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Most common causes of recurrent pregnancy loss

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Many women's dream is to start a family, to watch how one, two, three or even more little people grow up before their eyes and become big girls and boys, full of dreams and a desire for adventure. Unfortunately, however, not everyone is favoured with this opportunity. About 2-2.5% of women undergo two or more miscarriages, which is defined as recurrent pregnancy loss (RPL) and may be associated with reproductive problems (1).

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In this article, we will discuss the most common causes, as well as other main factors that are believed to contribute to repeated miscarriages. Finally, we will talk about what type of tests can be done to establish the cause and what treatments and methods are applied to overcome this problem.

Most-common-causes-of-recurrent-abortions

Most common causes of recurrent abortions

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There are many reasons that are considered leading in repeated pregnancy loss. As science and medicine progress, the influence of more and more factors is proven, which sometimes creates differences in conclusions between different state reproductive organizations. As leading factors, genetic, anatomical, endocrinological and immunological problems are noted.

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Anatomical-factors

Anatomical factors

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Anatomical defects in the uterus occur in 10%-15% of cases of repeated abortions (6). It is believed that the way they contribute to a miscarriage is by cutting blood circulation to the lining of the uterus (endometrium), which in turn leads to a number of reproductive problems. The most common anatomical defects found in women undergoing RPL are congenital genetic defects, intrauterine adhesions and uterine fibroids or polyps (6).

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Intrauterus adhesions, often associated with Asherman's syndrome, are common in RPL. They can be developed after a coarse curettage or other surgical interventions of the uterus, birth by caesarean section, radiotherapy, endometriosis or various infections such as genital tuberculosis. Adhesions of the uterus are caused by the formation of a cicatricial connective tissue resembling scars of the endometrium and leads to a change in its size and shape. Depending on the size of conglutination, this condition may not constitute a problem or even lead to infertility (7).

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Uterine fibroids and polyps are also associated with recurrent pregnancy loss. Fibroids, also called myomas or leiomyomas, are harmless growths from the muscle tissue of the uterus, while polyps are growths from the endometrium. Many women have such excrescences but most do not pose a problem. These formations can lead to miscarriage by preventing the egg from being properly implanted into the uterus. According to the American Society for Reproductive Medicine, 5%-10% of sterile women have myomas (8).

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Genetic-factors

Genetic factors

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Genetic factors include mainly chromosomal abnormalities, which can usually occur with the development of the embryo or be inherited from the parents. It is believed that about 2%-8% of couples who suffer from repeated pregnancy loss have an abnormal karyotype (karyotype is the totality of all chromosomes) (2), but embryonic chromosomal abnormalities are rare in RPL (4). About 50%-60% of all early miscarriages are due to defects in the karyotype (2). The most common hereditary chromosomal abnormalities in recurrent pregnancy loss are translocations, with the most commonly observed in RPL being reciprocal (about 60% of the translocations) and Robertson translocations (about 40% of the translocations).

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Reciprocal translocation is called the exchange of genetic material between two different chromosomes, and Robertson translocation is the joining of the long arms of one chromosome with the long arms of another chromosome and of the short ones with the short ones, forming two wrong-sized chromosomes (4). Although we have no influence on these genetic events, most parents who carry such genetic defects give life to a perfectly healthy child. If you have already suffered a miscarriage caused by chromosomal abnormalities, the probability of a subsequent abortion for the same reason is very low.

Endocrinological-factors

Endocrinological factors

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17%-20% of recurrent pregnancy loss is associated with endocrinological problems in women. The main ones are polycystic ovary syndrome, diabetes mellitus, thyroid disease. Scientists are discussing the possibility that a defect in the luteal phase of the menstrual cycle may have an impact on RPL, but this is still up for debate. Polycystic ovary syndrome is found in at least 40% of women who go through repeated pregnancy loss (9).

