposes in recurrent pregnancy loss, whereas other societies have not endorsed this.[1][60]​ At present, there is no general international consensus to offer this testing as a routine diagnostic test.

Environmental

Chemicals

There is a concern that chemicals, either in the surroundings or ingested, can contribute to recurrent miscarriage. However, it is difficult to provide accurate information regarding the reproductive impact of these chemicals, as evidence is not readily available.[61] The potential of an environmental chemical causing miscarriage is also dependent on the type and duration of exposure, the extent to which it enters the fetal circulation, gestational age of the pregnancy at exposure, and other related pregnancy factors, such as presence of any medical disorders. It is clear that heavy metals (e.g., lead and mercury), organic solvents, ionising radiation, and teratogenic drugs are toxins, and exposure could contribute to pregnancy loss.[61] If exposure to these occupational hazards is suspected as the cause of a miscarriage, then it is best to avoid further contact if possible, with the hope of preventing another miscarriage from occurring.

Alcohol and smoking

Alcohol is a teratogen that can lead to fetal alcohol syndrome, with a dose-response relationship.[61] There is no amount of alcohol that is considered safe in pregnancy, and even moderate alcohol consumption can lead to spontaneous miscarriage.[62] Thus, it can be assumed that this risk, if not removed, is also related to recurrent miscarriage. Similarly, many studies have found a dose-dependent association between miscarriage and smoking. Unfortunately, it is difficult to accurately validate the accuracy of reports of smoking with biochemical measurements of tobacco.[61] Evidence concerning lifestyle adaptation and its effect in women with unexplained miscarriage is lacking.

Caffeine

The association is not as evident with caffeine. Numerous studies have observed a positive correlation between maternal caffeine intake and the risk of miscarriage. Unfortunately, most of these studies have methodological problems and have potential bias that does not allow a comparison of results. Hence, evidence for this causal link remains inconclusive.[63] Genetic factors may be involved, demonstrated by a possible increased susceptibility to recurrent miscarriage with increased caffeine intake if genetic polymorphisms are present.[64]

Diagnostic x-rays, radiation, air travel, ultrasound, and cosmetics

Diagnostic x-rays, air travel, ultrasound, and cosmetics such as nail polish and hair dye are not thought to cause recurrent miscarriage.[61] Radiation <5 rad is not teratogenic, and most diagnostic radiological imaging delivers less than this. Additionally, any risk attributed by low radiation is much lower than the background risk of spontaneous miscarriage or congenital abnormality. Ultrasound is also thought to be safe if done for the right indications, and reduces the necessity of exposure to radiation.[65]

Unexplained

No causes or associations are found in >50% of patients with recurrent miscarriage, and these patients fall into the category of unexplained or idiopathic recurrent miscarriage.[4][5] However, they have an excellent prognosis. Up to 75% achieve a successful live birth in future pregnancies if given only supportive care (with regular ultrasound scans for reassurance) and psychological support in a dedicated early pregnancy assessment unit (EPAU).[7][26]​​​ Thus, empirical treatment in this group of women is unnecessary and not recommended.[26]​​

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