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This chapter should be cited as follows:
Melo P, Devall A, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419033

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 19

Pregnancy shortening: etiology, prediction and prevention

Volume Editors: Professor Arri Coomarasamy, University of Birmingham, UK
Professor Gian Carlo Di Renzo, University of Perugia, Perugia, Italy
Professor Eduardo Fonseca, Federal University of Paraiba, Brazil


Recurrent Miscarriage

First published: January 2024

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Recurrent miscarriage, often used interchangeably with recurrent pregnancy loss, refers to the loss of more than one pregnancy before the fetus reaches viability. While the term recurrent pregnancy loss encompasses both intrauterine and ectopic pregnancies, recurrent miscarriage refers solely to the loss of intrauterine clinical pregnancies, i.e., after a gestational sac containing a fetus has been visualized within the endometrial lining using ultrasound technology.1,2 In high-income countries, the gestational age of viability has historically been defined as 24 weeks of gestation, although advances in neonatal care over the past decade have resulted in improved prognosis for some babies born before that time.3

This chapter discusses the latest evidence on the prevalence, risk factors, recommended investigations and therapies in people suffering with recurrent miscarriage.


Recurrent miscarriage affects 1–2% of couples trying to conceive a baby.1 This is possibly an underestimation, because many women lose pregnancies at home without reporting their losses to health care practitioners. In addition, there is a lack of national registries compiling miscarriage records, resulting in underreporting.4 The prevalence of recurrent miscarriage is also intrinsically dependent upon how the condition is defined, increasing as the inclusion criteria become less restrictive. For example, according to the Royal College of Obstetricians and Gynaecologists (RCOG), recurrent miscarriage involves the loss of three or more pregnancies in succession,5 whereas the European Society for Human Reproduction and Embryology (ESHRE) defines it as the previous loss of two pregnancies, irrespective of whether the losses were consecutive.1 Using the former criteria leads to a substantial underestimation of the prevalence of recurrent miscarriage as compared to the latter. This variation in the definition of recurrent miscarriage results in uneven prevalence estimates, ranging between 0.8% where only clinical miscarriages are considered to approximately 3% when biochemical losses are included.6 Regardless of the overall prevalence of recurrent miscarriage, however, existing data indicate that the risk of miscarriage goes up as the number of previous miscarriages increases, so that a woman without a history of miscarriage has an 11.3% risk of pregnancy loss, whereas after three or more previous losses the risk of miscarriage increases to 42.1%.4


The most common cause of miscarriage is embryonic aneuploidy, accounting for 50–60% of pregnancy losses.7 However, there is evidence that as the number of pregnancy losses increases, so does the percentage of chromosomally normal miscarriages, indicating that non-embryonic causes are likely to play a more prominent role in recurrent pregnancy loss.8 It is plausible to postulate that some of the factors implicated on increasing the risk of sporadic miscarriage may also play a contributory role in recurrent pregnancy loss, although there is a scarcity of studies investigating recurrent miscarriage specifically. In addition, despite the known associations between prognostic factors and the risk of miscarriage, some remain non-modifiable (e.g., female age), whereas for others it remains unclear whether tackling these risk factors with interventions (e.g., dietary changes, micronutrient supplementation) increases the likelihood of subsequently experiencing a live birth.

Risk factors for recurrent miscarriage include female and male age, extremes of body weight, smoking, caffeine, alcohol, stress, autoimmune and endocrine disorders, endometrial factors, and environmental exposure.


Female age constitutes one of the principal non-modifiable determinants of a couple’s reproductive potential. As women grow older, there is an inevitable decline in ovarian reserve and oocyte quality. Increased rates of oocyte aneuploidy are responsible for chromosomally abnormal embryos, resulting in lower implantation rates and higher risk of miscarriage. Cohort studies investigating the impact of female age on reproductive outcomes have found that women aged 30 to 39 years are on average 43% more likely to experience miscarriage than controls aged 20–29 years, whereas compared to this younger group women beyond the age of 40 exhibit miscarriage rates more than six-fold higher (OR 6.43, 95% CI 4.69 to 8.82). Importantly, however, women younger than 20 years old also exhibit higher odds of miscarriage than those aged 20–29 years (OR 1.60, 95% CI 1.02 to 2.53).4 It is possible that socioeconomic factors associated with teenage pregnancy may contribute to the poorer prognosis in women within this age bracket.

