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Recurrent miscarriage
Recurrent miscarriage
Recurrent miscarriage
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Recurrent miscarriage
Other namesHabitual abortion, recurrent pregnancy loss (RPL)
SpecialtyObstetrics

Recurrent miscarriage or recurrent pregnancy loss (RPL) is the spontaneous loss of 2-3 pregnancies that is estimated to affect up to 5% of women. The exact number of pregnancy losses and gestational weeks used to define RPL differs among medical societies.[1] In the majority of cases, the exact cause of pregnancy loss is unexplained despite genetic testing and a thorough evaluation. When a cause for RPL is identified, almost half are attributed to a chromosomal abnormality (ie. aneuploidy). RPL has been associated with several risk factors including parental and genetic factors (ie. advanced maternal age, chromosomal abnormalities, sperm DNA fragmentation), congenital and acquired anatomical conditions, lifestyle factors (ie. cigarette smoking, caffeine, alcohol, stress), endocrine disorders, thrombophila (clotting disorders), immunological factors, and infections. The American Society of Reproductive Medicine recommends a thorough evaluation after 2 consecutive pregnancy losses; however, this can differ from recommendations by other medical societies.[1][2] RPL evaluation can be evaluated by numerous tests and imaging studies depending on the risk factors. These range from cytogenetic studies, blood tests for clotting disorders, hormone levels, diabetes screening, thyroid function tests, sperm analysis, antibody testing, and imaging studies. Treatment is typically tailored to the relevant risk factors and test findings. RPL can have a significant impact on the psychological well-being of couples and has been associated with higher levels of depression, anxiety, and stress. Therefore, it is recommended that appropriate screening and management (ie. pharmacologic, counseling services) be considered by medical providers.   

Epidemiology

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Pregnancy loss, also referred to as miscarriage or spontaneous abortion, occurs in up to 25% of pregnancies. Recurrent pregnancy loss occurs less frequently and it is estimated that 5% of women experience two consecutive pregnancy losses while only 1% experience three or more.[3][4]

Etiology and risk factors

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Relative incidences of causative findings in cases with recurrent miscarriage[5]

The cause of recurrent pregnancy loss is unknown in about 50% of cases. Risk factors that have been associated with RPL include parental and genetic factors (advanced maternal age, chromosomal abnormalities, sperm DNA fragmentation), anatomical conditions, lifestyle factors, endocrine disorders, thrombophila (bleeding disorders), immunological factors, and infections. Despite thorough evaluation for these risk factors, the exact cause for recurrent pregnancy loss is unknown in about 50% of cases.[6][7]

Parental and genetic factors

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  • Advanced maternal age: Maternal age is associated with increased risk of miscarriage with a rate of 50% in women over 40 years of age. This higher likelihood of pregnancy loss can be attributed to the higher incidence of trisomies, a chromosomal abnormality, seen in women over the age of 35.[3]
  • Chromosomal abnormalities: Recurrent pregnancy loss is most commonly found to be caused by chromosomal abnormalities in the fetus, accounting for approximately 50% of cases. These include structural aberrations (such as chromosomal inversions, insertions, deletions, and translocations) and numerical aberrations, also called aneuploidies (trisomies, monosomy X, and triploidy).[7] These can be detected by cytogenetic testing such as karyotyping (test that analyzes the structure and quantity of chromosomes), FISH, MLPA, aCGH, and SNP array.[8] Some research suggests that chromosomal abnormalities occur more frequently in sporadic pregnancy loss than in recurrent pregnancy loss, and the incidence of RPL is lower in women with 3 or more pregnancy losses.[7] Parental chromosomal abnormalities is a rare cause of RPL, found in approximately 2-4% cases. Studies comparing pregnancy outcomes in couples experiencing RPL with and without chromosomal abnormalities found that parental carriers of chromosomal abnormalities had a lower live birth rate, specifically carriers of a reciprocal/balanced Robertsonian translocation. This evidence suggests that although RPL can occur in both couples with and without chromosomal aberrations, those that do are at higher risk of pregnancy loss.[9] Previous studies produced conflicting results. Genetic evaluation of RPL is generally recommended in order to determine the need for genetic counseling and appropriate treatment.[3] This, however, can differ among medical societies where others recommend against routine cytogenetic testing for couples experiencing RPL as it is of little clinical benefit.[10] It is instead considered after individual risk assessment (ie. family history) and recommended to test parental chromosomes rather than the products of conception.[8][10]
  • Paternal Factors: There is emerging research that suggests male factors may contribute to recurrent pregnancy loss. A systematic review found that sperm DNA fragmentation, defined as breaks in the DNA strand of sperm cells, may be associated with RPL. Their findings included higher rates of SDF and other sperm parameters (ie. lower sperm number, motility, or ejaculation volume) in men experiencing RPL. No evidence of a relationship between RPL and paternal age, BMI, smoking, or alcohol use.[11] The European Association of Urology Guidelines on Sexual and Reproductive Health therefore recommends SDF testing in cases of infertility or recurrent pregnancy loss.[12]

Anatomical conditions

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Fifteen percent of women who have experienced three or more recurring miscarriages have some anatomical reason for the inability to complete the pregnancy.[13] The structure of the uterus has an effect on the ability to carry a child to term. Anatomical differences are common and can be congenital or acquired.

