1. Epidemiology of recurrent pregnancy loss

INTRODUCTION

Epidemiology can be defined as ‘the scientific study of disease frequency, determinants of disease, and the distribution of disease in a population’. The determinants of disease considered in epidemiological studies are normally demographic parameters (age, sex, occupation, and economic status), in addition to some clinical parameters relevant for the specific disease (e.g., tobacco and alcohol consumption, and reproductive and family history) – all information that can be obtained through registers and questionnaires, whereas parameters requiring special interventions such as blood samples are normally not included in purely epidemiological studies.

DEFINITION OF MISCARRIAGE AND RECURRENT

PREGNANCY LOSS

at least three consecutive miscarriages, whereas recurrent pregnancy loss (RPL) could also include pregnancy losses up to gestational week 28. However, there is no consensus regarding the definition of recurrent miscarriage or RPL.2 Pregnancy losses after week 20 are rare, so defining recurrent miscarriage and RPL as above will result in almost identical populations.

Unfortunately, many studies include women with only two previous miscarriages in studies of recurrent miscarriage/RPL, which, from an epidemiological point of view, is very problematic. This issue will be discussed later.

EPIDEMIOLOGICAL PARAMETERS

RELEVANT FOR RPL

OCCURRENCE

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 generally accepted definition stipulates that the fetus or embryo should weigh 500 g or less – a stage that corresponds to a gestational age of up to 20 weeks, according to the World Health Organization (WHO).1 Unfortunately, this definition is not used consistently, and pregnancy losses at higher gestational ages are also classified as miscarriage in some studies instead of as stillbirth or preterm neonatal death. Thus, from a definitional perspective, it is important to characterize the population being studied so that comparisons across therapeutic trials can be made more appropriately and reliably.

Recurrent miscarriage should be defined, according to the above definition of miscarriage, as

The incidence of RPL is the number of new women each year (or in some other defined period) suffering their third consecutive pregnancy loss, while the prevalence of RPL is the number of women in a population who, at a specific timepoint, have had three or more consecutive pregnancy losses. The incidence or prevalence is often expressed as a rate of those individuals being at risk for the disorder. The number in 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. Indeed, the estimate of the incidence or prevalence of RPL is very uncertain, since in most countries there is no nationwide registration of miscarriages or RPL, and many early miscarriages are not treated in hospitals and thus are not registered. There is no valid estimate of the incidence

of RPL, whereas there are a few estimates of its prevalence. One of the most informative studies of the prevalence of RPL was performed by Alberman,3 who asked female doctors to report retrospectively about the outcome of their previous pregnancies. Seven hundred and forty-two women had had three previous pregnancies, and 355 women had had four previous pregnancies. Nine women (0.8%) had had three or more consecutive pregnancy losses. This study is probably the best estimate of the prevalence of RPL, since the cohort was restricted to women who had attempted pregnancy at least three times. As the study consisted of physicians, delayed menstruation, induced abortions, ectopic pregnancies, and miscarriages were unlikely to be misclassified. However, since the study was carried out before 1980, many early miscarriages may not have been registered due to a lack of highly sensitive human chorionic gonadotropin (hCG) tests and ultrasound examinations at that time. Furthermore, female doctors may not reflect the background population: they may be healthier than other women, which may lower the miscarriage risk, but (due to their long education) they may be older than other women when attempting pregnancy, which increases the miscarriage risk.

Other estimates of the prevalence of RPL are generally in accordance with that of Alberman. A RPL prevalence of 2.3% was found in 432 randomly identified women in a multicenter study.4 In a group of 5901 Norwegian women with at least two pregnancies screened for Toxoplasma antibodies, 1.4% had experienced RPL.5 Data from a Danish question- naire-based study6 found, in a random sample of 493 women with at least two intrauterine pregnancies, that 0.6% had had at least three consecutive miscarriages, 0.8% at least three consecutive pregnancy losses during all trimesters, and 1.8% at least three, not necessarily consecutive, losses at some time during pregnancy. Overall, these studies thus find the prevalence of RPL to be between 0.6% and 2.3%.