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Endocrinological-factors_0_2

These women are known to have insulin resistance and hyperinsolemia, hyperandrogemia and increased levels of a plasminogen activator-1 inhibitor – factors that have been proven to interfere with the course of normal pregnancy (6,10). In women suffering from diabetes mellitus, there is no increased risk of miscarriage, as long as insulin and glycosylated haemoglobin levels are kept to normal (11). &nbsp;Similarly, women with hypothyroidism may have a normal pregnancy and a healthy child if maintaining normal levels of thyroid hormone. If levels are not regulated during pregnancy, the risk of abortion, as well as of congenital genetic problems of the child after birth increase (12).

Immunological-factors

Immunological factors

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With the development of science there is deeper understanding of the influence of immunological factors on RPL. During implantation of the egg in the uterus, in the formation of the placenta and in the development of the embryo, a large number of different immune processes are involved, immune teams of guards, the role of which is to accompany and preserve the normal course of all these reproductive processes.

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Unfortunately, however, in some cases, the immune cells – guards make mistakes and cause problems in pregnancy. A main such problem is antiphospholipid antibody syndrome, which occurs in 15% of patients who undergo recurrent abortions (13). This is a rare autoimmune disease in which the immune system mistakenly attacks parts of the cell membrane called phospholipids. The cells that make up the lining of blood vessels are damaged, which causes increased formation of clots in the blood. This is a major problem in pregnant women, because communication between the mother and the embryo happens by blood. This disease can lead to blockage of blood vessels in the placenta, which would interfere with the development of the embryo and therefore lead to miscarriage. Another immunological factor for RPL is considered the possibility of the mother organism not recognizing the fetus as its own and disposing of it. Since the embryo carries genetic information from both the mother and the father, the paternal antigens which the fetus presents may be identified as alien by the mother's immune system and the placenta may be discarded (14).

Other-factors-associated-with-THE-PA

Other factors associated with THE PA

Thrombophilia

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Thrombophilia_1_1

The main thrombophilia most often associated with repeated pregnancy loss are:

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(a) Hyperhomocysteinemia, which occurs from a mutation in a specific gene called methylenetetrahydrofolate reductase (MTHFR). Opinions in science are still conflicting about whether this gene has any connection to vascular diseases at all, but many of the women who undergo repeated abortions have this mutation.

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b) Resistance to activated protein C – occurs from a mutation in Factor V Leiden. This mutation is a major genetic change in thrombophilia, since with its presence it is considered that the body goes into a state of hypercoagulation.

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c) Deficiency of activated protein C and protein S – these can be both congenital and acquired as a result of liver diseases, some infections, vitamin K deficiency and others. Congenital protein C deficiency arises from a mutation in the PROC gene, and in protein S - from a mutation in the PROS1 gene.

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(d) Mutations in prothrombin and antithrombin.

Fragmentation-of-sperm-DNA

Fragmentation of sperm DNA

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In a large number of cases of repeated abortions the cause is not in the woman but in the other partner, whose genetic material is also transmitted to the fetus. Most men have a subpopulation of sperm in their ejaculate, the DNA of which is damaged before or during ejaculation. In some subfertile men, the number of such spermatozoa is increased and this may be associated with the advent of repeated miscarriages (18).

Impact-of-environmental-factors-on-the-occurrence-of-recurrent-miscarriages

Impact of environmental factors on the occurrence of recurrent miscarriages

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There are various factors which some people face every day, which may contribute to the risk of recurrent miscarriages. Daily alcohol, cigarettes and coffee intake are most commonly discussed. Drinking alcohol 3 times a week for the first 3 months or 5 times a week during pregnancy has been shown to increase the risk of miscarriages. Smoking cigarettes is associated with constriction of blood vessels due to the presence of nicotine in them, which reduces blood circulation to the placenta and can be the cause of miscarriage (6). Coffee intake can also be a factor in miscarriage, as has been demonstrated in some studies (16,17). Although there are clearly risks of taking these substances, no link has yet been found between their intake and RPL.

What-tests-can-you-do-to-find-the-cause?

What tests can you do to find the cause?

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A visit to the gynecologist is inevitable after a miscarriage. While you are in the office, hysteroscopy can be done – a study in which the doctor examines the condition of the uterus from the inside using a small camera. Another study that is done in a specific place for the procedure is a hysterosalpingogram. In this study, fluoroscopy is performed – a contrast agent is injected into the cervix, which diffuses along the uterus and fallopian tubes. The process is observed on an X-ray and it visualizes whether there is a blockage of the fallopian tubes.