  • Congenital: Congenital uterine malformations include unicornuate, septate, bicornate, didelphic, and arcuate uteri. The relationship between uterine abnormalities that are present from birth and RPL is unclear, however, there is an association with pregnancy loss. These structural anomalies are a result of disruption of the Müllerian tract during development. These can be found in approximately 12.6% of RPL cases with the highest incidences occurring in patients with septate (44.3%), bicornuate (36%), and arcuate (25.7%) uteri. These Structural uterine abnormalities can be visualized by several imaging studies including, hysterosalpingography, ultrasound, and MRI.[3]
  • Acquired: Other structural uterine anomalies such as uterine fibroids, polyps, and adhesions (also known as Asherman's syndrome) have a less clear association with recurrent pregnancy loss.[3] Cervical weakness has been shown to lead to premature pregnancy loss resulting in miscarriages or preterm deliveries. It has been estimated that cervical insufficiency is a cause in about 8% of women with second trimester recurrent miscarriages.[14]

Lifestyle factors

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While lifestyle factors have been associated with increased risk for miscarriage in general, and are usually not listed as specific causes for RPL. These include cigarette smoking, caffeine intake, alcohol use, BMI, and stress.[15][3]

  • Smoking: There is limited research that directly looks at the association of cigarette smoking and RPL. Recently, a systematic review that looked at studies evaluating the link between RPL and smoking was unable to find a significant difference in risk of recurrent pregnancy loss between people that smoke and non-smokers.[6] This review did not address e-cigarettes and vaping given that the authors did not find any studies that looked into the relationship between these forms of smoking and RPL. The relationship between smoking and the risk of miscarriage has been extensively researched. According to a systematic review and meta-analysis, there is some evidence that active cigarette smoking increases the risk of miscarriage and this risk is further increased the more cigarettes that a person smokes a day.[16] This same review highlights that according to the Surgeon General's report in 2010, research supports that smoking during pregnancy can also lead to pregnancy complications such as placental abruption, preterm delivery, and low birthweight among other maternal health risks.[16][17]
  • Caffeine: research regarding the association of caffeine intake and spontaneous pregnancy loss has produced inconsistent results in previous years due to the influence of multiple factors and limitations in data collection among the studies.[18] The same systematic review that looked at the relationship between cigarette smoking and RPL in 2021 found that there was no increased risk of RPL with the consumption of caffeine.[6] There have been more recent studies that have assessed the relationship between caffeine and miscarriage. A systematic review found that coffee consumption before and during pregnancy was associated with a higher risk of pregnancy loss. The risk of pregnancy loss increased by 3% with each additional cup of coffee consumed during pregnancy. There was also an increased risk of pregnancy loss of 14-26% with the consumption of an additional 100 mg of caffeine (coffee, tea, soda, cacao) per day during pregnancy. This increased risk was not seen if the caffeine products were consumed prior to pregnancy.[19] The harmful effects of caffeine during pregnancy can be attributed to its ability to absorb rapidly into the bloodstream and cross into the placenta, along with the slowed breakdown of caffeine that occurs during pregnancy which can expose the fetus to caffeine and its metabolites for a prolonged period of time. Caffeine consumption can also lead to maternal cardiovascular effects that reduce placental blood flow, putting the development of the fetus at risk.[6][18][19]
  • Alcohol Use: Prenatal exposure to alcohol has been shown to have damaging effects on the cognitive development of the fetus and has been associated with low birthweight among other features of Fetal alcohol spectrum disorders due to its teratogenic effects.[20][21] Similar to smoking and caffeine consumption, research studies assessing the relationship between alcohol use and pregnancy loss have produced inconsistent results. A systematic review that looked at several maternal lifestyle factors and the risk of recurrent pregnancy loss found no statistically significant increased risk in women that consumed any form of alcohol during pregnancy compared to those that did not.[6] These findings are similar to a recent review that looked at alcohol intake in the first and second trimester and found no increased risk of miscarriage. The authors report that this may have been due to a limited number of studies included in the review, considering the exclusion of studies that did not differentiate trimesters or account for other external factors (such as smoking, maternal age, maternal BMI) that have been linked to pregnancy loss.[22] There is evidence that in women that drink 5 or less alcoholic drinks per week, there is a 6% increased risk of miscarriage with each additional alcoholic drink consumed when the specific trimester is not specified.[23] Due to the inability to determine a safe range of alcohol consumption during pregnancy, multiple medical societies recommend avoiding alcohol to prevent the potential harm to the fetus.[21][24][25]
  • BMI: Maternal obesity and an elevated Body mass index (BMI) has been associated with an increased risk of miscarriage, although no clear cause has been established.[26] Studies suggest that pregnancy loss could be influenced by the downstream effects of the hormonal disruption of the HPA axis and insulin resistance that can be associated with obesity, on the reproductive system disrupting the development of oocytes, embryos, or the integrity of the endometrium (uterine lining).[27] Despite this evidence, research studies aimed to establish a relationship between RPL and BMI, which incorporates height and weight, have produced inconsistent results. A systematic review found that women with a history of RPL had higher BMI's by an average difference of 0.9 kg/m² than women without. These findings, however, were not statistically significant and not exclusive to BMI's within the overweight and obese range.[27] Another review and meta-analysis found that women with a BMI above 25 were more likely to have RPL and more likely to have a subsequent miscarriage, although the quality of evidence was low given that most of the studies were observational.[6] It is important to consider that BMI can be influenced by numerous other conditions and modifiable risk factors (ie. poor nutrition, activity level, diabetes), therefore should not be regarded as a direct cause of RPL.[27]
  • Stress: Research found that there is "increased relative risk of spontaneous abortion (odds ratio 1.28, 95% confidence interval 1.05-1.57)...for women experiencing high job stress."[28] Another research review found that the risk of miscarriage is higher for women with a "history of exposure to psychological stress (OR 1.42, 95% CI 1.19–1.70)"[29] However, the authors of these studies[28][29] also point out that measuring stress is difficult, and that the results must therefore be interpreted with some caution. In addition, one of the studies[29] notes that, while there are no randomized trials to study stress as it relates to pregnancy loss, one study found that a program of structured psychological support increased live birth rate among women with recurrent miscarriage.[30]