Data from cohort studies also suggest an association between rising male age and an increased risk of miscarriage, with males aged ≥40 years exhibiting a 69% increase in the odds of miscarriage compared to those between the ages of 20 and 29 years.4

Extremes of body weight

Obesity exerts a deleterious effect upon pregnancy outcomes.9 In a case-control study including nearly 5000 women, Lashen, Fear10 identified a higher than three-fold increase in the risk of recurrent pregnancy loss in women with a body mass index (BMI) >30 kg/m2 compared to women with a normal BMI (OR 3.5, 95% CI 1.03 to 12.01).10 Unsurprisingly, interventional studies have identified improvements in fertility outcomes in people trying to conceive following gradual weight loss,11 although these data do not pertain specifically to a population suffering with recurrent miscarriage, in whom further research is required. In males, the impact of excessive body weight on a couple’s risk of miscarriage remains understudied, although indirect evidence evaluating the effect of male weight on sperm DNA fragmentation suggests a possible association.12

While there is mounting evidence of the negative effect of parental obesity on pregnancy outcomes, data on the association between low BMI and miscarriage are fewer and less certain, requiring further investigation.13


Although smoking is universally accepted as a risk factor for sporadic pregnancy loss, there is a paucity of data on whether maternal smoking cessation improves long-term outcomes for women with recurrent miscarriage. Passive smoking has been shown to increase the risk of RPL in a dose-dependent manner in a population of Chinese women, with the rate of subsequent miscarriage rising as the total daily duration of exposure to others’ smoking grew.14 In the same study, however, maternal active smoking was not found to directly influence the risk of recurrent miscarriage, and further studies are warranted to further elucidate this association.


Data on the association between caffeine consumption and recurrent pregnancy loss are scarce. However, a small study in couples with recurrent pregnancy loss showed that women with unexplained recurrent miscarriage exhibited a dose-dependent increase in the adjusted odds of further miscarriage (adjusted OR 2.724, 95% CI 2.715 to 2.733).15


Although alcohol is known to be a powerful teratogen, increasing the risk of sporadic fetal loss,16,17 there is a lack of studies on how it may affect the risk of recurrent loss, and whether reduced intake improves outcomes.


In a recent systematic review and meta-analysis, the authors found that among eight studies investigating the association between stress and miscarriage, the risk of miscarriage was on average 42% higher in women who had been exposed to psychological stress (OR 1.42, 95% CI 1.19 to 1.70).18 Not all studies included in this review were well designed, however, and there was variation in the timing of assessment of stress in relation to the occurrence of miscarriage. In addition, included studies used different scales to measure people’s perception of stress, resulting in significant clinical heterogeneity. Finally, there was a lack of studies focusing specifically on recurrent miscarriage. In the absence of well-designed prospective studies considering temporal relationships, it remains difficult to categorically determine whether stress may be a causative factor or simply a consequence of recurrent miscarriage.

Environmental exposure

Small observational studies have suggested that women with a history of exposure to occupational and environmental hazards, including heavy metals and pesticides, experience higher rates of recurrent pregnancy loss.19,20 However, these findings require further corroboration by large-scale studies and national registries.

Autoimmune and endocrine disorders

Thrombophilia, defined as altered blood coagulation resulting in increased risk of thrombosis, may be inherited (e.g., factor V Leiden mutation, prothrombin mutation, and deficiency in protein C, S and/or antithrombin) or acquired (referring to antiphospholipid syndrome). The evidence on whether inherited thrombophilia is associated with recurrent miscarriage remains inconclusive, yet the association between antiphospholipid syndrome and recurrent pregnancy loss is strong.1,4

Among various conditions featuring metabolic and endocrine dysfunction, studies have found that the risk of recurrent pregnancy loss is increased in women with subclinical hypothyroidism, positive thyroid peroxidase (TPO) antibodies and polycystic ovary syndrome. For disorders including hyperprolactinemia, vitamin D deficiency and hyperhomocysteinemia, the evidence of an association remains unclear.1,2

Endometrial factors

Embryo implantation and pregnancy success require a receptive endometrium, capable of tolerating a blastocyst in whom at least half the genetic makeup is paternal in origin and thus recognized as foreign by the maternal immune system. Successful implantation relies upon a tightly coordinated dialog between the embryo and the secretory endometrium, where maternal immune regulators such as T lymphocytes and natural killer (NK) cells play a crucial role.21 It is thought that a state of heightened immunity may be nefarious to the embryo, resulting in rejection, implantation failure, and possibly miscarriage.22