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Conducting cytogenetic analysis is a commonly prescribed study in patients who have suffered repeated miscarriages. Cytogenetic analysis allows to see all the chromosomes of the patient after only one blood collection. Chromosomes are isolated from the blood cells and then stained by a special method, allowing them to be seen under a microscope and to find out if any chromosomal defects are present.

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Examination of hormones such as thyroid stimulating hormone (TSH), checking the ovarian reserve by examining follicle-stimulating hormone (FSH) and estradiol may be useful in RPL. If you experience irregular menstruation, it can be seen whether antithyroid antibodies are present, which are detected in 17%-33% of women who have suffered 3 or more miscarriages (19). Checking if insulin resistance is present may also be helpful after undergoing RPL.

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Since antiphospholipid syndrome is indisputably associated with repeated abortions, it is significant to test for the presence of anticardiolipin antibodies and lupus anticoagulant, which will indicate whether the patient has an increased risk of forming blood clots.

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What-tests-can-you-do-to-find-the-cause?_2_6

Despite numerous associations of thrombophilia with miscarriages in women, they have not yet been accepted as a major factor in repeated abortions, but rather as an accompanying factor to other factors that make a greater contribution to the occurrence of such events. Nevertheless, it is advisable that women who have a history of thrombosis take a blood test for the presence of thrombophilia.

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Last but not least, it is important to establish whether the cause of RPL comes from the male partner by examining the seminal fluid for DNA fragmentation. There are several different methods that can be conducted for this analysis, but all of them evaluate whether there is damage in sperm DNA.

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Therapies-that-may-improve-the-chances-of-conception-in-RPL

Therapies that may improve the chances of conception in RPL

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If an anatomical problem is detected, it can be removed surgically which often gives good results. If there are genetic abnormalities, including fragmentation of DNA in spermatozoa, the best option is to approach various in vitro procedures. Therapy with insulin-sensitive agents such as metformin improves performance in women with polycystic ovary syndrome (20). If there is an increased risk of thrombus formation, therapy with low molecular weight anticoagulants, such as heparin, is recommended. For some women, it is even advisable to continue taking them during pregnancy. Other easy changes that can be done in everyday life that can have big impact on the improvement in the chances of conception is the management of a healthy lifestyle by both partners – healthy eating, more movement, no drinking of alcohol, coffee and no smoking cigarettes, taking vitamins and antioxidants.

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Conclusion

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Nowadays, about 25%-30% of women go through hardships to discover the cause of repeated abortions, many of which even remain unclear. It is believed that in about 40%-50% of cases the exact cause cannot be found (6). However, most women who undergo repeated miscarriages (about 70%-75% of them) subsequently manage to give life to a healthy child (3).

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Dimitriadis, E., Menkhorst, E., Saito, S.&nbsp;et al. (2020).&nbsp;Recurrent pregnancy loss.&nbsp;Nature Reviews Disease Primers6, <a href="https://doi.org/10.1038/s41572-020-00228-z" target="_blank" rel="noopener">https://doi.org/10.1038/s41572-020-00228-z</a>

Pal, A. K., et al. (2018). Chromosomal Aberrations in Couples with Pregnancy Loss: A Retrospective Study.&nbsp;Journal of human reproductive sciences, 11(3), 247–253. <a href="https://doi.org/10.4103/jhrs.JHRS_124_17" target="_blank" rel="noopener">https://doi.org/10.4103/jhrs.JHRS_124_17</a>

Hyde, K. J., &amp; Schust, D. J. (2015). Genetic considerations in recurrent pregnancy loss.&nbsp;Cold Spring Harbor perspectives in medicine, 5(3), a023119. <a href="https://doi.org/10.1101/cshperspect.a023119" target="_blank" rel="noopener">https://doi.org/10.1101/cshperspect.a023119</a>

El Hachem, H., et al. (2017). Recurrent pregnancy loss: current perspectives.&nbsp;International journal of women's health, 9, 331–345. <a href="https://doi.org/10.2147/IJWH.S100817" target="_blank" rel="noopener">https://doi.org/10.2147/IJWH.S100817</a>

Danielsson, K. (2020). How a septate uterus increases miscarriage risk. VeryWellFamily

Ford, H.B., &amp; Schust, D. J. (2009). Recurrent pregnancy loss: etiology, diagnosis, and therapy.&nbsp;Reviews in obstetrics &amp; gynecology, 2(2), 76–83.

