Below you’ll find an overview of the different types of miscarriage and their main known causes
INTRODUCTION TO MISCARRIAGE
Sporadic miscarriage (fetal loss) is quite common and occurs in about 15% to 25% of pregnancies. Most sporadic miscarriages before the 10th week of pregnancy are due to non‑hereditary chromosomal errors and are more common in women under 18, over 35 or with a history of miscarriage. Their frequency increases with parity.
In contrast, recurrent miscarriage (RM) is a distinct pathological phenomenon, defined by two or more consecutive clinical miscarriages. Less than 5% of women have two consecutive miscarriages and less than 1% have three or more.
Who should be assessed?
The challenge is often differentiating between sporadic miscarriage and recurrent miscarriage. A clinical examination is usually considered useful after two or three clinical pregnancy losses detected by ultrasound or the identification of placental tissue during miscarriage. Medical records are checked for a history of antiphospholipid syndrome (thrombosis, fetal death), uterine deformity, diabetes, poorly controlled thyroid disease, obesity, smoking and excessive alcohol and caffeine use.
Causes of recurrent miscarriage (RM)
The causes of RM are very varied. They include genetic factors, advanced maternal or paternal age, antiphospholipid syndrome, a particular susceptibility to thrombosis (hereditary thrombophilia), anatomical uterine factors, metabolic or hormonal disorders, impaired sperm quality and unhealthy lifestyles. Scientific knowledge in this field, however, is constantly changing as 45% to 50% of RMs are still unexplained.
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Blood karyotype of parents
Current literature encourages research on the genetic causes of RM. Clinical tests, however, are still fairly basic: a karyotype blood test (photographic representation of the chromosomes of a cell) of the couple. They rarely include a more in-depth molecular analysis. Approximately 50% to 60% of chromosomal abnormalities are found in the products of conception of sporadic miscarriages. Most are trisomies, partly associated with parental age.
The risk of sporadic miscarriage between the 6th and 12th week of pregnancy is 9% to 12% in women under 35 and 50% in women over 40.
As a pregnancy progresses, fewer and fewer chromosomal abnormalities that might explain miscarriage are found:
- 90% in very early pregnancies where no fetus is detected (clear eggs)
- 50% between the 8th and 11th week
- 30% between the 16th and 19th week
Finding a chromosomal abnormality in one of the parents is quite rare in all of the above situations. There is less risk of finding a fetus with a chromosomal abnormality in RM than in sporadic miscarriage. Parents must, however, have a karyotype blood test performed because in 2% to 5% of cases, a chromosomal abnormality is found. Very often it is due to a balanced translocation: a part of one chromosome is transferred to another (reciprocal or Robertsonian translocation).
The probability of a live birth depends on whether genetic defects are detected. Genetic counselling is therefore essential. If one of the parents is a balanced translocation carrier, the prognosis is usually quite good with 70% of cases resulting in a live birth. Once pregnancy is established, an invasive diagnostic test—such as an amniocentesis at around the 15th week or a CVS (placental biopsy), which can be performed earlier, from the 11th week—is usually recommended.
Pre-implantation genetic diagnosis
A pre-implantation genetic diagnosis (PGD) on embryos obtained following IVF is rarely considered. The live birth rate for IVF with PGD is 31% to 35% per attempt. The cumulative live birth rate is 55% to 74%. Current data do not warrant, however, offering PGD as a routine procedure to couples with RM.
Analysis of products of conception
A cytogenetic analysis (karyotype) of products of conception can sometimes be performed in some complex cases, and can have a positive psychological impact on the couple. Identification of a chromosomal abnormality actually indicates a better outcome for the next pregnancy. However, this approach has some pitfalls, such as possible contamination of the sample by maternal tissue or insufficient products of conception for culturing and cytogenetic analysis. Recent data suggests that a chromosomal analysis of products of conception using DNA microarray has some advantages in comparison to the classic karyotype. Cultivation of the sample studied is not necessary, results are obtained more quickly and additional submicroscopic genetic causes can be identified thanks to a better resolution of the test.