Endocrine disorders

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Women with hypothyroidism are at increased risk for pregnancy losses. Unrecognized or poorly treated diabetes mellitus leads to increased miscarriages. Women with polycystic ovary syndrome also have higher loss rates possibly related to hyperinsulinemia or excess androgens. Inadequate production of progesterone in the luteal phase may set the stage for RPL.

  • Luteal phase defect: The issue of a luteal phase defect is complex. The theory behind the concept suggests that an inadequate amount of progesterone is produced by the corpus luteum to maintain the early pregnancy. Assessment of this situation was traditionally carried out by an endometrial biopsy, however recent studies have not confirmed that such assessment is valid.[15] Studies about the value of progesterone supplementation remain deficient, however, such supplementation is commonly carried out on an empirical basis.[citation needed]

Thrombophilia

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An important example is the possible increased risk of miscarriage in women with thrombophilia (propensity for blood clots). The most common problem is the factor V Leiden and prothrombin G20210A mutation.[15] Some preliminary studies suggest that anticoagulant medication may improve the chances of carrying pregnancy to term but these studies need to be confirmed before they are adopted in clinical practice.[31] Note that many women with thrombophilia go through one or more pregnancies with no difficulties, while others may have pregnancy complications. Thrombophilia may explain up to 49–65% of recurrent miscarriages.[32]

Immune factors

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A common feature of immune factors in causing recurrent pregnancy loss appears to be a decreased maternal immune tolerance towards the fetus.[33]

  • Antiphospholipid syndrome: The antiphospholipid syndrome is an autoimmune disease that is a common cause of recurrent pregnancy loss.[34][15] Around 15% of the women who have recurrent miscarriages have high levels of antiphospholipid antibodies.[34] Women who have had more than one miscarriage in the first trimester, or a miscarriage in the second trimester, may have their blood tested for antibodies, to determine if they have antiphospholipid syndrome.[34] Women diagnosed with antiphospholipid syndrome generally take aspirin or heparin in subsequent pregnancies, but questions remain due to the lack of high quality trials.[35][36]
  • Thyroid antibodies: Anti-thyroid autoantibodies are associated with an increased risk of recurrent miscarriage with an odds ratio of 2.3 with a 95% confidence interval of 1.5–3.5.[37]
  • Increased uterine NK cells: Natural killer cells, a type of white blood cell, are present in uterine tissue. High levels of these cells may be linked to RPL but high numbers or the presence of these cells is not a predictor of pregnancy loss in women who have not have had a miscarriage.[38]
  • Male-specific minor histocompatibility: Immunization of mothers against male-specific minor histocompatibility (H-Y) antigens has a pathogenic role in many cases of secondary recurrent miscarriage, that is, recurrent miscarriage in pregnancies succeeding a previous live birth. An example of this effect is that the male:female ratio of children born prior and subsequent to secondary recurrent miscarriage is 1.49 and 0.76 respectively.[39]

Infection

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There are numerous bacterial, fungal, protozoal, and viral infections that have been associated with risk of pregnancy loss, however, no direct link to recurrent pregnancy loss has been established. Infections known to increase the risk of miscarriage include bacterial vaginosis (M. hominis and U. urealyticum), syphilis, CMV, dengue fever, malaria, brucellosis, and HIV. There is mixed evidence regarding the risk of miscarriage with Chlamydia trachomatis, HPV, Hepatitis B, Toxoplasma gondii, HSV1/HSV2, and parvovirus B19.[40]

Assessment

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Transvaginal ultrasonography has become the primary method of assessment of the health of an early pregnancy.

In non-pregnant patients who are evaluated for recurrent pregnancy loss the following tests are usually performed. Parental chromosome testing (karyogram) is generally recommended after 2 or 3 pregnancy losses. Blood tests for thrombophilia, ovarian function, thyroid function and diabetes are performed.

