For a pregnancy to occur physiologically, several factors must interact. On the female side, ovulation must happen, and the fallopian tubes must be open and capable of catching and transporting the egg. On the male side, the sperm must be deposited near the cervical canal and be able to reach and fertilize the egg in the fallopian tube. The resulting embryo then paves its way toward the uterine cavity, where, assuming the integrity of the mucous membrane, it implants.
Normal fertile couples have an average pregnancy rate of around 20-25% per cycle.
Some couples can achieve pregnancy, but the pregnancy ends in the first trimester (before the 12th week). This fact can be an immense psychological and physical burden. Often, couples are put off by statements such as “this is natural and very common” or “next time, it will work.”
This article aims to offer couples answers to the question “Why?” and recommend solutions.
Genetic factors
Most of all pregnancy losses are due to chromosomal abnormalities that occur in the egg (less commonly) in the sperm or during early embryonic development. In approximately 4-8% of couples with recurrent miscarriages, one of the partners has a chromosomal abnormality associated with an increased tendency to produce unhealthy embryos.
Options
To be able to diagnose the latter and initiate appropriate treatment steps, a karyotype test should be carried out on the couple. It is a simple blood test that allows us to look at the number and integrity of the chromosomes.
Age and aneuploidy of the gametes
As the female ages, the number of available eggs decreases. More importantly, those still open showing increased chromosomal abnormalities. On the one hand, this makes fertilization difficult. In some cases, it can even lead to the creation of embryos with an abnormal number of chromosomes, which either fail to implant or result in miscarriage before the 12th week of pregnancy. Studies suggest that aneuploidy of oocytes is relatively low (<10%) before age 35 but increases abruptly to approximately 100% by age 45. Compared to the impact of oocyte aneuploidy on the risk of miscarriage, chromosomally abnormal sperm are insignificant as a predisposing factor for recurrent pregnancy loss, as sperm aneuploidy rarely rises above 1-2%.
Options
In women of advanced reproductive age and with a good oocyte reserve, genetic testing of embryos (PGT-A) as part of IVF treatment could be crucial to success. The transfer of a chromosomally tested inconspicuous embryo is associated with a much higher pregnancy/ and live birth rate, and frustrating embryo transfers are spared to the couple.
Factor uterus
Congenital malformations of the uterus, fibroids, and intrauterine adhesions can lead to miscarriage.
The prevalence of complex uterine malformations is about 2% in the general population and is about three times higher (6-7%) in women with early pregnancy loss. Losses with congenital uterine anomalies usually occur later in pregnancy, in the second trimester, and are generally due to reduced intrauterine volume, endometrial dysfunction, or poor vascular supply. Suppose fibroids do not invade or occupy the uterine cavity. In that case, surgery is not indicated unless other specific symptoms are attributable to fibroids. Adhesions, for example, in the context of Asherman’s syndrome, can repeatedly lead to early miscarriages. Any injury severe enough to remove or destroy the lining of the uterus can cause adhesions, and a pregnant woman’s uterus seems particularly vulnerable to such injuries.
Options
The first step is to examine the uterine cavity. Imaging using 3D ultrasound, sonohysterography, or magnetic resonance imaging (MRI) may be required to differentiate precisely what pathology is present. Uterine fibroids are very often detected in women with recurrent miscarriages. Still, only fibroids located directly under the mucosa of the uterus (submucosal) and those that grow in the muscle layer (intra- and transmural) and deform the uterine cavity are relevant. Intrauterine adhesions are a rare but known cause of repeated miscarriages. Pregnancy outcomes are significantly better after hysteroscopic resolution but generally poor.
Immunological factors
Autoimmune disorders are immune reactions directed against a specific part of the woman’s body. Diseases associated with recurrent pregnancy loss include certain classic autoimmune disorders such as systemic lupus erythematosus and antiphospholipid syndrome. Several mechanisms may explain how antiphospholipid antibodies predispose to placental thrombosis or disrupt the normal development of the uteroplacental circulation, causing both early and late pregnancy loss.
Options
The lupus anticoagulant, anticardiolipin antibody, and anti-B2 glycoprotein-1 antibody tests are the only validated immunological tests with clinical utility in assessing women with recurrent pregnancy loss. Combined aspirin and heparin therapy are effective and are the preferred treatment for women with recurrent pregnancy loss associated with antiphospholipid syndrome. Normal pregnancy also requires maternal immunological recognition and response to paternal antigens on embryonic tissue, and abnormalities in the maternal alloimmune response may promote or cause recurrent pregnancy loss. Dysregulation of immune mechanisms at the maternal-fetal interface is the most likely pathophysiological mechanism. Suspected alloimmunopathology, HLA testing, and assessment of immune cells in the mucosa or blood are available. The data regarding the benefit of treatment has yet to be precise, so each case must be assessed individually.