NUMBER OF PREVIOUS MISCARRIAGES

Almost all prospective studies of RPL patients show remarkable consistency in finding an increasing risk of miscarriage as the number of

previous miscarriages increases. The chance of subsequent live birth in untreated RPL patients with 3, 4, and 5 or more miscarriages has been found to be 42–86%, 41–72%, and 23–51%, respec- tively7–10 (Figure 1.1). The significant variability in the estimate of the subsequent risk of miscarriage in RPL patients can probably be attributed to the time of ascertainment of the pregnancies (Figure 1.2), since the average age of the patients and the duration of follow-up in the various studies were not different. The information in Figure 1.2 is based on the data given in the literature8,10,11 or data that can unequivocally be deduced from the literature. In studies where the patients are urged to contact the department for inclusion in a treatment trial as soon as menstruation is delayed by 2–3 days, and a highly sensitive pregnancy test is positive,10 almost all preclinical losses (including biochemical pregnancies) are identified, and the patients will be registered as having a high fetal loss rate (47.1%) but a low non-pregnancy rate (14.7%) during the observation period. In studies where the patients are told to call the department in gestational week 6–7 to be included in treatment trials,11 or patients are

enrolled only after ultrasonographic demonstration of fetal heart activity,8 most preclinical miscarriages are not ascertained, and therefore significantly higher non-pregnancy rates (38.3–55.6%) and significantly lower miscarriage rates (11.1–14.4%) are registered (Figure 1.2). The subsequent probability of a live birth in RPL can best be estimated from the placebo arm of studies of RPL (Figure 1.2), because in placebo-controlled trials the ascertainment of pregnancies is generally better than in non-ran- domized studies since the patients are included according to a strict protocol and are more closely monitored in early pregnancy. Hence, more very early pregnancy losses are included in placebo-con- trolled trials and the live birth rate in the placeboarm is expected to be lower than in non-randomized studies. In accordance with this, Carp et al12 have shown that the live birth rate in untreated patients in randomized studies was 15–20% lower than that of non-randomized patients independent of the number of previous miscarriages.

The prognostical negative effect of the number of previous miscarriages could, in theory, be attributed

to the fact that maternal age and the presence of age-related risk factors for miscarriages are positively correlated to gravidity. However, in multivariate analyses of clinical and paraclinical parameters of potentially prognostic importance in RPL, the number of previous miscarriages has without exception remained the strongest prognostic parameter, even after adjustment for other risk factors.7,13,14

MATERNAL AGE

In a register-based study of 634 272 Danish women achieving pregnancy between 1978 and 1992 and who attended a hospital during the pregnancy,15 the miscarriage rates were almost identical in women of age 30–34 years with RPL and those of age 35–39 (38–40%), but increased to 70% in women aged 40–44 (Figure 1.3). It seems that the impact of age on the miscarriage rate in RPL is quite modest until age 40, but beyond this age it is the strongest prognostic factor. In concordance with this, several multivariate analyses7,13,14 of prognostic variables for live births in RPL patients (almost all of whom were

Birth rate (%)

80

70

60

50

40

30

20

10

0 Nybo Andersen et al15 Clifford et al9

Maternal age

< 30 years 31–35 years

36–39 years 40–44 years

younger than 40) found that maternal age was not a significant predictor of miscarriage after adjustment for other relevant independent variables, the adjusted odds ratios (OR) for live birth being very similar in two studies: 0.93 (95% confidence interval (CI) 0.8–1.1)7 and 0.94 (95% CI 0.9–1.0).13

SUBGROUPS OF RPL

The pregnancy history in women with RPL may include pregnancies that have ended in live births. Three different groups can be identified that should be assessed separately:

●The primary RPL group consists of women with three or more consecutive pregnancy losses with no pregnancy progressing beyond 20 weeks gestation.

●The secondary RPL group consists of women who have had three or more pregnancy losses following a pregnancy that progressed beyond 20 weeks’ gestation (which may have ended in live birth, or less commonly a stillbirth or neonatal death).

●The tertiary RPL group (which is a group that has not been well characterized or studied) consists of women who have had several pregnancy losses before a pregnancy that progressed beyond 20 weeks’ gestation followed by at least three more pregnancy losses.12

In some studies, secondary RPL is defined as RPL after a live birth or a pregnancy that progressed beyond gestational week 28;12,16 however, in this survey, 20 weeks is taken as the cut-off point.