Asherman syndrome - adhesions in the uterine cavity - en

Care England. Uterine Fibroids, Polyps &amp; Abnormalities. womenandinfants.org

Raj, Raj, Backos, M., Rushworth, F., Regan, L. (2000). Polycystic ovaries and recurrent miscarriage—a reappraisal, Human Reproduction, Volume 15, Issue 3, Pages 612–615, <a href="https://doi.org/10.1093/humrep/15.3.612" target="_blank" rel="noopener">https://doi.org/10.1093/humrep/15.3.612</a><a href="https://pubmed.ncbi.nlm.nih.gov/14669168/" target="_blank" rel="noopener">https://pubmed.ncbi.nlm.nih.gov/14669168/</a>

Mills, J. L. et al. (1988). Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identifies within 21 days of conception. The New England Journal of Medicine. 319:1617-1623. DOI: 10.1056/NEJM198812223192501

Thyroid Disorders and Pregnancy | Children's Hospital of Philadelphia

Di Prima, F. A. et al. (2011). Antiphospholipid Syndrome during pregnancy: the state of the art. Journal of prenatal medicine, 5(2), 41–53.

W. Tang, Z. Alfirevic, S. Quenby, Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review, Human Reproduction, Volume 26, Issue 8, August 2011, Pages 1971–1980, <a href="https://doi.org/10.1093/humrep/der164" target="_blank" rel="noopener">https://doi.org/10.1093/humrep/der164</a>

Kwak, J.Y., Beer, A.E., Kim, S.H. and Mantouvalos, H.P. (1999), Immunopathology of the Implantation Site Utilizing Monoclonal Antibodies to Natural Killer Cells in Women with Recurrent Pregnancy Losses. American Journal of Reproductive Immunology, 41: 91-98.&nbsp;<a href="https://doi.org/10.1111/j.1600-0897.1999.tb00080.x" target="_blank" rel="noopener">https://doi.org/10.1111/j.1600-0897.1999.tb00080.x</a>

Rasch, V. (2003), Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion. Acta Obstetricia et Gynecologica Scandinavica, 82: 182-188.&nbsp;<a href="https://doi.org/10.1034/j.1600-0412.2003.00078.x" target="_blank" rel="noopener">https://doi.org/10.1034/j.1600-0412.2003.00078.x</a>

Cnattingius, et al. (2000). Caffeine Intake and the Risk of First-Trimester Spontaneous Abortion. New England Journal of Medicine. 343.25. Pages 1839-1845. DOI: 10.1056/NEJM200012213432503

Robinson, L., et al. (2012). The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis, Human Reproduction, Volume 27, Issue 10, Pages 2908–2917, <a href="https://doi.org/10.1093/humrep/des261" target="_blank" rel="noopener">https://doi.org/10.1093/humrep/des261</a>

Antithyroid antibodies TATE MAT. Reproinova.com

Feng, Ye &amp; Yang, H. (2017) Metformin – a potentially effective drug for gestational diabetes mellitus: a systematic review and meta-analysis, The Journal of Maternal-Fetal &amp; Neonatal Medicine,&nbsp;30:15,&nbsp;1874-1881,&nbsp;DOI: <a href="https://doi.org/10.1080/14767058.2016.1228061" target="_blank" rel="noopener">10.1080/14767058.2016.1228061</a>

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Most common causes of recurrent pregnancy loss

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 Most common causes of recurrent pregnancy loss

Ивелина Янкова

Author: Elena Marinova, Master of Pharmacy

We all know that a panacea, unfortunately, does not exist, but chamomile has been considered as such for many years. Known since ancient times, this herb deservedly received the nickname "the star among the medicinal species", which is still relevant today. Chamomile is used for both internal and external use, and the rich set of biologically active substances determines its various healing properties.

