Recurrent pregnancy loss (RPL) affects 2-5% of all couples worldwide. Recurrent pregnancy loss brings not only grief for the patient, but also physical damage to the female reproductive organs. In addition, regardless of how early pregnancy occurs the loss of a baby is almost the same as a child’s loss. Thus, a significant role for evaluation after two losses, in patients without prior live births is strongly recommended.
There is a small amount of etiology, such as genetic, anatomical, immunological, endocrine and other, common for recurrent pregnancy loss. On the other hand, it is widely recognized that aneuploidy is the most common cause of miscarriage. Although every etiologic factor has its own treatment strategies, any treatment cannot prevail over aneuploidy. Preimplantation genetic screening (PGS) was offered as a method of reducing miscarriage by selecting euploid embryos for transfer. The previous PGS study by FISH did not demonstrate its reliability. Nevertheless, PGS, using the latest technology, such as CCS, demonstrates its validity in preventing miscarriages. PGS with the latest technology is possible to reduce subsequent miscarriages in patients with recurrent pregnancy loss. The disadvantage is that patients should have ART for the next conception.
Recurrent pregnancy loss is defined as two or more demise of pregnancy at any gestational age. Identifiable causes are antiphospholipid syndrome (APS), an abnormality of the uterus, an anomaly of the parental and embryonic chromosome. APS is the most important curable etiology. Antibiotic-resistant lupus is the priority of anticardiolipin antibody in obstetric APS. However, it has not been established which items should be measured to detect antiphospholipid antibodies. There are no established methods of treatment, although many treatments are offered for unexplained patients, such as heparin, aspirin, progesterone and prednisone. The birth rate is about 80% in patients with previous two miscarriages, 70% in patients with 3 miscarriages, 60% in patients with 4 miscarriages and 50% in patients with 5 miscarriages without medication. This knowledge is important before the subsequent pregnancy.
Psychological support with tender love can be the most important to induce such couples to continue to think until the results of live births are obtained.
Miscarriage is the most common complication of pregnancy with a prevalence of 15%.
Recurrent miscarriage (RM): three or more consecutive clinical miscarriages occurring up to 20 weeks after menstruation,
Recurrent pregnancy loss: two or more pregnancy losses (demise) at any gestational age.
Non-visualized pregnancy (biochemical pregnancy and unsuccessful pregnancy of unknown location in combination) is not included in the RM and recurrent pregnancy loss.
Recommended tests are antiphospholipid syndrome (APS), uterine abnormalities, and parental and embryonic abnormal karyotype. APS, uterine anomalies and abnormal chromosomes in both partners established the reasons for recurrent pregnancy loss. The distribution of each cause depends on the characteristics of patients, such as the age of women or the number of previous miscarriages. The age of women, obesity, assisted conception, smoking and alcohol are associated with recurrent pregnancy loss.
“Causes of recurrent pregnancy loss” should be strong predictors for a subsequent miscarriage in a prospective study. It has not been established whether endocrine disorders such as hypothyroidism, diabetes mellitus and polycystic ovarian syndrome, thrombophilia, immune dysfunction, infection and psychological stress can contribute to recurrent pregnancy loss, as there have been a limited number of randomized controlled trials related to these issues.
Antiphospholipid Syndrome (APS)
APS is the most important curable etiology. A low dose of aspirin plus combination therapy with heparin is accepted as standard treatment for patients with APS. Nevertheless, the birth rate is limited to 70-80%. International classification criteria for the diagnosis of APS include obstetric clinical signs as follows:
Three or more consecutive unexplained miscarriages before the 10th week of pregnancy,
One or more unexplained deaths of a morphologically normal fetus at week 10 of gestation or later,
One or more preterm births of a morphologically normal fetus at 34 weeks of gestation or earlier, associated with severe preeclampsia or placental insufficiency.
Fetal Death is The Priority of An Early Miscarriage
Recommended tests include at least two kinds of reagents, such as diluted activated partial thromboplastin time (aPTT) and diluted breeding time of Russell’s toxic poison (RVVT) and β2-glycoprotein I (β2GPI)-dependent anticardiolipin antibodies (aCL) IgG/IgM or anti-β2GPI IgG/IgM antibodies. Patients can be diagnosed as having APS when positive for at least one antiphospholipid antibody (aPL) persist for 12 weeks to avoid pseudo-positivity. The combination of unfractionated heparin and low-dose aspirin is the standard treatment. However, there are differences in the cut-off values for APS diagnostics.
Congenital Malformation of the Uterus
The probability of a large uterine anomaly, with the exception of the arcuate uterus, is 3.2-10.4% in patients with recurrent pregnancy loss. This variation largely depends on the methods and criteria chosen for diagnoses. The relationship between the arcuate uterus and recurrent pregnancy loss remains controversial.