Obstetric antiphospholipid syndrome (APS) is characterized by recurrent miscarriage and the presence of antiphospholipid antibodies. More generally, diagnosis of APS requires a combination of at least one clinical criteria and one laboratory criteria (Table 1). About 8% to 42% of women with RM test positive for antiphospholipid antibodies in the blood. The most common antibodies associated with this syndrome are lupus anticoagulant, anticardiolipin and anti-ß2 glycoprotein I. A search for these antibodies should be performed in all women who have (1) had three or more consecutive miscarriages before the 10th week (2) lost a morphologically normal fetus at 10 weeks or later or (3) had a premature birth before the 34th week caused by severe pre-eclampsia, eclampsia or placental insufficiency.
Administration of prophylactic low-dose aspirin (80 to 100 mg/day) and an anticoagulant, unfractionated heparin (5,000 U subcutaneously twice a day), significantly improves the prognosis of RM associated with APS. Recent studies suggest that aspirin alone, at low doses, could also be effective. However, heparin is always recommended if a woman has a history of thromboembolism.
Testing for an inherited predisposition to thrombosis (thrombophilia) may be warranted for RM, but is usually performed if a woman has a personal or first-degree family history of venous thromboembolism. Otherwise, the association between thrombophilia and RM has not been clearly established by prospective studies. Women with a history of thrombosis associated with hereditary thrombophilia are, however, usually treated, either with unfractionated heparin or low molecular weight heparin.
Uterine anatomical factors
Abnormalities of the uterine cavity have been associated with an increased risk of miscarriage in the second trimester, preterm labour, fetal malpresentation at birth (breech for example) and therefore caesarean section. They can be congenital (uterine septum, arcuate uterus, unicorn uterus, bicornuate uterus, didelphic uterus) or acquired (uterine fibroids for example). Congenital malformations of the uterus are found in 13% of women with RM compared to 4% in the general population. There is evidence that the probability of having a miscarriage increases with a uterine septum (44%), a bircornuate uterus (36%) and an arcuate uterus (26%). An assessment of uterine anatomy is therefore usually required. The procedures used to look for these abnormalities are hysterosalpingography, hysterosonography or 2D/3D ultrasound. In some complex cases, a magnetic resonance imaging (MRI) is required to clarify the diagnosis. Surgical correction of a partition in the uterine cavity is beneficial (83% of live births) and should be considered in women with RM once other causes have been ruled out.
Surgery is not, however, recommended for an arcuate, bicornuate or unicorn uterus. With specific regard to uterine leiomyomas, endometrial polyps and intrauterine synechiae (adhesions or scars), the role of surgery is controversial. Yet clinical practice encourages surgical correction of acquired defects of the uterine cavity, such as submucosal uterine fibroids, polyps and synechiae, once other causes have been ruled out.
Endocrine disorders (hormonal or metabolic)
In cases of recurrent miscarriage, certain endocrine functions should be assessed. Although diabetes does not, in itself, increase the risk of RM, it should be well controlled, and can be confirmed by a glucose and hemoglobin A1c test. The same is true for thyroid function. Thyroid-stimulating hormone (TSH), which is secreted by the anterior pituitary gland, regulates the secretion of thyroid hormones. Untreated hypothyroidism is associated with an increased risk of miscarriage. Treatment is quite simple and involves oral administration of thyroid hormones. The goal is to have a TSH of 2.5 mUI/L or less.
Even for women with normal thyroid function, the presence of antithyroid antibodies increases the likelihood of recurrent miscarriage by two to four times. These antibodies indirectly reflect an autoimmune imbalance or subtle hypothyroidism.
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Recurrent miscarriage creates significant psychological stress and certain studies confirm that medical and psychological follow-ups combined with tender loving care have a positive impact. The grief reaction should never be underestimated and support should always be given to a couple going through the stages of grief, which can be extremely difficult.
Although certain infections have been associated with sporadic miscarriage, including Ureaplasma urealyticum, Mycoplasma hominis, Listeria monocytogenes, Toxoplasma gondii, rubella, cytomegalovirus and parvovirus, there is no compelling data indicating their role in recurrent miscarriage. Testing for them is therefore not recommended in an evaluation of RM.
