What are recurrent miscarriages? – Causes, diagnosis and treatment

Repeated miscarriage also called recurrent miscarriage, is defined as the gestational loss of 3 or more pregnancies before 20 weeks. In this case, the couple is not sterile because they are able to conceive, but there is a problem of infertility because they are unable to carry the pregnancies to term.

Repeated miscarriages have a great emotional consequence on expectant parents, as the disappointment of not having a baby adds to the frustration of having lost several pregnancies.

The causes of repeated miscarriage are very diverse, sometimes unknown, which aggravates the situation of infertility and increases the waiting time to find the appropriate treatment to have a child.

What are the repeated miscarriages?

According to the World Health Organization (WHO), an abortion is defined as the spontaneous termination of pregnancy before the fetus is viable (weighing less than 500 grams or 20-22 weeks of gestation). If, in addition, we attach the tag "repeat", it means that 3 or more consecutive gestational losses have occurred before the 20th week.

On the other hand, suffering repeated miscarriages does not mean that it is not possible to have a viable pregnancy and a healthy child between gestational losses. Depending on the cause of the miscarriages, the probability of suffering a new loss may be higher or lower, but there is a chance of achieving a live newborn.

Therefore, even if the definition of repeat miscarriage specifies that gestational losses are consecutive, if there have been 3 or more miscarriages during the woman's entire reproductive life, one must already think that there is an underlying problem.

Obviously, only spontaneous abortions are counted for the diagnosis of recurrent abortion. In no case will voluntary and induced abortions are included as a woman's decision.

Finally, it should be noted that the American College of Obstetricians and Gynecologists( ACOG) already consider recurrent miscarriage when there are 2 consecutive gestational losses, although there is no clear consensus on this.

However, specialists recommend starting studies to find out the causes of miscarriages if two pregnancy losses have already occurred.

Causes of recurrent miscarriage

Recurrent pregnancy loss occurs among 3-5% of couples or single women seeking pregnancy.

Epidemiology varies depending on maternal age. A woman under 30 years of age has only a 25% chance of a new miscarriage. On the other hand, over the age of 40, there is a 50-60% chance of a recurrence of gestational loss.

Sometimes it is difficult to know what is causing repeated miscarriages. Other times, on the other hand, it is found out after some analysis, and the necessary measures can be taken.

Below, we discuss the causes of repeat miscarriage in order of probability:

Genetic Causes

In 50% of cases of miscarriage, the origin is genetic. However, a genetic cause is attributed to only 3-8% of couples with repeated miscarriages.

The most influential factor in terms of miscarriages due to genetic causes is advanced maternal age. With the decrease in ovarian reserve and oocyte quality, the probability of fertilizing embryos with trisomies (3 chromosomes instead of 2) that are not compatible with life increases.

On the other hand, it may happen that one or both parents carry a chromosomal alteration that goes unnoticed but, when they have offspring, gives rise to non-viable embryos. This is what is known as a balanced chromosomal rearrangement, which can be of different types:

• Reciprocal translocations
• Robertsonian translocations
• Investments

Finally, it is worth noting the possible alterations in male spermatogenesis, resulting in the formation of spermatozoa with genetic alterations.

Consequences of being a carrier of a balanced chromosomal mutation

Immunological causes

Today, several factors related to the immune system have been found to be associated with repeat miscarriage. Generally speaking, we will divide them into the following two groups:

Autoimmune causes

here we find thrombophilias, both inherited and acquired, which translate into a state of hypercoagulability of the maternal blood, which causes clots to form that can reach the placenta and affect blood flow to the fetus, causing gestational loss.

Special attention should be paid to antiphospholipid syndrome (APS), a type of acquired thrombophilia that is responsible for 12-15% of recurrent miscarriages. As for inherited thrombophilias, the most frequent genetic mutations that cause them are Factor V Leiden and the prothrombin mutation.

Alloimmune causes

in this case, miscarriages occur because the body does not recognize the fetus as its own structure and, as a consequence, produces antibodies to reject it. This involves the so-called Natural Killer (NK) cells, a type of lymphocyte with the capacity to destroy organisms that it does not recognize as part of the woman's body, and its KIR receptors, which are responsible for identifying and recognizing the fetus as its own or foreign.

So that this immunological rejection does not occur in all pregnancies, women have an immunological tolerance mechanism that allows embryo implantation without problems. When this immunosuppression mechanism fails, pregnancy loss occurs.

Cervical incompetence

Anatomical causes

They refer to malformations or other alterations that the woman's uterus may have where gestation takes place.

These causes are usually more obvious and some can be diagnosed with an ultrasound scan.

For example, the most common alterations are the following:

• Uterus septum
• Submucous uterine myoma
• Asherman's syndrome
• Cervical insufficiency

In general, any alteration that distorts the morphology of the uterus or alters its functionality. In the latter case, the role of the endometrium, its innermost layer, and the one in which the embryo implants, must also be emphasized.