Treatment

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If the likely cause of recurrent pregnancy loss can be determined treatment is to be directed accordingly. In pregnant women with a history of recurrent miscarriage, anticoagulants seem to increase the live birth rate among those with antiphospholipid syndrome and perhaps those with congenital thrombophilia but not in those with unexplained recurrent miscarriage.[41] One study found that in many women with chronic endometritis, "fertility was restored after appropriate antibiotic treatment."[42]

For women with unexplained recurrent pregnancy loss, research suggests that specific antenatal counseling and psychological support may result in a higher chance of pregnancy success.[43] Some research finds that for these patients psychological support and ultrasound in early pregnancy "gives 'success rates' of between 70% and 80%".[44]

However, each additional loss worsens the prognostic for a successful pregnancy[citation needed] and increases the psychological and physical risks to the mother. Aspirin has no effect in preventing recurrent miscarriage in women with unexplained recurrent pregnancy loss.[45] Immunotherapy has not been found to help.[46]

In certain chromosomal situations, while treatment may not be available, in vitro fertilization with preimplantation genetic diagnosis may be able to identify embryos with a reduced risk of another pregnancy loss which then would be transferred. However, in vitro fertilization does not improve maternal-fetal tolerance imbalances.[citation needed]

Psychological Impact

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Main article: Miscarriage and grief

Experiencing pregnancy loss can have a significant and at times prolonged psychological impact, including higher levels of stress anxiety, and depression. There is evidence that women struggling with recurrent pregnancy loss in particular may be affected to a greater degree.[47] Grief is a normal and expected response to the loss of a pregnancy.[3] However, prolonged and intense grief can be significantly distressing and detrimental to the mental health of the individual. This can particularly be seen in women that developed maladaptive coping mechanisms following a miscarriage, isolated themselves as a result of the cultural and societal stigma, or received inadequate social support from medical providers, partners, families, and other personal relationships.[48] In heterosexual couples, men also experience grief as a result of pregnancy loss and have reported feeling obligated to disregard their feelings in order to support their partner.[47] The psychological effects of RPL on paternal emotional and mental wellbeing has not been studied extensively, however, there are emerging studies that further look into this. According to a recent meta-analysis that compared the psychological impact among men and women with a history of RPL, women were found to have higher levels of moderate to severe depression, stress, and anxiety than women without RPL and than men who experienced RPL.[47]

Given the impact that RPL can have on the mental health and psychologic well-being of couples, mental health evaluation, anxiety/depression screening, and treatment can be considered.[3][47] There is also emerging research that suggests that untreated depression and depressive symptoms can lead to adverse outcomes in future pregnancies such as preterm birth and low Apgar scores.[49] Consequently, there has been a rise in antidepressant (ie. SSRI) use during pregnancy over the last few years with a prevalence of 1-8%. This decision should be made with the guidance of a medical provider given the teratogenicity and potential adverse effects of antidepressants on the fetus.[47][49]

In addition to psychotherapy, psychological care for people experiencing recurrent pregnancy loss can include counseling and other supportive services. There is some evidence to support that women that received bereavement counseling (based on the Guidelines for Medical Professionals Providing Care to the Family Experiencing Perinatal Loss, Neonatal Death, SIDS, or other Infant Death) after pregnancy loss were able to cope better, with women reporting 50% less despair than those that did not receive this intervention.[48]

Prognosis

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Recurrent miscarriage in itself is associated with later development of coronary artery disease with an odds ratio of approximately 2,[50] increased risk of ovarian cancer,[51] increased risk of cardiovascular complications,[52] and an increased risk of all-cause mortality of 44%, 86%, and 150% for women with a history of 1, 2, or 3 miscarriages, respectively.[53]

Women with a history of recurrent miscarriage are at risk of developing preeclampsia in later pregnancies.[54]

References

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Bibliography

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Recurrent miscarriage

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from Grokipedia
Recurrent miscarriage, also known as recurrent loss (RPL), is defined as two or more failed clinical pregnancies prior to 20 weeks of , confirmed by or histopathologic examination; definitions vary, with some guidelines requiring three or more losses. This condition affects approximately 1% to 3% of couples attempting to conceive, with risk increasing after age 35 due to declining egg quality and chromosomal abnormalities. Although single miscarriages occur in 10% to 20% of recognized pregnancies, recurrent cases warrant thorough evaluation. The is multifactorial, with identifiable causes in about 50% of cases and the rest unexplained. involves personalized testing per guidelines from ACOG (reviewed 2024) and ESHRE (updated 2022), including , , and select labs, avoiding unproven tests like routine immunological screening. Management targets identified causes, with supportive care; most couples achieve live birth rates over 60% in subsequent pregnancies.