Unfortunately, few studies separate the patients into primary or secondary RPL, which may indicate that the authors consider the two disorders as identical entities. It is indeed possible that secondary RPL is not a particular entity but just the clinical appearance of the RPL syndrome among patients who, by chance, instead of delivering a child after three or four miscarriages deliver an infant in the first pregnancy and subsequently experience a series of miscarriages. However, if the chance of delivering a child is equal in all consecutive pregnancies of women destined to experience RPL, we would expect the prevalence of patients with secondary RPL and at least four miscarriages who delivered a child in the first pregnancy to be equal to that of those who had delivered a child in the second pregnancy. We studied a cohort of patients with secondary RPL and four miscarriages17,18 and found that four times as many had had a successful outcome in the first pregnancy compared with the second pregnancy (Table 1.1). Since it is unlikely that patients in the latter group have a lower likelihood of being admitted to our clinic than patients in the former group, we conclude that the risk of suffering RPL is much higher after a birth in the first pregnancy than in the second pregnancy. This observation supports the theory that some risk

factors for RPL have a high chance of developing during the first ongoing pregnancy and that secondary RPL is not a chance phenomenon.

If primary and secondary RPL have different pathophysiological backgrounds, we should expect different prognoses for the two conditions. Summarizing the placebo-treated patients included in our placebo-controlled trials of immunotherapy,10,19 the live birth rate was 17/35 = 48.6% in the first pregnancy in women with primary RPL, compared with 11/34 = 32.4% in women with secondary RPL (not significantly different) matched for number of previous miscarriages and age. Other studies have reported success rates8,9 in the two subsets that are not different, which must be considered to be the commonly accepted view.

In the secondary RPL group, however, the sex of the firstborn seems to affect the prognosis. In a prospective study of 182 patients with secondary RPL followed up from 1986 to 2002,17 the cumulative chance of giving birth to a child after a seriesof miscarriages was 58% in patients with a male firstborn, compared with 76% in those with a female firstborn (p = 0.01). The hazard ratio for a live birth (the relative chance for live birth adjusted for the follow-up period and a series of prognostic factors) in patients with a male firstborn was 0.59 (95% CI 0.41–0.86) compared with those with a female firstborn. The previous birth of a boy is therefore a prognostic negative factor in these patients, which may be attributed to immunization against malespecific minor histocompatibility antigens (HY antigens) in the first ongoing pregnancy.

RPL patients with second-trimester losses also constitute a subset with particular characteristics. Drakeley et al20 found that 25% of their RPL

patients had had at least one second-trimester loss. Among 228 RPL patients admitted to our clinic in 2000–2004, 39 (17.1%) had experienced a mixture of firstand second-trimester miscarriages, but only three had suffered exclusively second-trimester losses. Since almost all patients with secondtrimester miscarriages had experienced at least one first-trimester miscarriage, early and late RPL must have pathogenetic factors that partially overlap – but the observation that the overwhelming majority of patients only suffer first-trimester miscarriages suggests that some pathogenetic factors are specific for those with early miscarriages. Several prospective studies indicate that a history of one or more second-trimester pregnancy losses is a strong risk factor for a poor prognosis,21,22 which also suggests that some pathogenetic factors are specific for patients with late losses.

FAMILIAL AGGREGATION

Few studies have investigated the genetics of RPL in families of RPL couples with normal chromosomes. Results from the published family studies are shown in Table 1.2. Johnson et al23 and Alexander et al24 compared the prevalence of three not necessarily consecutive miscarriages among blood relatives of women with RPL with the corresponding prevalence in relatives of fertile controls. Ho et al25 compared the prevalence of RPL in relatives of couples with RPL with that in relatives of fertile control couples. The data concerning the relatives were those stated by the probands. Christiansen et al26 obtained information concerning relatives’ pregnancy outcomes from questionnaires completed by the relatives themselves, and the stated pregnancy

loses were confirmed from hospitals’ and practitioners’ records. The prevalence of at least three, not necessarily consecutive, pregnancy losses in relatives with at least two pregnancies was compared with an external control group.6 Table 1.2 shows that the risk of RPL in first-degree relatives of RPL patients is 2–7 times higher than in the background population. The relative frequency λ (the frequency of RPL in relatives divided by the frequency in the general population) is a measure of the degree of heritability of a disorder: the higher the value of λ, the higher is the genetic component. For type 1 (‘insulin-dependent’) diabetes mellitus, λ for sisters is 15, suggesting a high degree of heritability. In the Danish RPL study,26 λ can be calculated to be 5.9 for sisters and 3.5 for brothers’s wives when compared with the prevalence in the general population,6 indicating a moderate degree of heritability. If a condition is determined by multifactorial or polygenic inheritance, it is expected that λ equals the inverse square root of the population prevalence, i.e., 1 / 0.018 = 7.5, which is very close to the observed λ in sisters, and this emphasizes the hypothesis that RPL is a disorder following a polygenic mode of inheritance.27

