41 D. Keith Edmonds1,2 1 Imperial College London, London, UK 2 Queen Charlotte’s and Chelsea Hospital, London, UK Recurrent miscarriage has several definitions. The Royal College of Obstetricians and Gynaecologists (RCOG) defines recurrent miscarriage as the loss of three or more consecutive pregnancies before viability [1]. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation. However, advances in neonatal care have resulted in a small number of babies surviving birth before 24 weeks of gestation. Hence some late second‐trimester miscarriages can also be considered as extreme preterm labour. At the other end of the spectrum is the issue of biochemical pregnancy losses. The European Society of Human Reproduction and Embryology defines biochemical losses as a transient positive pregnancy test without ultrasonic visualization of the pregnancy [2]. Miscarriage can be further classified, on ultrasound findings, into loss of an empty gestation sac (loss of pregnancy before 10 weeks’ gestation) or loss of fetus (loss of a pregnancy after visualization of fetal heart activity) [2] (Table 41.1). Table 41.1 Classification of miscarriage. Despite attempts at standardization of definitions, some investigators consider two consecutive losses as a recurrent miscarriage, as two losses have been found to increase the chance of a subsequent pregnancy ending in miscarriage [3]. Approximately 15% of all pregnancies that can be visualized on ultrasound end in pregnancy loss [4]. Three or more losses affect 1–2% of women of reproductive age and two or more losses affect around 5% [4]. Despite extensive investigation of women with three or more miscarriages, the cause of recurrent pregnancy loss remains unknown in the majority of cases [5]. Advancing maternal age is associated with miscarriage. Age‐related miscarriage rates are as follows: 12–19 years, 13%; 20–24 years, 11%; 25–29 years, 12%; 30–34 years, 15%; 35–39 years, 25%; 40–44 years, 51%; and 45 or more years, 93% [6]. This is because with increasing maternal age there is a decline in both the number and quality of the remaining oocytes. Paternal age over 40 also increases the risk. An increasing number of previous miscarriages also adversely affects the risk of future miscarriage [5]. A history of a live birth followed by consecutive miscarriages does not reduce the risk of further miscarriage substantially [5]. Being both underweight and obese has been associated with recurrent miscarriage [7]. A body mass index (BMI) over 30 kg/m2 is an independent variable with significant increase in miscarriage risk (odds ratio of 1.7–3.5). Factors that have been associated with early recurrent miscarriage include parental and fetal chromosomal abnormalities [8,9], structural uterine abnormalities [10], antiphospholipid syndrome [11], some thrombophilias [12], autoimmune disease, and endocrinological disorders such as polycystic ovarian syndrome and untreated diabetes [13]. It is important to realize that many of these associations are weak and there are only a very few published observational studies that give prognostic implications for positive tests for conditions associated with recurrent miscarriage. Hence the evidence that many of the associated factors are causative is poor. There are even fewer high‐quality, large‐scale, randomized controlled trials showing that a treatment for women with recurrent miscarriage is effective at preventing a subsequent miscarriage. Ideally, evaluation of a couple with recurrent miscarriage would achieve the aim of guiding management options by finding contributory factors to the pregnancy losses, providing prognostic value in the subsequent pregnancy and directing treatment of proven benefit to improve live birth rates. This ideal has not been achieved by current research. Chromosomal abnormality in the miscarried pregnancy is the most common cause of early pregnancy loss, especially in older women. This accounts for up to 70% of early pregnancy losses, falling to only 20% when the pregnancy loss is between 13 and 20 weeks’ gestation [8]. Defects are commonly trisomy, polyploidy or monosomy. Ideally, products of conception should be sent for karyotyping, as an abnormal fetal karyotype is diagnostic for the cause of miscarriage and is an important prognostic factor, suggesting a successful outcome of more than 75% in the next pregnancy [8]. However, this investigation is not perceived to be cost‐effective. Parental chromosomal abnormalities are found in about 2% of women with recurrent pregnancy loss, with the most common being a balanced reciprocal translocation [14]. Couples with balanced translocations are at risk of conceiving future children with unbalanced translocations. However, a large case series of couples with recurrent miscarriage and balanced translocation have found the