In addition to altered immune regulation, endometrial inflammation and infection may contribute to an increase in the risk of recurrent pregnancy loss. In recent years, the concept of chronic endometritis has gained prominence as a potentially explanatory phenomenon for recurrent implantation failure and miscarriage.23 It has been suggested that an ongoing phenomenon of recurrent endometrial inflammation, possibly refractory to antimicrobial therapy where infection is present, may be implicated in the loss of multiple pregnancies. However, there is no consensus on how to diagnose chronic endometritis. Some believe that hysteroscopy should be routinely undertaken to allow for the direct visualization of endometrial inflammation and targeted biopsies, whereas other authors recommend blind endometrial sampling.24 Furthermore, although immunohistochemistry with antibodies to CD138 have been historically used to diagnose plasmacyte infiltration signaling endometrial inflammation, there are no universally accepted criteria on what constitutes a high level of CD138-positive cells in relation to clinical severity and likelihood of recurrent pregnancy loss.25 Yet, the concept of chronic endometritis has led to a widespread movement towards empirically treating recurrent miscarriage with courses of antibiotics whose effectiveness and safety remain uncertain.26 Given the lack of high-quality randomized trials in this field, ESHRE recommends against screening women for endometritis.1


The aforementioned risk factors vary in the strength of their association with recurrent miscarriage, and causal relationships remain largely elusive. This is compounded by the paucity of interventions with proven efficacy and safety in recurrent pregnancy loss, suggesting that testing for some conditions may be futile other than for possibly explaining some of the losses sustained by the individual or couple.

Table 1 summarizes evidence-based recommendations for investigations in couples with recurrent miscarriage. These should be conducted in the context of specialized services with access to multidisciplinary input.1


Summary of evidence for investigations in people with recurrent miscarriage (adapted from1,2,4,5).


Evidence of association
with recurrent miscarriage

Prognostic value

Existing treatment known to be efficacious and safe

Lupus anticoagulant antibody



Yes – low-certainty evidence27

Anticardiolipin antibodies



Yes – low-certainty evidence27

Beta-2-glycoprotein 1


No data

No data27

Hereditary thrombophilia (factor V Leiden, prothrombotic genetic variant, MTHFR genetic variant, protein C, S and antithrombin deficiency)




Karyotyping of pregnancy tissue



No – explanatory purposes only1

Parental genetic testing



Preimplantation genetic testing or antenatal testing in future pregnancies, adoption, gamete donation1


Only sporadic pregnancy loss


Levothyroxine treatment1,2

Subclinical hypothyroidism



Levothyroxine treatment – effectiveness uncertain1,2

Thyroid peroxidase antibodies




Transvaginal ultrasonography and serum hormone testing for polycystic ovary syndrome



No studies on metformin for recurrent pregnancy loss1

Transvaginal ultrasonography to diagnose congenital uterine malformations



Septoplasty not shown to improve outcomes, but more studies required1,31

Transvaginal ultrasonography to diagnose acquired uterine malformations




Vitamin D deficiency



Yes – vitamin D supplementation1,2




Yes – dopamine agonists may be considered with endocrinology input1,32




High-dose folic acid and vitamin B6, low molecular weight heparin, aspirin – effectiveness uncertain1

Cytokine testing




Antinuclear antibodies (ANA)



No – explanatory purposes only1

Natural Killer cell number in peripheral blood




Natural killer cell cytotoxicity in peripheral blood




Natural killer cells in the endometrium




Sperm DNA damage



Lifestyle changes, although specific recommendations are lacking1


There is a plethora of interventions aimed at improving the chance of live birth in people with recurrent pregnancy loss, although few treatments exist whose efficacy and safety have been proven by high-quality studies.


Progesterone, a steroid hormone secreted by the corpus luteum after ovulation, is essential for pregnancy success. The total or partial absence of progesterone in early pregnancy has been associated with miscarriage and abnormal implantation, suggesting an underpinning role of the corpus luteum and its secretory products in ensuring the presence of an optimum immune-endocrine environment at the time of placentation. After 7–9 weeks of gestation, the placenta takes over steroid hormone synthesis, including estrogen and progesterone, although it is unclear whether there remains a role of corpus luteum in ensuring a healthy pregnancy continues beyond what has been termed the luteo-placental shift.