PARTNER SPECIFICITY

It is commonly assumed that unexplained RPL is a partner-specific condition, and a criterion that all pregnancies should be with the same partner has been included in the definition of primary and secondary RPL by some authors.28 However, no

study has really addressed the question of partner specificity. Out of 228 RPL patients admitted to our clinic in 2000–2004, 38 (16.7%) had experienced miscarriages with two or more partners, and with regard to pregnancy prognosis they do not behave differently from those who had all pregnancies with the same partner. In a multivariate analysis (Nielsen et al, unpublished work), we have found that, after adjustment for all relevant prognostic factors, the chance of a subsequent live birth was not different in patients with secondary RPL who have had all pregnancies with the same partner compared with those who have had two different partners. The observation that there is a clear familial predisposition to RPL, at least in the female partner (Table 1.2), also argues against RPL as being partner-specific.

CLINICAL ASSOCIATIONS

An association has been found between RPL and various late obstetric complications. These are fully described in Chapter 16.

LIFESTYLE FACTORS

Lifestyle factors are rarely, if ever, major causes of RPL; however, epidemiological studies have indicated that a series of lifestyle factors can increase the risk of miscarriage. There is good evidence that obesity,29,30 high daily caffeine intake,31–34 alcohol consumption,34 and use of non-steroidal antiinflammatory drugs35,36 increase the risk of

miscarriage significantly. Social class and occupation also increase the chance of miscarriage, with the greatest risk ocurring in women exposed to high physical or psychological stress during work.37,38 Several studies now also indicate that previous subfertility or infertility treatment may increase the risk of miscarriage.14,39

INTEGRATION OF EPIDEMIOLOGICAL

FACTORS IN THE RESEARCH

AND MANAGEMENT OF RPL

OCCURRENCE

Estimation of the prevalence of RPL has several applications: it can be used for comparing risks of RPL between different populations or in subgroups within the same population, and it can be used for comparing change in risk over time – which is necessary for identifying risk factors. Furthermore, the observation that the prevalence of RPL is greater than 1% indicates that RPL is not a random event but rather a disorder affecting women who have an increased risk of pregnancy loss. In theory, a woman could have RPL, and each of the three consecutive pregnancy losses may be caused by the same factors as those causing ‘sporadic’ miscarriages, especially fetal chromosome abnormalities. However, if all RPL cases were caused by a random accumulation of ‘sporadic’ miscarriages, the prevalence of RPL should be 0.143 = 0.27% (based on a prevalence of 14% for single pregnancy loss6) rather than 1%. The prevalence of 1% indicates that at least three out of four RPL cases are caused by non-random factors that increase the risk of miscarriage in each pregnancy.

NUMBER OF MISCARRIAGES

EPIDEMIOLOGY OF RECURRENT PREGNANCY LOSS

study has not been undertaken. It is quite likely that by stratifying the sample by number of previous miscarriages, the effect of the experimental intervention will become easier to demonstrate in those women with higher numbers of previous miscarriages than in those with fewer previous miscarriages, because the spontaneous success rate is so much lower in the former group.12,40

Unfortunately, in many studies, patients with only two previous miscarriages are included. The occurrence of two miscarriages may in many cases be a chance phenomenon caused by de novo fetal chromosome abnormalities (in particular, autosomal trisomies) rather than a recurrent maternal factor. Cytogenetic evaluations of specimens of sporadic abortions have revealed an overall incidence of chromosomal abnormalities of 43%.41 Thus, in theory, in 0.43 × 0.43 = 18.5% of all women with two consecutive miscarriages, the cause is the occurrence of two chromosomally abnormal conceptions. The inclusion of women with only two early miscarriages in a study of RPL will ‘dilute’ the estimate of the risk factor (in case–control and cohort studies) or the treatment effect in controlled clinical trials. The proportion of RPL patients in whom the disorder can be explained by a random accumulation of ‘sporadic’ miscarriages declines with the number of previous miscarriages.42 Conversely, the proportion of cases that can be explained by a factor increasing the risk of miscarriage of euploid embryos may increase with the number of previous miscarriages. Hence, the frequency of many immunological risk factors43–45 and the possible effect of immunotherapy,12,40 increase and the frequency of chromosomally abnormal abortions decreases,46 with the number of previous pregnancy losses.