Special-Aroma

Special Aroma

Special-Aroma_0_0

Near or in populated areas, by roads or on meadows, in turbulent and abandoned places, between May and July, you will surely find the small yellow-and-white flowers of chamomile. You will recognize it even blindfolded only by the aroma, which is so specific, so pleasant and soothing, so familiar... This aroma is due to the high content of essential oils and is one of the main criteria that distinguish chamomile from its doppelgangers.

What-Is-Chamomile-And-How-To-Recognize-It

What Is Chamomile And How To Recognize It

What-Is-Chamomile-And-How-To-Recognize-It_1_0

Chamomile is a herbaceous plant that belongs to the family Compositae. It is distributed in Europe, Asia and North America. Two close varieties of the plant Chamomilla recutita are used as an herb - German chamomile and Chamaemelum nobile - Roman chamomile.

What-Is-Chamomile-And-How-To-Recognize-It_1_1

From the Greek its name means "earth apple". The leaves of chamomile are filamentous, and the flowers are collected in a basket inflorescence. Besides the aroma, the other important distinguishing feature of the herb is the flower bed, which is conical and hollow.

A-Look-At-Antiquity

A Look At Antiquity

A-Look-At-Antiquity_2_0

Chamomile was used thousands of years ago by the ancient Romans, Egyptians and Greeks to treat various diseases and conditions - <a href="/p/krviashchitie_vientsi_kak_da_sie_spravim_s_probliema_s_prirodni_sriedstva_512d3da9_67c1_47e1_bf6a_6c9d9bef6c59" target="_blank" rel="noreferrer">inflammation of the gums</a>, sore throat, <a href="/p/inkhalatsiia_s_bilki_pri_bronkhit_kashlitsa_zachiervieno_ghrlo_khriema_i_trievozhnost" target="_blank" rel="noreferrer">lung diseases</a>, <a href="/p/trievozhnost_i_biezsniie_kakvo_priedlagha_prirodata_eef882c6_b669_4aea_9d2d_1e11852fbcfe" target="_blank" rel="noreferrer">insomnia</a> and others.

A-Look-At-Antiquity_2_1

In the Tibetan mountains lived monks who had a lot of knowledge about herbs. They invented a special recipe for rejuvenation, the main component being chamomile. Unfortunately, the herb cannot rejuvenate us, but it contributes to our skin being smooth, tender, beautiful and it is no coincidence that it is part of many herbal creams and lotions.

A-Look-At-Antiquity_2_2

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Ancient Egyptian doctors emphasized the internal application of chamomile and the benefits it brings - every third day of the month, chamomile tea was drunk to detoxify the body.

A-Look-At-Antiquity_2_4

Chamomile---A-Herb-With-Many-Names-And-Useful-Properties

Chamomile - A Herb With Many Names And Useful Properties

Chamomile---A-Herb-With-Many-Names-And-Useful-Properties_3_0

Its other Latin name Matricaria recutita is related to the application of chamomile in case of problems with the female reproductive system. The herb is used in:

Chamomile---A-Herb-With-Many-Names-And-Useful-Properties_3_1

<ul>
<li style="font-weight: 400;" aria-level="1">inflammation</li>
<li style="font-weight: 400;" aria-level="1">muscle spasms</li>
<li style="font-weight: 400;" aria-level="1">menstrual disorders</li>
<li style="font-weight: 400;" aria-level="1">skin irritations and wounds</li>
<li style="font-weight: 400;" aria-level="1">gastro-intestinal disorders</li>
<li style="font-weight: 400;" aria-level="1">hemorrhoids</li>
<li style="font-weight: 400;" aria-level="1">hay fever <a href="https://www.bioseek.eu/en/eng/research/pubmed/Chamomile_A_herbal_medicine_of_the_past_with_bright_future_21132119" target="_blank" rel="noopener"> [ref.1]</a></li>
<li style="font-weight: 400;" aria-level="1">cosmetics and <a href="/p/aromatierapiiata_kak_sami_da_prilozhim_tazi_praktika_ot_drievnostta" target="_blank" rel="noreferrer">aromatherapy</a></li>
</ul>

The-Rich-Chemical-Composition-Of-The-Herb

The Rich Chemical Composition Of The Herb

The-Rich-Chemical-Composition-Of-The-Herb_4_0

Chamomile contains many diverse biologically active substances. The greatest is their quantity in the flowers, therefore for healing purposes the "basket" of the plant is used, which are collected during flowering (May-July), and then dried.