The knowledge that progesterone deficiency is associated with subfertility, implantation failure and miscarriage, has led researchers to investigate whether exogenous progesterone supplementation may reduce the risk of further pregnancy losses in women with a history of recurrent miscarriage. The largest clinical studies investigating the use of progesterone to prevent pregnancy loss were the PROMISE and the PRISM randomized controlled trials.

The PROMISE trial focused on an enriched population of asymptomatic women with a history of recurrent miscarriage. A total of 1568 participants were randomized to receive vaginal micronized progesterone (n = 404) or placebo (n = 432) from the time of a positive pregnancy test. The evidence showed that for the primary outcome of live birth ≥34 weeks, progesterone did not exhibit improved effectiveness compared to placebo (relative rate [RR] 1.04, 95% CI 0.94 to 1.15).33

In order to ascertain whether further population enrichment might identify a protective role of progesterone, the investigators conducted the subsequent PRISM trial, in which 4153 women with bleeding in early pregnancy (threatened miscarriage) were randomized to receive vaginal micronized progesterone or a placebo until 16 completed weeks of gestation. Although for the overall trial population there was a small degree of uncertainty about the benefit of progesterone (RR 1.03, 95% CI 1.00 to 1.07, P = 0.08), the data showed an improvement in live birth rate among participants with threatened miscarriage and a history of one or more previous miscarriages (RR 1.09, 95% CI 1.03 to 1.15, P = 0.01).

Based on the above findings and subsequent meta-analyses,34 NICE and the RCOG recommend the use of vaginal micronized progesterone in women with a history of one or more miscarriages and threatened miscarriage in the index pregnancy,5,35 while in its recent update of the recurrent pregnancy loss guideline ESHRE recommends consideration of such treatment only in those with a history of three or more miscarriages and vaginal bleeding in the current pregnancy.1

Anticoagulant therapy

Antiphospholipid syndrome, an acquired thrombophilia, is associated with impaired placental perfusion and pregnancy complications, including recurrent miscarriage and pre-eclampsia. Systematic reviews and meta-analyses have investigated the use of anticoagulant treatment (low-dose aspirin, heparin, or both) to prevent miscarriage and increase the live birth rate in women with thrombophilia. Although the existing trials have thus far exhibited substantial methodological flaws, meta-analysis has shown a reduction in miscarriage (RR 0.48, 95% CI 0.32 to 0.71, low-certainty evidence) and increase in live birth (RR 1.27, 95% CI 1.09 to 1.49, low-certainty evidence) with the combined use of low-dose aspirin and heparin compared with placebo in women with antiphospholipid syndrome and recurrent miscarriage.1,2,5,27

In women with inherited thrombophilia, the recently published ALIFE-2 study, an international multicentre randomized controlled trial investigating the use of heparin versus placebo in 326 women with inherited thrombophilia and recurrent miscarriage, did not find evidence of an improvement in live birth with heparin (adjusted OR 1.08, 95% CI 0.65 to 1.78). Importantly, 71% of trial participants went on to experience a live birth after sustaining two losses, reiterating that most women with inherited thrombophilia go on to experience a live birth in the absence of any intervention.28


Overt hypothyroidism is a recognized cause of recurrent miscarriage, and guidance from the Royal College of Obstetricians and Gynaecologists recommends that women treated with levothyroxine should aim for thyroid stimulating hormone (TSH) serum levels lower than 2.5 mIU/l while trying to conceive and in early pregnancy.5 As maternal thyroxine requirements increase in the first trimester, the dose of levothyroxine should be empirically increased from the point of a positive pregnancy test by doubling it on 2 days per week and repeated thyroid stimulating hormone (TSH) measurements at least once per trimester until 34 weeks of gestation.36

For women with subclinical hypothyroidism or thyroid autoimmunity, the evidence is less certain. The RCOG recommends that women with normal thyroid function tests and thyroid autoimmunity should not receive levothyroxine treatment as this has not been shown to reduce the risk of miscarriage. Where subclinical hypothyroidism is present, the guidance suggests considering levothyroxine treatment for women with TSH levels >4.0 mIU/ml), and to aim for a maintenance dose that achieves serum TSH levels <2.5 mIU/l.36