MATERNAL AGE

It is clear from the evidence showing that the number of previous miscarriages is the most important prognostic factor in RPL that this parameter has to be taken into account when planning therapeutic trials. The ideal trial should stratify for the number of previous miscarriages, with randomization between control and experimental treatments within each stratum. To date, such a

Because increased maternal age increases the subsequent miscarriage rate, stratification for age should be taken into account in therapeutic trials. However, in RPL, age seems to display a significant impact on pregnancy outome only after age 4015 (Figure 1.3). Consequently, it may be sufficient to stratify according to two age groups: below and above 40. Advanced age is associated with several

disorders such as uterine fibroids and endocrine and autoimmune abnormalities, so age is a confounding factor that should be adjusted for when the real impact of these disorders on subsequent reproductive performance is assessed.

SUBGROUPS OF RPL

If secondary and primary RPL and RPL with firstand second-trimester losses have different pathogenetic backgrounds, the frequency of recognized risk factors for RPL and the efficacy of treatments may differ between the groups. Indeed, a series of studies have provided data suggesting that such differences exist (Table 1.3).

The factor V Leiden mutation is the commonest cause of activated protein C (APC) resistance, which is a risk factor for thrombosis and is probably also associated with RPL.47 Wramsby et al48 found factor V Leiden to be significantly associated with primary but not secondary RPL, and Rai et al49 found that APC resistance was significantly associated with the absence of a previous live birth among patients with RPL. In a study of three congenital thrombophilic factors (including the factor V Leiden mutation), 25.5% with primary RPL compared with 15.1% of those with secondary RPL were positive for at least one factor.50 The literature thus points towards a lower prevalence of factor V Leiden/APC resistance in secondary rather than primary RPL patients. Most studies also point

towards a higher prevalence of thrombophilic factors, especially the factor V Leiden mutation in patients with second-trimester miscarriages compared with those with only early losses.47,51

It is unclear whether parental chromosome abnormalities (e.g., balanced translocations) have a different prevalence in primary or secondary RPL. In a review52 of 79 relevant studies on the prevalence of parental chromosome abnormalities in couples with RPL, a higher frequency of aberrations (3.7%) was found in couples with multiple pregnancy losses and one or more live births compared with couples with exclusively repeated pregnancy losses, among whom it was 2.9%. Franssen et al53 found that the frequency of parental chromosome abnormalities was not different between couples with RPL including a live birth and RPL couples without a previous birth. The frequency of parental chromosome anomalies thus seems to be almost similar in primary and secondary RPL, and the consequence is that screening of parental chromosomes should be a part of the routine workup in both types of RPL.

A series of immunological parameters have been described as being important for RPL and would be expected to show a different distribution between the subgroups of RPL patients if the pathogenetic backgrounds were different. Research in immunological factors in RPL has concentrated on alloantibodies, autoantibodies, natural killer (NK) cells, and HLA (human leukocyte antigen) molecules of the major histocompatibility complex (MHC).

There is much evidence that the maternal immune system recognizes and reacts to the trophoblast and fetus in an ongoing pregnancy: alloantibodies directed against paternal/fetal HLA antigens are produced with increased gestation54 due to traffic of fetal cells into the mother’s circulation in the third trimester and at delivery. Anti-HLA antibodies often persist for years and can therefore be found more often in women with secondary compared with primary RPL,55 but seem not to exhibit any pathological action.19,56

Most autoantibodies can be found with increased prevalence in patients with RPL, and their presence is associated with a poor pregnancy prognosis;13 however, few studies of autoantibodies in RPL have differentiated between primary and secondary RPL. In patients with primary RPL, the prevalence of positive anticardiolipin or antinuclear antibody concentrations has been reported to be higher than in those with secondary RPL.13,57,58 None of the individual differences were statistically significant, but the clear trend emphasizes the importance that future studies of autoantibodies in RPL clearly distinguish between primary and secondary RPL. There is, however, a consensus that antiphospholipid antibodies (aPL) display a stronger association with late miscarriages than with early RPL51 – a fact that is integrated into the definition of the antiphospholipid (APS) syndrome.59 APS is considered to be present in an aPL-positive patient with a history of only one death of a normal fetus beyond week 10, whereas at least three miscarriages are needed for the diagnosis in an APL-positive patient with miscarriages before 10 weeks.