risk of unbalanced translocation in offspring to be less than 1% [15]. This 1% miscarriage rate is close to the miscarriage rate of normal pregnancies after invasive prenatal diagnosis. Observational studies of couples with recurrent miscarriage and balanced translocations have found live birth rates of over 70% in the subsequent pregnancy [15]. This 70% live birth rate is similar to that in couples with recurrent miscarriage without chromosomal abnormalities [4]. Thus, the cost‐effectiveness of investigating parental karyotype has been questioned [14]. If balanced translocation is detected, supportive care with the option of invasive prenatal diagnosis is appropriate [1]. A significant number of candidate genes have been studied to try to demonstrate a genetic basis for recurrent miscarriage but no conclusive results have emerged [16]. There was hope that pre‐implantation genetic diagnosis (PGD) and assisted reproductive techniques (ART) would improve the live birth rate for women with recurrent miscarriage and balanced translocations. However, in practice PGD‐ART has a series of disadvantages. Not all the cells in a four‐ or eight‐cell embryo are genetically identical, so PGD is not a reliable measure of the pregnancy karyotype. The pregnancy rate and live birth rate from PGD‐ART is lower than from natural conception [17]. Furthermore, natural conception involves the selection of normal oocytes, then the selection of normal pregnancy, allowing genetically abnormal pregnancies to miscarry. These natural selection steps are circumvented in PGD‐ART, creating large numbers of abnormal embryos. Consideration can be given to PGD where women have subfertility and recurrent miscarriage and a balanced translocation, as observational studies show that PGD‐ART has better pregnancy outcomes, despite lower rates of embryo transfer and shorter time to a successful pregnancy [17]. However, a recent study comparing natural conception and PGD‐ART in patients with a balanced translocation failed to demonstrate improved live birth rates [18]. The prevalence of congenital uterine anomaly, such as septated, bicornuate or arcuate uterus, in the general population is about 6.7% but approximately 16.7% in women with recurrent miscarriage [10], though a direct causative link is uncertain due to the vast difference in criteria and techniques for diagnosing abnormal uterine morphology. Advances in hysteroscopic surgery mean that these malformations can be corrected using a resectoscope. Observational studies suggest that surgery (hysteroscopic metroplasty) may improve pregnancy outcome [19,20] and a recent prospective case‐controlled study demonstrated improved live birth outcome in resected septated uteri but not bicornuate uteri [21]. However, there have been no randomized controlled trials of this treatment so efficacy of intrauterine surgery has yet to be demonstrated [19]. Cervical weakness is a recognized contributing factor to second‐trimester loss. There is no satisfactory objective test of cervical weakness as the diagnosis is a clinical one. Treatment with cervical cerclage is associated with potential hazards related to the surgery and the risk of stimulating uterine contractions and hence should only be considered in women who are likely to benefit [1]. Cervical cerclage is discussed in more detail in Chapter 28. Acquired uterine abnormalities such as fibroids or intrauterine adhesions (Asherman’s syndrome) have also been associated with recurrent miscarriage (Fig. 41.1). In a study by Saravelos et al. [22], the incidence of fibroids in recurrent miscarriage was 8.2% and women with intra‐cavitary distortion, whose fibroids were resected, significantly reduced their mid‐trimester miscarriage rate (21% to 0%). However, women with fibroids not distorting the cavity behaved similarly to women with unexplained recurrent miscarriage, with 70% birth rates in both groups. There are very few studies of any beneficial intervention for Asherman’s syndrome [23]. Fig. 41.1 Submucous fibroid projecting significantly into the endometrial cavity.
Recurrent Miscarriage
Definition
Type of miscarriage
Gestation range (weeks)
Fetal heart activity
Ultrasound findings
First trimester
Biochemical
0–6
Never
Not visualized
Empty gestation sac
4–10
Never
Empty gestation sac or large sac with minimal structures without fetal heart activity
Fetal
6–12
Lost
Crown–rump length and fetal heart activity previously identified
Second trimester
12–24
Lost
Fetus identified of size equivalent to 12–24 weeks’ gestation
Epidemiology
Other associated factors and their management
Structural genetic factors
Fetal chromosomal abnormality
Parental chromosomal abnormalities
Anatomical factors
Congenital uterine anomaly
Cervical weakness
Acquired uterine anomaly
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