Introduction
The probability that a pregnancy will end as a miscarriage is highly dependent on the age of the mother, but approximately 15% of all clinically recognized pregnancies end in spontaneous abortion. Recurrent pregnancy loss (RPL) is traditionally defined as three or more consecutive, involuntary losses of pregnancy prior to 20 weeks’ gestation or fetal weight less than 500 g. Between 0.4% and 1% of women have three consecutive miscarriages, a higher percentage than would be expected solely by chance (0.15 [mult] 0.15 [mult] 0.15 = 0.3%), suggesting that there is a specific cause for RPL in some women.
The products of conception of women who have three or more abortions are more likely to be chromosomally normal (80–90%) than those of women with a single spontaneous abortion. Women with recurrent abortions also have a tendency to abort later in gestation, with two-thirds of such abortions occurring beyond 12 weeks’ gestation, indicating that maternal or environmental factors are a more likely cause of repeated pregnancy loss. If a woman has had no livebirths and three spontaneous abortions, without treatment she has about a 50% chance of having a viable gestation in her next pregnancy, and if she has had one livebirth, this chance is increased to about 70%. Couples with recurrent losses require careful, sympathetic management by the practitioner, because an abortion is an emotionally traumatic experience that can result in as much grief as intrauterine fetal death in late pregnancy or a neonatal death. With RPL, this emotional trauma is magnified, and the practitioner needs to express sympathy and understanding as counseling is performed and a diagnostic regimen is outlined.
An extensive evaluation is not generally recommended after a single first-trimester loss, as this is a relatively common event. However, because the etiology of a mid to late second-trimester loss is more likely to be uterine in origin and thus more likely to be amenable to diagnosis, a diagnostic evaluation should be performed after a woman has had only one second-trimester spontaneous abortion. There is no need to wait for a woman to have three first-trimester abortions, with their accompanying emotional trauma, before beginning a diagnostic evaluation. Work-up should be initiated after two losses because the risk of recurrence is similar to the risk of recurrence after three (25% vs 33%).
The etiology of recurrent pregnancy loss can be categorized into: genetic, anatomic (uterine), endocrinologic, immunologic, inherited and acquired thrombophilias, and infectious, and they will be discussed in this order.
Genetic chromosomal abnormalities
Between 40% and 60% of first-trimester losses have chromosomal anomalies, whereas such anomalies are found in only 5–10% of second-trimester losses. Chromosomal anomalies have been identified and reported in 2.5–8% of couples with RPL compared with an incidence of approximately 0.7% in the general population.
Chromosomal abnormalities occur in the female parent about twice as frequently as in the male. About 60% of all chromosomal abnormalities are balanced reciprocal translocations, and 40% are Robertsonian translocations. Sex chromosome mosaicism, chromosome inversions, deletions, duplications and other structural abnormalities can also be present. Therefore, when couples have had two or more spontaneous abortions, karyotypes should be obtained from both partners. If a balanced translocation is found in one parent, about two-thirds of their subsequent pregnancies will abort. If abortion does not occur in a subsequent pregnancy, fetal cytogenetic studies are indicated, because there is about a 3–5% incidence of an unbalanced fetal karyotype in these gestations. Therefore, if an abnormal karyotype is found in one of the members of the couple with RPL, genetic counseling is indicated.
Anatomic factors
Uterine abnormalities, either congenital or acquired, may not provide the optimal environment for nourishment and survival of the embryo and may cause miscarriage of a genetically normal embryo. Congenital uterine abnormalities can be divided into those brought about by abnormal uterine fusion, those produced by maternal diethylstilbestrol (DES) ingestion, and those caused by abnormal cervical function. The latter condition, the incompetent cervix, can also be acquired after mechanical cervical dilation. Other acquired anomalies are intrauterine synechiae and submucous myomas.
Anomalies of uterine development
The prevalence of congenital uterine malformations in the general population is, 3–4%. In comparison, 5–10% of patients with recurrent early loss and up to 25% of women with a late first- or second-trimester loss or preterm delivery will be found to have a uterine anomaly. The septate uterus is the anomaly most commonly associated with poor pregnancy outcome and RPL, with the first-trimester miscarriage rate reported to be 23–67%. The mechanism by which a uterine septum causes miscarriage is not completely understood, but is thought to be secondary to poor vascularization of the septum, leading to poor implantation and placentation. In contrast, unicornuate, bicornuate and didelphys uteri are more commonly associated with second-trimester loss or preterm delivery, possibly secondary to impaired uterine distension or cervical insufficiency.
Minor surgical procedures are most commonly used to treat uterine anomalies associated with pregnancy loss. Hysteroscopic metroplasty, a process by which a uterine septum is incised and thereby removed, is the procedure of choice for this condition. Cervical cerclage can be used to treat patients with uterine anomalies causing recurrent loss by cervical insufficiency. Uterine reunification procedures (for bicornuate and didelphys uteri) and metroplasty by laparotomy are now only rarely performed.
Uterine anomalies after diethylstilbestrol
Comparative studies have shown that women exposed to DES during their fetal life have a significantly greater incidence of spontaneous abortion than controls. Kaufman et al. reported that the percentage of first or all pregnancies in women exposed to DES that ended in spontaneous abortion was higher if their hysterograms revealed abnormalities in the shape of the uterine cavity or intrauterine defects. Haney et al. reported that the endometrial cavity of women exposed to DES in utero had a significantly smaller surface area than normal, which could perhaps contribute to the increased spontaneous abortion rate in women exposed to DES in utero. No therapy, including routine cervical cerclage, has been shown to be beneficial in lowering the abortion rate in women exposed to DES who have abnormalities of the uterine cavity and recurrent losses. The length of gestation tends to increase with subsequent pregnancies, and therefore most of the women who had fetal DES exposure ultimately have a viable pregnancy.
Cervical insufficiency
The diagnosis of cervical insufficiency is best made by a history of second-trimester pregnancy loss accompanied by spontaneous rupture of the fetal membranes without preceding uterine contractions. Cervical insufficiency has been found to be associated with uterine anomalies, including both mullerian anomalies as well as those produced by fetal DES exposure, though the majority of cases occur as a result of cervical trauma including loop electrosurgical excision procedure (LEEP), obstetric laceration and cervical dilation.
Cervical insufficiency is treated with the placement of a concentric Mersilene suture at the level of the internal os (cerclage), using the technique described by either Shirodkar or McDonald. Because these techniques yield a similar rate of success, with a significant increase in the rate of fetal survival, the McDonald procedure is preferable, since this procedure is technically easier and is associated with less morbidity than the Shirodkar technique. It is recommended that the suture be placed electively between 10 and 14 weeks of gestation after major embryogenesis has been completed and the incidence of spontaneous abortion caused by genetic abnormality has decreased. An ultrasound examination should be performed before cerclage to document a normal gestation. Occasionally, if there is a markedly shortened cervix or previous placement of the McDonald cerclage has failed to maintain a pregnancy, a transabdominal cervical cerclage may be performed. If the suture is placed externally, it is usually removed at 38 weeks’ gestation, and vaginal delivery allowed. However, because of cervical scarring, cesarean section is required in about 15% of pregnancies.
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