Definition and Terminology

Diagnostic criteria

Recurrent pregnancy loss (RPL), also known as recurrent miscarriage, is clinically defined as the loss of two or more pregnancies before 24 weeks of gestation, according to the European Society of Human Reproduction and Embryology (ESHRE) guideline update of 2022. This threshold represents a shift from earlier criteria that often required three or more losses, based on accumulating evidence as of the 2022 guideline demonstrating similar prognostic implications and improved research facilitation with the lower threshold. The American Society for Reproductive Medicine (ASRM) defines RPL as two or more failed clinical pregnancies before 20 weeks of gestation, excluding biochemical losses and aligning on the threshold of two but differing in gestational age limit and loss types included. RPL affects approximately 1-5% of couples attempting to conceive. Pregnancy losses qualifying for the RPL diagnosis are categorized as early or late. Early RPL refers to losses occurring before 10 weeks of , while late RPL involves losses from 10 weeks up to 24 weeks. These losses can be further classified by confirmation criteria: biochemical losses are identified by elevated serum or β-hCG levels or a positive without subsequent clinical ; clinical losses involve symptoms such as or cramping alongside ultrasonographic confirmation of an intrauterine ; and morphological losses include visualization of embryonic or fetal structures, potentially with heartbeat detection. Non-consecutive losses are included in the diagnostic count, as no indicates that consecutiveness alters the profile or . The also encompasses secondary RPL, defined as two or more losses following a prior viable beyond 24 weeks or a live birth. Certain pregnancy outcomes are explicitly excluded from the RPL criteria to maintain diagnostic specificity: ectopic pregnancies, molar pregnancies, and induced abortions do not count toward the threshold. This framework ensures a standardized approach to identifying couples warranting further investigation for underlying causes, such as uterine abnormalities that may contribute to qualifying losses.

Terminology variations

The terminology surrounding recurrent miscarriage has evolved to promote clarity, reduce stigma, and align with clinical evidence, with "recurrent pregnancy loss (RPL)" increasingly preferred over "recurrent miscarriage" in contemporary medical literature and guidelines. The European Society of Human Reproduction and Embryology (ESHRE) in its 2022 guideline explicitly adopts "recurrent pregnancy loss" to encompass the condition defined as two or more pregnancy losses before 24 weeks' gestation, excluding ectopic and molar pregnancies, emphasizing a neutral and precise descriptor for affected individuals. This shift reflects broader efforts to standardize language that supports patient-centered communication without implying fault. Historically, the condition was termed "habitual ," a phrase originating in mid-20th-century medical texts to denote repeated losses, often requiring three or more events for . This has largely been abandoned due to its stigmatizing connotations, as "" evokes moral or ethical judgments rather than a medical event, and patients and clinicians alike favor "" or " loss" for its less judgmental tone. By the late 20th century, professional bodies began transitioning away from such language to mitigate emotional distress for those experiencing losses. Specific variations include "recurrent early pregnancy loss (REPL)," which refers to two or more losses occurring before 10 weeks' , including non-consecutive events and sometimes biochemical pregnancies detected only by levels without confirmation. This term is particularly useful in contexts to distinguish early losses from later ones. International differences persist in usage and thresholds; for instance, in the United States, the American Society for Reproductive Medicine (ASRM) defines RPL as two or more clinical pregnancy losses before 20 weeks (documented by or ), while in the , the Royal College of Obstetricians and Gynaecologists traditionally requires three consecutive miscarriages before investigation. These distinctions aid in diagnostic criteria, typically involving two or more losses, but biochemical events are often excluded from RPL counts unless recurrent and clinically significant.

Epidemiology

Prevalence and incidence

Recurrent pregnancy loss (RPL), defined as two or more consecutive miscarriages before 20 weeks of gestation, affects approximately 1-5% of couples attempting conception worldwide. This range aligns with estimates from major reproductive health organizations, where the prevalence is about 1-2% for three or more losses and up to 5% when including two losses. The figure may vary based on whether biochemical pregnancies are included, with rates reaching 2-3% in such cases. The risk of subsequent miscarriage increases with the number of prior losses, providing key incidence data for RPL. After two consecutive miscarriages, the probability of another loss rises to about 25%, compared to 15-20% after a single miscarriage. Following three or more losses, this risk further escalates to 30-40%. Differences exist between early RPL (before 10 weeks) and late RPL (10-24 weeks), with early losses more commonly linked to chromosomal anomalies (up to 45% in sporadic cases, 39% in subsequent RPL) and late losses associated with factors like uterine malformations or thrombophilias. RPL appears more frequent in () cycles, often due to higher maternal age and . Underreporting is common, particularly for early biochemical losses that may go unrecognized without sensitive testing. Prevalence rates have remained stable over recent decades, though improved diagnostics have led to greater recognition of cases. Recent studies suggest that prior infection may increase the risk of early loss by 2-3 times in affected pregnancies.