Most of these pathologies can be eliminated with surgery. You can read more about this topic at the following link: Female infertility due to a uterine factor.

Endocrine causes

Recurrent miscarriages may also be related to hormonal problems in the woman, although this is one of the least likely factors. Specifically, there are 3 different situations:

Corpus luteum insufficiency

refers to the inability of the ovary to produce progesterone, a hormone that is very important for the maintenance of pregnancy.

Diabetes mellitus

elevated blood glucose concentration.

Thyroid disorders

hypothyroidism and hyperthyroidism.

Obviously, not all women suffering from these disorders will suffer repeated miscarriages: only the most severe cases are associated.

Diagnosis

A multitude of tests are available to determine the cause of recurrent miscarriages. The following are the most important ones:

• Male and female karyotypes
• Imaging tests in women to view the anatomy of the uterus: hysterosalpingography, ultrasound or hysteroscopy
• Endometrial biopsy
• Hormonal analysis: prolactin level, progesterone and thyroid gland function
• Sperm DNA fragmentation study (TUNEL)
• FISH of spermatozoa
• Study of thrombophilias: lupus anticoagulant factor and anticardiolipin antibodies
• Immunological study
• Levels of vitamin D

In 50% of the cases in which repeat abortion is studied, the results of all tests are normal. This results in what is known as idiopathic or unexplained recurrent miscarriage.

In a situation of repeated miscarriages of unknown cause, the woman is recommended to follow strict control of the next pregnancy, including psychological support if necessary, in order to avoid a recurrence of gestational loss.

Treatment of recurrent miscarriage

The strategy for achieving a viable pregnancy and the birth of a healthy child in women who suffer repeated miscarriages will depend on the specific cause of the miscarriage. Therefore, each couple or woman will need a personalized treatment.

Below, we will discuss some strategies that can be followed in order to have a baby:

PGD

when there is a genetic alteration that stops embryonic development.

Gamete donation

if pregnancy is not achieved after several attempts, if it is not possible to identify the genetic cause or if no healthy embryo is obtained after PGD.

Heparin and/or aspirin

for coagulation problems or thrombophilic causes. It is necessary to keep a strict control of the pregnancy and to personalize the dose of medication needed at each moment.

Surrogacy

in cases where the woman is unable to gestate because this would endanger her life.

Treatments for having a child

Some of the causes of recurrent miscarriage, such as immunological causes, may require combined treatment by various specialists. In this case, all physicians treating the woman or the couple will have to agree on the strategy to be followed.

Interview with Dr. Miguel Dolz

The following is an interview given by Dr. Miguel Dolz, medical director of the IVF Valencia clinic, about the causes and possible ways of dealing with a case of repeated miscarriages.

Question: What are the main causes of repeat abortion?

Response: There are many causes of repeated miscarriage, but the main ones are chromosomal alterations, alterations in the uterine architecture... as well as other types of alterations that affect the interior of the uterus, the thickness of the endometrium (where the embryo implants), and that refers to the immune system, thrombophilias, blood coagulation...

There are many causes, but fundamentally and in the 21st century, advanced age is possibly one of the most important causes, whereas in the past we did not refer to this concept. Many times we see in the doctor's office a couple that comes with repeated miscarriages, who have had two or three consecutive miscarriages, but the woman is 42 years old. A study must be done to see what the causes are, but most probably the fundamental cause is the age of this woman, which will give rise to embryos that have the capacity to implant but do not have the capacity to give rise to a healthy baby. They usually have chromosomal alterations and that is why in the end they do not implant.

Other causes are those that affect the architecture. There are alterations that affect the morphology of the uterus, such as the double uterus, septa, a uterus that we call "low receptivity" or dysmorphic, which cause these miscarriages. Other times, for example, altered blood coagulation or an over-responsive immune system may be responsible for this rejection of the embryo.

Q: Does maternal age influence repeat abortions?

R: Maternal age is critical in repeat abortions. Advanced maternal age is associated with many chromosomal and genetic errors when fertilization mechanisms occur and are therefore responsible for many negative pregnancy tests, but also for many pregnancies that end in miscarriage.

In this type of patient, the miscarriage rate is often higher than 50%, precisely because of age, which will cause these poor quality eggs to generate embryos with chromosomal alterations that will make them unviable. Either they fail to implant and will result in a negative test, or they implant but stop in the first weeks of pregnancy and result in a miscarriage.

Q: How does thrombophilia influence repeat miscarriages?

R: Thrombophilia is defined as a state of hypercoagulability of a woman's blood. Therefore, if we think of the development of an embryo, for it to "take root" and implant, maternal and fetal blood will have to come into contact, and there are mechanisms of thrombosis in this union, that is, in these interfaces, we can deduce that a state of hypercoagulability in a thrombophilia will be responsible for a percentage of repeated miscarriages, which account for approximately 12-15% of the causes of miscarriage.

