Recurrent pregnancy loss (RPL) has various definitions, but most specialists would define it as the loss of 3 or more clinically confirmed pregnancies. This criterion has been fixed on the basis of epidemiological studies.
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RPL itself is subdivided into primary and secondary types, depending on whether the woman has never carried a successful pregnancy or has had one successful pregnancy succeeded by consecutive miscarriages. It is seen to affect about 1 in 100 women of reproductive age, but the reported incidence varies between 0.4 to 3%. Of this 1%, about a third is attributable to chance alone.
According to the Practice Committee of the American Society for Reproductive Medicine, RPL is diagnosed as two or more miscarriages, and the risk increases after each loss. The true incidence is harder to find because of the impact of age, definition of pregnancy loss (biochemical versus clinical pregnancy).
Causes and classification
Identified causes consisted chiefly of anomalies of the uterus, chromosomal defects, and endocrine defects, including polycystic ovarian syndrome. In more than 50% no reason was detected.
Other studies show that it is possible that much RPL is the product of chance, but a small percentage is actually associated with definite pathology. This has led to another type of classification for unexplained RPL, namely:
This refers to unexplained RPL occurring purely by chance and with a good pregnancy outcome to be expected in future.
These women are usually older. Women who are between 40–44 are a hundred times at risk of RPL (13.3%) due to chance alone, in comparison with those aged 20–24 years (0.13%). The miscarriages involve mostly or only biochemical (very early) pregnancies (when the pregnancy test is positive, but no clinical confirmation of pregnancy was achieved before the miscarriage).
Biochemical pregnancy loss is very common, occurring in 6 of 10 early pregnancies in the general population. About one in five women can, therefore, have three or more biochemical pregnancy losses just by chance.
In these cases, the karyotypes of aborted fetuses are likely to be abnormal in at least half the cases, and three losses are likely.
This refers to unexplained RPL associated with an unidentified but existing pathology and which has therefore a worse expected prognosis.
Such women are typically below 30 years. They have had four or more miscarriages with normal karyotypes. The fetal heartbeat, which normally signifies a very low risk of miscarriage, was detected prior to the loss.
Defining the criteria for RPL is important because biochemical pregnancies are often lost unlike clinical pregnancies. Additionally, women with a history of previous miscarriage are likely to be monitored more closely so that pregnancy is detected in the biochemical stage itself, unlike other pregnant women who are diagnosed only after clinical pregnancy begins.
For instance, a woman with two or more previous losses would have serum beta-HCG levels measured quite early, enabling even biochemical pregnancies to be identified and their loss to be detected. This causes a higher rate of pregnancy loss to be calculated in this subpopulation, compared with women in the general population, in whom a miscarriage is identified only after a clinical pregnancy is first confirmed.
Thus, the reported incidence of spontaneous abortions can vary significantly, depending on the population being studied, whether of an infertile group under fertility treatment or of the general female population of reproductive age. In fact, women undergoing in vitro fertilization have been found to have 18% pregnancy loss compared with the almost 8% found in women with RPL.
The risk of RPL varies from about 11% 11% in the age group between 20 and 24, to over 50% in women between the ages of 40 and 44 years.
The risk of having a miscarriage is between 17% and 25% after 2 consecutive abortions, but between 25% and 46% after 3.
One common identified cause of RPL is a thrombophilia, which is also associated with preterm births, pregnancy-induced hypertension and eclampsia, antiphospholipid syndromes (APS), intrauterine growth restriction and placental insufficiency.
The most common mutations behind heritable thrombophilias are those of factor V Leiden (FVL) and prothrombin gene (G20210A). FVL causes the risk of thrombosis to increase by 5-10 times even in carriers (with one normal and one defective gene), and 80 times in homozygotes (both genes carry the same defect).
The discrepancy in carriers results from the interaction between the small increase in absolute risk and the effects of additional risk factors such as pregnancy-associated hypercoagulable states, which results in serious thrombosis. On the other hand, the G20210A mutation does occur in 1-4% of the general population in the US, especially among those who originally came from the south of Europe.
Women with this mutation have 3 times the average risk of venous clots, as well as higher odds for heart attacks and strokes, compared to those who do not carry the mutation.
Research shows the risk of RPL is increased by 2 times in women with either G20210A or FVL mutations. The interesting fact is that these inherited thrombophilias are far more likely to cause sporadic miscarriages than to result in RPL.
Most carriers fail to show any clinical signs of hypercoagulability, and may have one or no pregnancy losses with one or more successful pregnancies. Thus, most carriers are probably missed due to lack of testing in women who have carried at least one fetus to term and had a live delivery.
APS occurs in only 2% of healthy pregnancies, but in a fifth of women who have unexplained RPL, but a third of women with systemic lupus erythematosus.
These are found in 3% of women overall, but in 27% of women with RPL. The rate of miscarriage in women with a bicornuate uterus is 47%, in uterine septa it is 26%, but with a unicornuate uterus it is 17%.
Single gene mutations
Several mutations such as G6PD deficiency or phenylketonuria can cause a higher risk of miscarriage.
When diabetes is poorly controlled, the risk of sporadic miscarriage increases because of several mechanisms. However, the actual increase in the risk of RPL is not significant, according to several studies.
The same is true for deficient thyroid function. Some of the confusion may be because disruptive thyroid antibodies are not always associated with overt abnormality in thyroid hormone levels, but may still undermine normal thyroid function as well as be associated with other autoimmune states, and lead to miscarriage. High prolactin levels independent of thyroid disease may also be associated with miscarriage.
Pregnancies in a woman with a history of anovulation, such as polycystic ovarian syndrome, are more prone to miscarry because of the abnormal hormonal environment which may lead to an unfavorable endometrium for proper implantation and growth of early pregnancy.
Smoking, drinking and drug abuse
While each of these is associated with sporadic abortions, RPL as a direct result of any of these is not established.
Luteal phase defects
The lack of specific diagnostic tests and evidence for the efficacy of treatment of supposed luteal phase defects has led to controversy over the actual existence or importance of this factor. Luteal phase support is possible with appropriate administration of estrogen and progesterone.
Alloimmune factors and environmental causes such as chemical exposure through tap water are also linked to RPL but evidence is weak.
One study showed that of 1214 pregnancies, those with RPL were generally older but had the same number of deliveries as the general population. However, these women were typically at higher risk of having bad pregnancy outcomes, such as:
- Increased history of antepartum hemorrhage (bleeding before delivery), either in the patient or her family
- Increased chance that the personal or family history was positive for fetal anomalies
- Increased number of stillborn babies
- Increased newborn deaths
Reviewed by Afsaneh Khetrapal Bsc (Hons)