Demographic patterns

Recurrent miscarriage risk escalates with advancing maternal age, particularly after 35 years, due to diminished quality, reduced , and elevated embryonic chromosomal abnormalities. Studies demonstrate a nearly linear increase in incidence after age 30, culminating in risks approaching 54% for women aged 45 and older. Advanced paternal age exceeding 40 years further contributes, with affected men exhibiting 69% higher odds of miscarriage compared to those aged 20-29 ( 1.69, 95% CI 1.18-2.43). Parity significantly shapes the of recurrent miscarriage, with varying between nulliparous and multiparous women. Overall rates stand at 1-2% among couples attempting conception, but primary recurrent pregnancy loss—occurring in nulliparous women without prior live births—accounts for roughly 15-20% of cases, while secondary recurrent pregnancy loss in multiparous women predominates at 80-85%. Secondary cases are linked to lower risks of certain complications relative to primary cases. Geographic and ethnic disparities highlight elevated rates in regions with prevalent consanguineous marriages, such as the , where affects 20-50% of unions and correlates with higher recurrent miscarriage incidence (P < 0.001 in Iranian cohorts). This pattern stems partly from increased homozygosity for genetic variants, though not all studies confirm a direct causal link. In contrast, high-resource settings exhibit lower effective incidence through superior prenatal screening and management. Socioeconomic factors exacerbate disparities, as low-income groups face heightened risks from restricted prenatal care access and elevated stress or environmental exposures. Enhanced healthcare availability in higher socioeconomic contexts mitigates incidence by facilitating timely diagnostics and interventions.

Causes

Genetic factors

Genetic factors play a significant role in recurrent pregnancy loss (RPL), encompassing both inherited parental chromosomal rearrangements and de novo embryonic abnormalities that disrupt normal development. These genetic contributions account for a substantial portion of RPL cases, with embryonic aneuploidy being the predominant mechanism, often arising from errors in meiosis or early mitosis. Parental genetic variants, including balanced translocations, further elevate the risk by producing unbalanced gametes that lead to nonviable embryos. Parental chromosomal abnormalities, particularly balanced translocations, are identified in approximately 2-5% of couples experiencing RPL, compared to less than 1% in the general population. These include Robertsonian translocations, where two acrocentric chromosomes fuse at their centromeres, and reciprocal translocations involving segments exchanged between non-homologous chromosomes; carriers are phenotypically normal but produce gametes with unbalanced chromosomal content, resulting in frequent miscarriages. For instance, a 2025 study of over 4,000 couples with RPL detected structural chromosomal anomalies in 3.3% of cases, predominantly translocations. Such abnormalities follow mendelian inheritance patterns, with each pregnancy having a 50% chance of being balanced, unbalanced, or normal depending on segregation during meiosis. Embryonic aneuploidy, characterized by an abnormal number of chromosomes, underlies 50-70% of RPL cases, far exceeding rates in sporadic miscarriages due to recurrent production of chromosomally unstable embryos. Common trisomies involve chromosomes 13, 16, 21, and 22, which often lead to arrest in the first trimester; monosomy X (Turner syndrome) is also frequent. These de novo errors typically occur during maternal meiosis, influenced by advanced maternal age, and result in embryonic lethality, explaining the high miscarriage rate in affected couples. Cytogenetic analysis of miscarriage products confirms aneuploidy in over 50% of RPL specimens, highlighting its central etiologic role. Single gene disorders contribute to RPL through inherited variants affecting hemostasis and placentation, with thrombophilias such as the factor V Leiden mutation (a G1691A polymorphism in the F5 gene) increasing risk via hypercoagulability that impairs trophoblast invasion. Heterozygous carriers face a 2-7-fold elevated odds of RPL, particularly in certain populations like Iranians, following autosomal dominant inheritance with incomplete penetrance. Other monogenic causes include variants in genes related to antiphospholipid syndrome pathways, such as those in the complement system or coagulation factors, which promote thrombosis and inflammation at the maternal-fetal interface. These disorders are less common than aneuploidy but identifiable through targeted sequencing, with inheritance patterns varying from autosomal recessive (e.g., certain protein C deficiencies) to dominant. Preimplantation genetic testing (PGT) for aneuploidy, performed on embryos during IVF, improves outcomes in RPL by selecting euploid embryos for transfer, reducing miscarriage rates by up to 58% and boosting live birth rates per transfer by over twofold in unexplained cases. A 2024 meta-analysis reported clinical pregnancy rates of 73% and live birth rates of 62% with PGT versus 61% and 41% without, particularly benefiting women over 35 with prior losses. However, cumulative live birth rates may not differ significantly across cycles due to the limited number of transferable embryos. Despite comprehensive karyotyping of parents and products of conception, 10-15% of RPL cases remain unexplained by 2025 data, often attributed to undetected submicroscopic variants or complex polygenic interactions rather than overt chromosomal issues. Genetic counseling is recommended for affected couples to discuss recurrence risks based on identified inheritance patterns.