Q: What treatment is appropriate to prevent repeat miscarriage?

R: The treatment of repeated miscarriage is etiological, which means that the cause or causes of the miscarriage must be determined because many times there are several causes and all of them must be treated at the same time. If we solve one but do not solve other options, then obviously we will continue to have abortions.

Let us think that in a woman who comes for consultation and is 40 years old, age is an important causal factor, but perhaps this woman has thrombophilia and, in addition, she may have a low receptivity uterus. If we solve the problem of age through preimplantation genetic diagnosis (PGD) or the issue of thrombophilia with heparin, but we do not take into account that this woman has a low uterine receptivity, abortion will continue to occur.

Therefore, the treatment is etiological, depending on the cause or causes that are provoking it. When a woman starts the study of repeated miscarriage, a study of all the possible causes that cause this miscarriage must be made and treatment must be given to all the causes or everything that is provoking and may be responsible for the miscarriage.

Q: Is PGD recommended in case of repeated miscarriages?

R: Preimplantation genetic diagnosis (PGD) is a fundamental tool for the genetic and chromosomal evaluation of an embryo. If we suspect that the cause of the miscarriage is chromosomal, PGD is the fundamental tool. Therefore, yes, PGD must be performed when the suspected cause of the repeated miscarriage is chromosomal alterations of the embryo.

Q: Why is long culture recommended in patients with repeat miscarriages?

R: Long culture to blastocyst is simply an attempt to optimize an in vitro fertilization (IVF) cycle. Normally, if we start on the third day of six embryos, it is normal for 50% to reach blastocyst. There is a better selection that translates into a 15% increase in the pregnancy rate but at the same time a 15% reduction in chromosomal alterations. Therefore, although not the perfect solution, blastocyst transfer could optimize an IVF cycle in a patient with repeated miscarriages.

FAQs from users

What are the causes of repeated biochemical pregnancies?

A biochemical pregnancy is an early pregnancy loss that occurs shortly after implantation.

The exact cause of a biochemical pregnancy is unknown. But in most cases miscarriage is due to problems with the embryo, possibly caused by poor quality sperm or eggs.

Other causes may include:

• Abnormal hormone levels
• Uterine abnormalities
• Implantation outside the uterus
• Sexually transmitted infections
• Being over 35 years of age increases the risk of a biochemical pregnancy
• Blood clotting and thyroid disorder

Read more

What is antiphospholipid syndrome?

Antiphospholipid syndrome (APS) is an entity with specific clinical and analytical features independent of other autoimmune entities. The etiopathogenesis of the condition is unknown. This means that the mechanism by which antiphospholipid antibodies cause fetal losses is not known. However, it seems that a coagulation phenomenon (thrombosis) may be at the basis of the problem.

Ultimately, pregnant patients affected by SAP are at risk of recurrent miscarriages and recurrent late fetal losses. Therefore, it is imperative to rule out this syndrome in these patients by determining the possible presence of APL or ACA.

Once other causes of miscarriage have been ruled out, and a diagnosis of SAP has been made, treatment will be based fundamentally on drugs with an antiplatelet (acetylsalicylic acid) and/or anticoagulant (Heparin) effect.

Can repeated miscarriages have a male cause?

The truth is that, after a detailed study of the individual case, we are sometimes unable to make an aetiological diagnosis. That is, we do not determine the cause of the miscarriages. It is important to note that in couples with repeated miscarriages in which the cause of the miscarriages is not found, the probability of a subsequent full-term pregnancy is greater than 50%.

Among the most common causes of repeat miscarriages are genetic causes and the so-called primary antiphospholipid syndrome.

However, recent studies point to a possible male factor as the origin of repeat miscarriages. In recent years, semen quality has declined, largely due to stress, long working hours, environmental pollution, exposure to heat, alcohol and tobacco, poor eating habits and even the use of tight underwear.

Tests are available to identify chromosomal alterations in semen samples.

What tests are included in the repeat miscarriage study?

Normally, the study of repeated miscarriages consists of an analysis of the Antiphospholipid Syndrome, genetic testing, assessment of thrombophilias, hysteroscopy, and transvaginal ultrasound to study anatomy.
Read more

What are the signs and symptoms of recurrent miscarriage?

The main symptoms of recurrent miscarriage are the same as those a woman has when she has a miscarriage: heavy bleeding and severe pelvic or abdominal pain.

Urinary tract infections and vaginal infections are also indicative of miscarriage risk.

Recommended readings

As we have said, it is necessary to do many tests on the couple after having several repeated miscarriages in order to know the cause and what treatment to apply. In the following article, you will find information about these tests in women: What are the tests of a female fertility study?

Similarly, there are also tests to evaluate male fertility. In the case of repeated miscarriage, the malefactor is studied to a lesser extent, but here you can find some of these tests: What do the tests of a male fertility study consist of?