NK-cell cytotoxicity, an important factor in innate immune defence, has been reported to be predictive for a poor prognosis in patients with RPL.60 Only one study has differentiated between primary and secondary RPL.16 NK-cell activity in peripheral blood has been reported to be significantly increased in women with primary but not secondary RPL when compared with controls.16

Class II HLA alleles are associated with most immunological disorders. In the largest published case–control study of HLA-DR alleles in patients with RPL,45 the immunological high-responder

EPIDEMIOLOGY OF RECURRENT PREGNANCY LOSS

allele HLA-DR3 was found significantly more often in the total patient group than in controls (OR 1.4, p < 0.02). However, among the 250 patients with secondary RPL, the frequency of the HLA-DR3 phenotype was 32.4%, compared with 21.0% in controls (p < 0.006). In patients with primary RPL, the frequency of the HLA-DR3 phenotype was 21.8%, which was clearly similar to that of controls. It is thus clear that HLA-DR3 is only associated with secondary RPL but not with primary RPL.

The finding that increased NK cytotoxicity is associated with primary RPL indicates that excessive innate immunity may be associated with primary RPL. However, the association between particular HLA-DR alleles and secondary RPL, and the epidemiological evidence that immunization against the male-specific HY antigen plays a role in secondary RPL,17 indicate that adaptive immunity may have a role in secondary RPL, since recognition of alloantigens by T lymphocytes and subsequent sensitization requires involvement of HLA-DR antigens.

There is evidence that immunotherapy such as allogeneic lymphocyte injections/infusions or intravenous immunoglobulin (IVIG) exhibit different effects in primary and secondary RPL, respectively (Table 1.3).

FAMILIAL AGGREGATION

As discussed above, family studies (Table 1.2) have shown that the RPL prevalence in siblings of RPL probands is in accordance with a multifactorial model for the inheritance of RPL. In internal medicine and other disciplines, the development of many common diseases (e.g., arterial hypertension, diabetes mellitus, and schizophrenia) is thought to be determined by a multifactorial threshold model. One risk factor is not sufficient to cause disease, but when several intrinsic and extrinsic factors come together in the same individual (or couple), the risk exceeds a threshold level and disease develops. In recent years, research has identified a series of predisposing factors for RPL. So many risk factors have now been identified that it is very common to find several in the same patient. Both thrombophilic61 and immunogenetic62 risk factors seem to aggregate

significantly more frequently than expected in RPL patients and the presence of several risk factors in the same couples affects the pregnancy prognosis negatively,63,64 indicating that they may exhibit an additive or multiplicative effect on the RPL risk. Traditionally, the causes of RPL have been divided into single sufficient factors as slices of a pie: uterine malformations 10%, endocrine factors 10%, APL 15%, etc., which, together with the unexplained group, comprise 100%. This model is probably not adequate due to the above arguments. We therefore encourage scientists and clinicians working in the area of RPL to think in a threshold rather than a pie model.65 The clinical implication is that, in principle, an RPL patient should be screened for all potential risk factors and the investigation should not stop as soon as the first risk factor has been identified. The recognition that RPL exhibits a high degree of heritability paves the way for the identification of susceptibility genes for RPL through the performance of genetic linkage analyses in families with several siblings experiencing miscarriage or RPL. Such linkage analyses have already documented that genes in the HLA region are important pathogenetic factors in RPL.66

PARTNER SPECIFICITY

Early studies on HLA in RPL were based on the hypothesis that increased HLA similarity between partners would lead to inadequate maternal protective immune responses and fetal loss. Although a considerable number of studies on HLA sharing in couples with RPL have been performed, the evidence did not support this hypothesis.67,68 If good-quality epidemiological studies showing little evidence of partner specificity in RPL had been performed (Nielsen et al, unpublished work) prior to the HLAsharing studies, the theories of increased HLA-sharing between RPL spouses might not have developed.

surveillance in late pregnancy (e.g., repeated ultrasound examinations) to decrease perinatal mortality and morbidity. A series of factors associated with RPL – aPL, hereditary thrombophilias, and mannosebinding lectin deficiency – have also been associated with low birthweight.44,51 Since RPL per se seems to be associated with low birthweight, prospective studies of the effect of the mentioned factors on perinatal complications should be adjusted for the confounding effect of the number and type (midtrimester losses) of previous miscarriages.