Uterine abnormalities

Uterine abnormalities encompass both congenital and acquired structural defects that can contribute to recurrent pregnancy loss (RPL) by disrupting normal embryonic implantation and development. These anomalies affect approximately 13.3% of women with RPL, compared to 5.5% in the general population. Congenital uterine malformations, arising from developmental errors in the Müllerian ducts, are particularly implicated, with the septate uterus being the most common type associated with RPL, occurring in 15-20% of cases involving uterine factors. Other congenital anomalies include the unicornuate uterus, which features a single functional uterine horn and is linked to reduced uterine capacity, further elevating miscarriage risk. Acquired uterine abnormalities, which develop later in life, include submucosal fibroids, endometrial polyps, and intrauterine adhesions, the latter often resulting from Asherman syndrome following uterine curettage procedures such as dilation and curettage after miscarriage or abortion. Submucosal fibroids distort the endometrial cavity, while polyps and adhesions impair the endometrial surface integrity. These acquired defects are identified in about 12.9% of women with RPL. The pathophysiology of these abnormalities centers on impaired implantation and inadequate vascular supply to the developing placenta. In congenital cases like the septate uterus, the fibrous or muscular septum reduces intrauterine space and disrupts blood flow, leading to early pregnancy failure. Similarly, the unicornuate uterus limits expansion and vascular support during gestation. For acquired anomalies, submucosal fibroids and polyps alter the endometrial environment, hindering embryo attachment, while adhesions in Asherman syndrome cause deficient endometrial vascularization and reduced receptivity, resulting in miscarriage. The 2022 European Society of Human Reproduction and Embryology (ESHRE) guidelines recommend assessing uterine anatomy in all women with RPL using transvaginal three-dimensional ultrasound as the initial imaging modality for detection, with hysteroscopy advised for confirming and evaluating specific defects like septate uteri or adhesions. Hysteroscopic resection of the septate uterus is not recommended by the 2022 ESHRE guidelines due to insufficient evidence of benefit in live birth rates from high-quality studies, such as the TRUST trial (RR 2.3, 95% CI 0.86-5.9). However, the 2024 American Society for Reproductive Medicine (ASRM) guideline moderately recommends offering hysteroscopic septum incision to patients with a septate uterus and recurrent miscarriage in a shared decision-making model, based on moderate evidence showing reduced miscarriage risk (pooled OR 0.45, 95% CI 0.22-0.90).

Endocrine disorders

Endocrine disorders contribute to recurrent pregnancy loss (RPL) through disruptions in hormonal balance that affect implantation, placentation, and early embryonic development. These imbalances often involve the thyroid, glucose metabolism, and ovarian steroidogenesis, with evidence indicating that targeted screening can identify at-risk individuals, though routine testing for all parameters is not universally recommended. Laboratory investigations, such as thyroid-stimulating hormone (TSH) assays and glucose tolerance tests, form the basis for evaluating these conditions in women with RPL history. Thyroid dysfunction, particularly subclinical hypothyroidism defined by TSH levels exceeding 2.5 mIU/L, is prevalent in 2.4% to 27% of reproductive-age women and up to 19% of those with RPL, with conflicting evidence on its direct impact on miscarriage risk. However, elevated TSH in this range has been associated with increased odds of pregnancy loss (OR 1.86, 95% CI 1.18–2.94), potentially doubling the baseline risk in some cohorts through impaired endometrial receptivity and embryonic development. Autoimmune thyroiditis, marked by thyroid peroxidase antibodies (TPOAb), affects 8% to 14% of fertile women and up to 31% of RPL cases, exacerbating miscarriage risk via inflammatory mechanisms that compromise placentation. The European Society of Human Reproduction and Embryology (ESHRE) 2022 guidelines strongly recommend screening for TSH and TPOAb in RPL evaluation, though levothyroxine treatment for euthyroid autoimmune cases does not improve live birth rates. Uncontrolled diabetes mellitus, characterized by hyperglycemia with HbA1c levels above 6.5%, significantly elevates RPL risk by impairing trophoblast invasion and placentation, leading to structural placental abnormalities and increased apoptosis in placental cells. In women with pregestational diabetes, poor glycemic control correlates with higher rates of early pregnancy loss due to oxidative stress and vascular dysfunction at the maternal-fetal interface. The American Society for Reproductive Medicine (ASRM) 2012 committee opinion emphasizes screening via HbA1c in RPL patients with suspected metabolic issues, as well-controlled diabetes does not confer additional risk. Luteal phase defect, arising from corpus luteum insufficiency and resulting in low progesterone levels during the luteal phase, has been implicated in 23% to 60% of RPL cases historically, though contemporary evidence describes an inconsistent association with pregnancy loss. This condition manifests as inadequate endometrial preparation for implantation, with progesterone deficiency potentially contributing to early miscarriage in a subset of patients; estimates suggest involvement in up to 35% of unexplained RPL through shortened luteal phases or suboptimal progesterone output. ESHRE guidelines advise against routine testing or progesterone supplementation for luteal phase defect in RPL due to low-quality evidence, prioritizing clinical history over invasive diagnostics like endometrial biopsy. Polycystic ovary syndrome (PCOS), driven by insulin resistance, is linked to RPL through hyperinsulinemia and hyperandrogenism that disrupt ovarian function and endometrial receptivity, with studies indicating a higher miscarriage odds (OR 1.49, 95% CI 1.20–1.85) in affected women. Approximately 15% of RPL cases may involve PCOS-related metabolic pathways, as insulin resistance prevalence reaches 24% in RPL cohorts versus 8% in controls (OR 3.6), exacerbating ovulatory irregularities and early loss. The 2023 International Evidence-based Guideline for PCOS highlights insulin resistance as a key mediator but notes insufficient RPL-specific data for routine screening; ASRM concurs that PCOS evaluation should be history-based rather than universal. Routine prolactin testing is not recommended in RPL evaluation, as hyperprolactinemia shows only tenuous links to pregnancy loss and lacks consistent prognostic value without symptoms like oligo- or amenorrhea. Elevated prolactin may indirectly contribute via ovulatory dysfunction, but ESHRE and ASRM guidelines deem it unnecessary in asymptomatic cases, reserving assessment for those with galactorrhea or irregular cycles.

