Recurrent Pregnancy Loss

Causes, Controversies and Treatment

Howard Carp, Howard Carp

• Editorial: CRC Press
• Año: 2020
• ISBN:
  9780429833274
• Edición: 3
• Categoría: Medicina
• Categoría: Teoría, práctica y referencia médicas

Major advances in genetics, immunology, and endocrinology have necessitated a new edition of this best-selling text. However, despite the advances, recurrent pregnancy loss presents a frustrating clinical problem. There is still disagreement about the number of pregnancy losses which warrant investigation and treatment and about which investigations should be performed.

This third edition provides an authoritative and comprehensive update on advances in the understanding and management of this troubling phenomenon, covering both basic scientific topics such as genetics and cytokines, and profiles major advances in immunology, endocrinology, and thrombotic mechanism. Clinical research is discussed, as is assessment of results when applying an evidence-based approach or a more personalised approach, which is now becoming possible due to advances in the diagnosis of cause. There are lively debates on the role of progestogens and immunotherapy, which remain controversial.

Designed for specialists working in reproductive medicine clinics and those involved with maternal-fetal care, the book is also ideal for generalists and gynecologists seeking a comprehensive view of developments in the field.

1

The Epidemiology of Recurrent Pregnancy Loss

Ole B. Christiansen

Substantial disagreement exists about spontaneous prognosis after recurrent pregnancy loss (RPL), probably due to differences in monitoring intensity between studies. In future studies of prognosis in RPL it is suggested that the live birth rate per time unit is introduced as the main outcome measure.

Introduction

The term miscarriage (or abortion) is used to describe a pregnancy that fails to progress, resulting in death and expulsion of the embryo or fetus. The World Health Organization (WHO) definition [1] stipulates that the fetus or embryo should weigh 500 g or less, a stage that corresponds to a gestational age of 20 weeks. The European Society for Human Reproduction and Embryology (ESHRE) defines a miscarriage as an intrauterine pregnancy demise prior to viability confirmed by ultrasound or histology, whereas miscarriages, biochemical pregnancy losses, and pregnancies of unknown location (PULs) are jointly termed pregnancy losses [2]. Recurrent miscarriage (RM) has traditionally been defined as ≥3 consecutive miscarriages, and recurrent pregnancy loss (RPL) as ≥3 pregnancy losses. However, the American Society for Reproductive Medicine (ASRM) RPL defines RPL as ≥2 not necessarily consecutive clinical miscarriages [3], and recently ESHRE’s RPL guideline group also defined RPL as ≥2 not necessarily consecutive pregnancy losses [4].

Including women with two previous pregnancy losses in studies of RPL is epidemiologically very problematic. If the ASRM/ESHRE definition of >2 losses is used, the vast majority of patients will have a good prognosis for live birth. The live birth rate after two consecutive pregnancy losses is 75%–80% in the next pregnancy [5,6] or within 3 years [7]. The ≥2 definition of RM/RPL assumes that the prognosis for pregnancy losses is similar in women with the same number of previous consecutive or nonconsecutive pregnancy losses, e.g., a woman with four pregnancy losses after a birth has the same prognosis in the next pregnancy as a woman with three pregnancy losses followed by a live birth followed by one miscarriage. Only one study [8] has addressed whether pregnancy losses prior to a live birth have similar prognosis as those subsequent to a live birth. In a multivariate analysis of 127 patients with unexplained secondary RPL, each pregnancy loss after the birth, and in particular the presence of a second trimester miscarriage after the birth, increased the risk for subsequent pregnancy loss with incidence rate ratio (IRR) = 1.14 (95% confidence interval [CI] 1.04–1.24, p = 0.002) and IRR = 2.15 (95% CI 1.57–2.94, p < 0.0001), respectively, whereas early and late pregnancy losses prior to the birth did not exhibit any prognostic impact. According to this study [8], a patient with four pregnancy losses after a birth will have a 50% chance of a live birth compared to a 90% chance in a patient with three losses prior to but only one loss after the live birth. Knowledge about the prognosis is important for designing valid trials.

Epidemiologic Parameters Relevant for RPL

Occurrence

The prevalence of RM/RPL is the number of women in a population who, at a specific time point, meet the definition, and the incidence is the number of new women per time unit suffering a new pregnancy loss, and the prevalence or incidence is often expressed as the proportion of individuals at risk for the disorder. The denominator could be all women in the population, women of fertile age, or women who had attempted pregnancy at least two or three times. The estimate of the prevalence or incidence of RM/RPL is uncertain since in most countries there is no nationwide registration of miscarriages or RM/RPL. In addition, many early pregnancy losses are not treated in hospitals and are thus not registered. There are a few older estimates of the prevalence of RM based on the definition of ≥3 consecutive miscarriages. One of the most informative studies was the retrospective study by Alberman [9]. Nine out of 1097 female doctors (0.8%) who had had three or four previous pregnancies reported ≥3 consecutive miscarriages. However, since the study was summarized before 1990, many early miscarriages may not have been registered due to the lack of highly sensitive hCG tests and ultrasound examinations at that time.

Other estimates of the prevalence of RM roughly concord with that of Alberman. In a group of 5901 women with ≥2 pregnancies screened for toxoplasma antibodies, 1.4% had experienced RM [10]. Data from a questionnaire-based study [11] found in a sample of 493 women with ≥2 intrauterine pregnancies that 0.6% had had ≥3 consecutive miscarriages and 1.8% had had ≥3, not necessarily consecutive, losses. Overall, the prevalence of RM according to the old definitions seems to be between 0.6% and 1.4%.

A problem in adapting the new RPL definitions is that the number of women who meet the criteria will expand substantially. In Alberman’s [9] study among 2062 women who had had two to four previous pregnancies, 42 reported ≥2 not necessarily consecutive miscarriages (3.25%) which is significantly higher than the 0.6%–1.4% prevalence of RM using the traditional definition. This suggests that adapting the new RM/RPL definition will triple the prevalence of the diagnosis. The implications of this are discussed later.

The observation that the RPL prevalence is >1% indicates that RPL is not a random event but a disorder affecting women who have an increased risk of pregnancy loss. If RPL (according to the old definition) were caused by a random accumulation of “sporadic” miscarriages mainly caused by fetal aneuploidy, the prevalence of RPL would be 0.153 = 0.34% (based on a frequency of sporadic miscarriage of 15% in the population [9]) rather than 1%. The 1% prevalence indicates that most RPL cases are caused by nonrandom factors which increase the risk of pregnancy loss in each pregnancy.

Knowledge of changes in the incidence of RPL are important and can inform us about changes in environmental or genetic risk factors of importance for pregnancy loss. Roepke et al. [12] in a nationwide register-based study found that the incidence of women with three or more consecutive pregnancy losses had increased significantly in Sweden from 2003 to 2012. If the denominator was all women in Sweden aged 18–42 years in the period, the incidence increased from 0.042% to 0.069%, relative increase 74% (p < 0.0001) and if the denominator was women with a least one pregnancy in the period, the incidence increased from 0.55% to 0.82%, relative increase 58% (p < 0.0001). Changes in maternal age, body mass index (BMI), and coding pra...