The patients were offered surgery in an attempt to restore the anatomy of the uterus. 35-66% of patients with bicornuate or septate of the uterus give live births after corrective surgery.
Abnormal Chromosomes in Both Partners
A review of the current evidence base of patients with a history of two or more miscarriages showed that the frequency of chromosomal structural rearrangements was 4.7%. The prognosis of recurrent pregnancy loss patients with reciprocal translocations is poor. The likelihood of having a healthy baby is higher than that of the unrelated couples, despite the higher risk of miscarriage.
It is reported that the fertility rate with preimplantation genetic diagnosis (PGD) is 14-58%. The birth rate with the natural concept, according to the first test, is 32-65%, and cumulatively 68-83%. Fertility rates with PGD in recipient translocation carriers are comparable or sometimes lower than with the subsequent first natural concept. Fertility with the use of new technology, microchip comparative genomic hybridization (CGH array) or single nucleotide polymorphism with polymorphism is also comparable with the indices followed by the first natural concept. It was found that PGD significantly reduces the level of miscarriage. However, the level of infertility of PGD was significantly higher (18.9% vs. 3.8%). The cumulative birth rate was 67.6% and 65.4%, respectively, in patients undergoing and not undergoing PGD.
While PGD significantly prevented further miscarriages, there were no advantages in improving the fertility rate. Couples should be fully informed about the advantages and disadvantages of PGD, such as a reduction in the frequency of miscarriages, a higher cost and failure of IVF.
Abnormal Embryonic (Fetal) Karyotypes
Embryonic aneuploidy is the most common cause of recurrent pregnancy loss. The G-banding technique is used in clinical practice. The approach to the CGH array showed about 80% of the abnormalities in the aborted embryo.
The frequency of normal embryonic karyotype was significantly higher in patients with recurrent pregnancy loss than in patients with sporadic miscarriage. The most frequent were trichomias 16, 22 and 21, and there was no monosomia except 45, X. The rate of miscarriage increased, and the normal rate of embryonic karyotype decreased. The level of fertility in patients with a previous abnormal embryonic karyotype was significantly higher than in patients with a previous normal embryonic karyotype. Embryonic karyotype can be a good predictor of success. Further examination can be maintained if the second miscarriage was caused by an abnormal fetal karyotype.
It was reported that the fertility rate with genetic preimplantation screening (PGS) for aneuploidy is 4-47%. In previous studies using PGS, there was no proper control. Subsequent fertility rates in unexplained patients, including patients caused by abnormal embryonic karyotype, with the previous two, three, four and five miscarriages are 80%, 70%, 60% and 50% without drugs, respectively. The cumulative birth rate was 85%. This information is important for genetic counseling. A RCT is required for patients with a recurrent pregnancy loss associated with aneuploidy.
Genetics and Thrombophilia in Truly Unexplained Patients
It has been reported that single nucleotide polymorphisms (SNP) of candidate genes are associated with recurrent pregnancy loss. The most frequently studied factor was V Leiden and prothrombin mutation. FV Leiden mutation frequencies, prothrombin mutations and protein S deficiency are higher in patients with fetal loss than in controls. However, the relationship between protein S deficiency and early recurrent pregnancy loss was not detected. It is suggested that thrombophilia causes fetal loss through placental dysfunction. It is important to distinguish between early miscarriage and fetal loss, because many parts of a recurrent pregnancy loss are an early miscarriage, in less than 10 weeks of pregnancy.
Six cross-sectional studies have shown that the incidence of patients with a low level of coagulation factor XII (FXII) activity is significantly higher in patients with a recurrent pregnancy loss than under control. In studies, the genotype CT of gene XII was also suggested as a risk factor for recurrent pregnancy loss. Nevertheless, both the CT genotype and the low activity of FXII did not predict a subsequent miscarriage.
These studies mean that risk factors with small ORs found in a cross-sectional study may have little clinical relevance. It is assumed that patients with a number of risk alleles with small relative risks may suffer more often from unexplained recurrent pregnancy loss. The effect of measurement and treatment of thrombophilia is not established.
Methods of Treatment of Unexplained Patients
Patients with an unexplained cause want to receive medication. Paternal immunization, combined therapy with a low dose of aspirin and heparin and progesterone did not affect the improvement in the fertility rate. Subsequent fertility rates in unexplained patients, including patients caused by abnormal embryonic karyotype, with the previous two, three, four and five miscarriages are 80%, 70%, 60% and 50% without drugs, respectively. The cumulative birth rate was 85%. It is important to inform patients that no drugs have been established to improve the fertility rates shown above.