Until recently, the man’s role in recurrent miscarriage was hardly mentioned in the literature and assessment was limited to a blood karyotype. However, more and more data seem to confirm the important role of male factors in recurrent miscarriage. We now know that higher rates of sperm DNA fragmentation and chromatin decondensation are associated with lower fertilization rates, defects in embryonic development and spontaneous abortions. The reasons for these impairments are varied. The older a man is, the higher the percentage of impaired sperm. Genital infections contribute to sperm DNA damage, particularly in young men. Also, prolonged exposure to environmental toxins, including insecticides, hydrocarbons, heavy metals, tobacco, and electromagnetic radiation, as well as heat and other oxidative stresses attack and impair sperm.
Investigations for men should therefore no longer be limited to a blood karyotype. Various methods for assessing sperm damage have been suggested, including semen analysis, assessment of the rates of sperm DNA fragmentation and chromatin decondensation (acetified aniline blue).
Lifestyle and Diet
Nutrition also plays a part in RM. Excessive caffeine and alcohol consumption or taking food supplements can have an impact. It is therefore essential to think carefully about nutrition—something all couples can do. The best diet is a varied and balanced one. We usually recommend a diet rich in antioxidants and omega-3s (green vegetables, fresh fruit, dairy products, eggs and fish) and low in saturated fats and high-glycemic carbohydrates.
Excessive weight and obesity have been identified as independent causes of recurrent miscarriage. The relative risk is twice as high and can be corrected if a healthy weight is maintained. If a patient is obese, a 5% to 10% loss of initial weight (30% body fat reduction) can reduce the risk of miscarriage from 75% to 25%.
Folic acid and multivitamins
Folic acid deficiency and elevated homocysteine levels have been observed more often in women who have had more than four miscarriages, especially in those with the methylenetetrahydrofolate reductase (MTHFR) gene mutation. A folic acid supplement is therefore always recommended, as it reduces the risk of miscarriage. Existing literature on the potential role of multivitamins in the prevention of miscarriage is more contradictory and does not confirm their usefulness. However, they do reduce the risk of certain fetal malformations.
Alcohol easily passes the placental barrier. As well as being associated with a risk of fetal alcohol syndrome, fetal growth restriction and intellectual disability, excessive alcohol consumption increases the likelihood of miscarriage by four times. During pregnancy women should be given clear and firm advice, and encouraged to abstain.
Caffeine is one of the most consumed substances in the world. Major sources are tea, coffee and certain energy drinks. The relationship between caffeine and RM is still controversial. Caffeine reduces placental blood flow to the placenta, so we recommend avoiding moderate to excessive consumption and limiting intake to three or fewer cups a day.
As well reducing fertility, tobacco increases the rate of miscarriage, the risk of placental abruption, placental previa, and fetal growth restriction. It also doubles the risk of sudden infant death syndrome. The harmful effects of tobacco on pregnancy are dose-dependent. Data that measure the association between tobacco and miscarriage are considerable (about 100,000 subjects). As with alcohol, couples should be given firm advice, encouraged to abstain and, ideally, to stop smoking at least three months before conceiving.
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Unexplained recurrent miscarriage (RM)
No cause is found in 45% to 50% of cases. Depending on their age and parity, the likelihood of women with unexplained RM carrying a pregnancy to term is usually 50% to 60%. According to current literature, there is no benefit in taking low-dose aspirin. However, vaginal administration of progesterone reduces the rate of miscarriage by 42% to 69%. Therefore, taking progesterone immediately after ovulation should be considered. As soon as a pregnancy has been confirmed by ultrasound (presence of fetal heartbeat) at around the 6th week, progesterone can be discontinued.
Areas of uncertainty and controversial matters
Polycystic ovary syndrome
Studies are conflicting regarding the elevated risk of RM in women with polycystic ovaries with insulin resistance and hyperandrogenism. The same is true for treatment with an oral hypoglycemic drug, such as metformin.
At the genetic level, cryptic deletions of genes in an apparently balanced translocation in the karyotype could be a cause of RM.
Alloimmunity is a condition in which the body develops immunity against antigens of another individual of the same species, which are perceived as foreign. It has been suggested that a maternal alloimmunity against paternal antigens in the fetus is a cause of recurrent miscarriage. Administration of immunoglobulins to induce tolerance has been unsuccessfully attempted, and therefore has no benefit. The same is true of maternal immunization with paternal white cells and the administration of corticosteroids.
In conclusion, Table 2 presents the recommended diagnostic evaluation for recurrent miscarriage.
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