LIFESTYLE FACTORS

As mentioned above, a number of lifestyle factors, including obesity, occupation, alcohol and caffeine consumption, and subfertility, are important risk factors for miscarriage. RPL is a complex disorder where lifestyle factors are expected to modify the effect of the non-lifestyle (intrinsic) factors discussed previously. The prevalence of the most important lifestyle factors should be described in research publications for both patients and controls, in order to document that studies assessing non-lifestyle risk factors or pregnancy outcome are matched for lifestyle factors. Since it is likely that smoking aggravates the effect of thrombophilic risk factors on pregnancy loss, details about smoking habits should be reported in all studies of RPL and thrombophilia. Another example of the importance of adjusting for lifestyle factors is that of the relationship between polycystic ovary syndrome (PCOS) and RPL. It is generally recognized that women with PCOS exhibit an increased rate of miscarriage and RPL. However, when adjustment for obesity is undertaken in multivariate analyses, the miscarriage rate in PCOS is not dependent on polycystic ovarian pathology or PCOS-associated endocrine abnormalities.30

Women with a history of RPL exhibit a significantly increased risk of late pregnancy complications. Hence, all RPL patients should be offered increased

Throughout medical science, epidemiological studies can provide indispensable knowledge when basic laboratory research, case–control studies, or controlled

treatment trials are planned and carried out. This is also true in RPL. However, it seems that epidemiological knowledge has only been integrated to a very limited degree into the current clinical research and management of RPL.

The population prevalence of RPL is much higher than would be expected if RPL were merely a random accumulation of ‘sporadic’ miscarriages, and this indicates that most RPL cases are caused by factors increasing an individual couple’s miscarriage risk.

Estimates of the future miscarriage risk in RPL patients vary significantly between studies, mainly due to different methods of ascertainment and monitoring. Some studies have estimated the prognosis too optimistically, as preclinical pregnancy losses have been classified as non-pregnancies. To overcome this potential source of error, in future treatment trials the take-home baby rate per time unit may be a better outcome measure than the miscarriage rate per registrated pregnancy

Not only is the number of previous miscarriages the strongest prognostic factor, but with an increased number of previous miscarriages, fetal aneuploidy seems to play a decreasing role and maternal factors an increasing pathogenic role. Therefore, stratification by the number of previous miscarriages is important both in association studies and in treatment trials. Primary and seconday RPL, from an epidemiological point of view, also seem to be distinct entities, and in many case–control and treatment studies these two subgroups have indeed been found to behave quite differently (Table 1.3).

There are almost no studies addressing the issue of partner specificity in RPL, and such studies are urgently needed. However, a series of family studies have unanimously found a familial aggregation of miscarriage and RPL among first-degree relatives of RPL patients – especially sisters – which indicates a significant degree of heritability. The pattern of inheritance is multifactorial, and this is also in accordance with clinical evidence: several risk factors for RPL can very often be found in a single patient, and an aggregation of risk factors aggravates the pregnancy prognosis.

A series of studies have unanimously reported that RPL is associated with a series of complications

EPIDEMIOLOGY OF RECURRENT PREGNANCY LOSS

in late pregnancy: reduced birthweight caused by increased risk for preterm birth and intrauterine growth retardation. It remains to be clarified from multivariate analyses which clinical and paraclinical factors among RPL patients determine the risks in late pregnancy.

Lifestyle factors are unfortunately rarely mentioned or are only reported very superficially in clinical studies in RPL. Since lifestyle factors can cause miscarriage by themselves, or through interaction with intrinsic factors, they should be reported in more detail in future studies, and appropriate stratification should be performed.

In conclusion, the multifactorial and polygenic background of RPL should be included in the models used for the pathogenesis of RPL. Additionally, the recognition of the different natures and pathogenic background of primary and secondary RPL, and the different nature of RPL with few miscarriages as opposed to RPL with many miscarriages, should help eliminate the practice of combining data from too heterogeneous studies for meta-analysis.

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