Metformin is a biguanide drug, working upon hepatic metabolic pathways to enable a euglycemic state.37 It is widely used for people with diabetes, with good effectiveness and safety.38 Polycystic ovary syndrome, whose etiology commonly includes increased insulin resistance, is associated with an increased risk of recurrent miscarriage.39 For this reason, it has been suggested that metformin may help regulate hyperinsulinemia and improve reproductive outcomes in with PCOS.40 A recent individual patient data meta-analysis of nearly 800 women with PCOS identified a reduction in a composite outcome of late miscarriage and preterm delivery when metformin treatment was administered compared with placebo (OR 0.43, 95% CI 0.23 to 0.79, P = 0.004).41 This was an important signal, which requires corroboration by high-quality trials specifically investigating a population of women with PCOS and recurrent miscarriage.

Human chorionic gonadotropin

Human chorionic gonadotropin (hCG), secreted by the syntiotrophoblast after implantation, is responsible for maintenance of the corpus luteum. In fresh in vitro fertilization cycles, exogenous hCG has been used historically to aid implantation by supporting corpus luteal function, although this practice has now largely been abandoned in favor of progesterone because of an increased risk of ovarian hyperstimulation syndrome following hCG administration.42

Given the association between luteal phase defect and increased risk of miscarriage, research has investigated whether hCG administration might prevent pregnancy loss in women with recurrent miscarriage. Nevertheless, some of the existing studies’ methodological flaws have rendered the evidence uncertain, warranting further high-quality trials investigating this question.43


Pregnancy relies on a state of relative maternal immunosuppression which enables the semi-allogenic embryo to attach itself to the endometrium without being recognized as foreign and rejected by the maternal immune system. Various cells play an important role in inducing maternal tolerance in pregnancy, including natural killer (NK) cells and T regulatory lymphocytes.44,45 It has been postulated that altered immune responses may be associated with impaired implantation and pregnancy loss. In addition to evaluating various diagnostic approaches to identify immune dysfunction in women with recurrent pregnancy loss (e.g., NK cell and cytokine activity in the endometrium and peripheral blood), studies have investigated whether the use of immunomodulatory drugs may benefit women with recurrent pregnancy loss and increase their odds of achieving a live birth. These interventions include corticosteroids, intravenous immunoglobulins, lymphocyte immunotherapy, and trophoblast membrane immunization. Systematic reviews have largely failed to confidently identify an increase in live birth rates in women administered these interventions.46 However, a recent high-quality randomized controlled trial conducted in Japan identified a higher than two-fold increase in the odds of live birth in women with four or more previous losses of unknown etiology receiving high-dose IVIG compared with placebo at 4–6 weeks of gestation (OR 2.60, 95% CI 1.15 to 5.86, P = 0.03).47 This difference was confidently reported despite a relatively low number of participants (n = 102), suggesting that the therapeutic potential of IVIG may be substantial. Additional studies on this topic are required to corroborate these findings and evaluate their generalizability to other populations of women living with RPL.


  • Couples with recurrent miscarriage should be advised about the importance of lifestyle optimization (e.g., weight management, smoking and alcohol cessation, caffeine intake reduction, folic acid, and vitamin D supplementation) while trying to conceive, as this has been shown to improve reproductive outcomes.
  • Women with a history of recurrent miscarriage should be offered the following tests:
    • Thyroid function and thyroid antibodies.
    • Acquired thrombophilia testing, specifically for lupus anticoagulant and anticardiolipin antibodies.
    • Transvaginal pelvic ultrasound, preferably with three-dimensional technology.
    • Cytogenetic analysis of the pregnancy tissue with the third miscarriage.
  • Parental karyotyping should be reserved for couples where cytogenetic analysis of pregnancy tissue has shown an unbalanced structural chromosomal abnormality, or where cytogenetic analysis has been unsuccessful due to sample contamination, technical failure, or a lack of fetal tissue for analysis.
  • There is a lack of high-quality evidence supporting any treatment in preventing miscarriage in couples with a history of recurrent pregnancy loss, but the evidence suggests benefit in the following treatments:
    • Micronized vaginal progesterone in women with threatened miscarriage and a history of previous pregnancy loss (moderate-certainty evidence).
    • Levothyroxine in women with subclinical hypothyroidism (low-certainty evidence)
    • A combination of aspirin and heparin in women with antiphospholipid antibodies (low-certainty evidence).


The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.



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