The-Rich-Chemical-Composition-Of-The-Herb_4_1

Of the active substances the highest is the content of essential oils. They are extracted from the flowers by distillation with water vapour, and the resulting oil Chamomillae oleum has a blue color.

The-Rich-Chemical-Composition-Of-The-Herb_4_2

Chamomile oil contains essential oils of the group of sesquiterpenes (farnesen, alpha-bisabolol) and polyins. They are due to antispasmodic, anti-inflammatory and sedative effects. Essential oils mainly determine the use of chamomile for internal use.

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It is applied alone or in combination with other herbs in the form of tea, using dried flowers. Both tea and chamomile oil help with gastrointestinal discomfort (swelling, pain), inflammation in the oral cavity (in the form of mouthwash), nervousness, inflammation of the upper respiratory tract, menstrual pain.

The-Rich-Chemical-Composition-Of-The-Herb_4_4

In the flowers of chamomile there are also flavonoids mainly apigenin, quercetin, luteolin. These are biologically active substances with various important effects for the body - antioxidant (defuse harmful free radicals), diuretic (increases the amount of urine released in 24 hours), anti-inflammatory action.

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Chamomile has been shown to have an antiaggregant effect (prevents the adhesion of platelets), which is due to another type of biologically active substances - coumarins. <a href="https://www.bioseek.eu/en/eng/research/pubmed/A_review_of_the_bioactivity_and_potential_health_benefits_of_chamomile_tea_Matricaria_recutita_L_16628544" target="_blank" rel="noopener">[ref.2]</a>

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 Which herbs to avoid when taking aspirin, nurofen and paracetamol

The-Rich-Chemical-Composition-Of-The-Herb_4_7

Studies have been carried out that chamomile has antimicrobial, antifungal and antitumor action. <a href="https://www.bioseek.eu/en/eng/research/pubmed/Chamomile_Matricaria_chamomilla_L_An_overview_22096322#ref20" target="_blank" rel="noopener"> [ref.3]</a>

The-Rich-Chemical-Composition-Of-The-Herb_4_8

Chamomile-For-External-Use

Chamomile For External Use

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Externally, chamomile is applied in the form of lotions, compresses, infusions, enters the composition of face and body creams. It has an anti-inflammatory and soothing effect on the skin and mucous membranes, which is again due to the essential oils. In addition, chamomile helps to heal wounds faster.

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An animal study has been done that proves that chamomile has a faster effect on wound healing than corticosteroids (drugs that have a strong anti-inflammatory effect, but their excessive use can harm the body). <a href="https://www.bioseek.eu/en/eng/research/pubmed/Comparative_analysis_between_Chamomilla_recutita_and_corticosteroids_on_wound_healing_An_in_vitro_and_in_vivo_study_18803230" target="_blank" rel="noopener">[ref.4]</a>

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How To Use Chamomile At Home

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Here's how to use chamomile:

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<ul>
<li style="font-weight: 400;" aria-level="1">tea - 1 tsp dried chamomile flowers is poured with 250 ml of boiling water;</li>
<li style="font-weight: 400;" aria-level="1">extract - 10 tbsp of dried herb are poured with 2 cups of cold water and allowed to sit for 8 hours;</li>
<li style="font-weight: 400;" aria-level="1">compresses - 1 tbsp of dried chamomile is poured with 250 ml of boiling milk;</li>
<li style="font-weight: 400;" aria-level="1">for mucous membrane washes - 1 tsp of the herb is poured with 1 liter of boiling water. After the extract cools down (but is still warm), rinse.</li>
</ul>

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