Hereditary coagulation disorders
In some women with recurrent pregnancy loss, thrombogenic changes during pregnancy exacerbate a genetic tendency to thrombosis, leading to reduced uteroplacental blood flow, placental thrombosis, and pregnancy loss. Among them, the most common is the factor V Leiden mutation and the prothrombin gene mutation. A third common mutation affects the gene that encodes the enzyme methylene tetrahydrofolate reductase. Individuals who have both mutated genes (homozygous) tend to have hyperhomocysteinemia, a known risk factor for thrombosis. Other inherited thrombophilias that have been identified include deficiencies of antithrombin III, XII, protein S, and protein C. These are also considered to predispose to thrombosis and pregnancy loss.
The evidence suggests that thrombophilias confer a higher risk of early and late pregnancy loss.
Options
Women with recurrent pregnancy loss should be screened for heritable coagulation disorders, especially in women with a history of thrombosis or first-degree relatives with a known or suspected coagulation disorder.
Endocrinological factors
Endocrine factors that may increase the risk of pregnancy loss include thyroid disease, diabetes mellitus, and luteal insufficiency. Available data suggest that subclinical hypothyroidism, defined as TSH above 4mIU/L, is associated with miscarriage and that treatment improves pregnancy rates.
Diabetes Mellitus
Diabetic women with elevated blood glucose and glycosylated hemoglobin (A1c) levels in the first trimester have a significantly increased risk of spontaneous miscarriage. In women with recurrent pregnancy loss, blood glucose and hemoglobin A1c level testing are indicated if diabetes is known or suspected but is not otherwise warranted. Diabetic women with recurrent pregnancy loss and elevated hemoglobin A1c levels are best advised to postpone new attempts to conceive until levels return to normal.
Polycystic ovarian syndrome (PCOS)
High blood insulin levels and high levels of PAI activity are thought to be the leading cause of the increased incidence of miscarriage (30-50%) in women with PCOS.
Luteal insufficiency
Since ovulatory dysfunction is widespread in PCOS, it is not surprising that the resulting corpus luteum may not be fully functional, and progesterone production may be insufficient.
Options
Inducing ovulation with medicaments is sufficient in many cases. Some prefer to treat luteal phase deficiency with exogenous progesterone supplementation starting 2 to 3 days after ovulation. However, this treatment approach often delays menstruation, creates false expectations of pregnancy, and increases stress.
Infection-related causes
There is a link between the risk of miscarriage and bacterial vaginosis. In one large study, a diagnosis of bacterial vaginosis at the first antenatal visit before 14 weeks gestation was associated with a fivefold increased risk of pregnancy loss before 20 weeks gestation.
Options
Considering the low cost and negligible risks, a 2-week empirical antibiotic treatment is more reasonable than numerous, repeated cultures.
Environmental factors
Smoking increases the risk of miscarriage and should be avoided. Alcohol consumption of more than two drinks per day and caffeine consumption of more than 300 mg/day may increase the risk of pregnancy loss and should be avoided.
Unexplained repeated pregnancy loss
No predisposing factor can be detected in more than half of all women with repeated pregnancy loss, even with a thorough investigation. Therefore, the longer-term prospects for a successful pregnancy are excellent. Careful monitoring in early pregnancy and support will help improve pregnancy outcomes.
For more information and to check if this examination suits you, please do not hesitate to contact us.
1 Pellestor F, Andreo B, Arnal F, Maternal aging and chromosomal abnormalities: new data from in vitro unfertilized human oocytes.
2 Salim, Regan, Woelfer, Backos, A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first-trimester miscarriage
3 Leible. Munoz, Walton, Uterine artery blood flow velocity waveforms in pregnant women with Mullerian duct anomaly: a biologic model for uteroplacental insufficiency
4 Younis, Brenner, Ohel, Activated protein C resistance and Factor V Leiden mutation can be associated with first- as well as second-trimester recurrent pregnancy loss
5 Rai, Regan, Thrombophilia and adverse pregnancy outcome
6 Regan, Owen, Jacobs, Hypersecretion of luteinizing hormone, infertility and miscarriage
7 Homburg, Armar, Eshel, Adams, Influence of serum luteinizing hormone concentrations on ovulation, conception, and early pregnancy loss in polycystic ovary syndrome
8 Donders. Van Bulck, Caudron, Londers, Relationship of bacterial vaginosis and mycoplasmas to the risk of spontaneous abortion