Coagulation disorders

Coagulation disorders contribute to recurrent pregnancy loss (RPL) primarily through thrombophilic conditions that disrupt normal hemostasis, leading to vascular complications in the placenta. Inherited thrombophilias, such as and the prothrombin G20210A mutation, are associated with an increased risk of RPL, with a combined prevalence of approximately 5-10% among affected women. These mutations impair the regulation of the clotting cascade, promoting a hypercoagulable state that can adversely affect placental development. Although not all carriers experience pregnancy loss, the odds ratio for RPL is elevated, at 2.02 (95% CI 1.60-2.55) for and 1.81 (95% CI 1.26-2.60) for prothrombin G20210A, particularly in cases involving fetal loss after 10 weeks of gestation. Acquired thrombophilias, notably antiphospholipid syndrome (APS), represent a more directly treatable cause, occurring in about 15% of women with RPL. APS is characterized by the presence of antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies (IgG/IgM), which trigger a prothrombotic state and are confirmed through persistent positivity after 12 weeks. The underlying pathophysiology involves microthrombosis within placental vessels, resulting in infarction, reduced blood flow, and subsequent fetal demise, often in the second trimester. This mechanism is distinct from broader immune dysregulation, focusing instead on aberrant activation of the coagulation system. According to the 2022 European Society of Human Reproduction and Embryology (ESHRE) guidelines, routine testing for inherited thrombophilias is not recommended due to limited clinical utility and weak causal evidence, but screening for APS—via lupus anticoagulant and anticardiolipin antibodies—is advised after two pregnancy losses. Protein C and protein S deficiencies, while rare (prevalence <1% in the general population), are significant when present, as they markedly increase the risk of late fetal loss through similar thrombotic pathways, warranting consideration in women with additional risk factors like family history of venous thromboembolism. These deficiencies highlight the need for targeted evaluation in select cases, though their overall contribution to RPL remains infrequent compared to more common thrombophilias.

Immunological factors

Immunological factors contribute to recurrent miscarriage through disruptions in maternal-fetal immune tolerance, where the maternal immune system inappropriately targets fetal antigens, leading to inflammation, impaired placentation, and pregnancy loss. This pathophysiology primarily involves alloimmune and autoimmune mechanisms that prevent the establishment of a balanced immune environment at the maternal-fetal interface. In alloimmune responses, the mother's immune system may fail to adequately suppress recognition of paternal antigens expressed by the fetus, resulting in heightened natural killer (NK) cell activity and cytokine dysregulation. Elevated peripheral and uterine NK cell levels or cytotoxicity have been associated with unexplained recurrent pregnancy loss (RPL), observed in approximately 20-30% of such cases, potentially disrupting trophoblast invasion and vascular remodeling essential for implantation. Additionally, a shift toward Th1-dominant responses promotes pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), while suppressing anti-inflammatory Th2 cytokines like interleukin-10 (IL-10) and IL-4, exacerbating immune rejection. Autoimmune mechanisms further compound these issues, with non-thrombotic immune dysregulation linked to RPL in about 20% of cases. For instance, elevated NK cell activity or pro-inflammatory cytokine profiles, including increased Th17-related IL-17, are frequently noted in unexplained RPL, contributing to chronic inflammation at the decidua. Celiac disease exemplifies this link, as undiagnosed cases carry up to a nine-fold increased risk of recurrent miscarriage due to autoimmune-mediated nutrient malabsorption and placental insufficiency, with serological screening recommended in evaluation. Current guidelines reflect ongoing controversies in managing these factors; the 2025 American Society for Reproductive Immunology (ASRI) recommendations advise against routine intravenous immunoglobulin (IVIG) therapy due to inconsistent evidence from randomized trials, emphasizing its use only in specialized, evidence-based contexts. Similarly, natural killer cell testing is deemed controversial and not routinely endorsed, given the lack of standardized assays and proven clinical utility for predicting or preventing RPL.

Infectious causes

Infections can contribute to recurrent pregnancy loss (RPL) by directly damaging fetal tissues, inducing inflammatory responses in the endometrium or placenta, or disrupting maternal-fetal immune tolerance, leading to miscarriage through mechanisms such as ascending genital tract infections or systemic effects. Bacterial infections, particularly those causing chronic endometritis, are implicated in RPL, where persistent low-grade inflammation in the endometrium impairs implantation and placental development. Common pathogens include Ureaplasma urealyticum and Mycoplasma hominis, which colonize the genital tract and have been detected in 10-20% of women with RPL based on cervical swab cultures or PCR testing. For instance, one case-control study found U. urealyticum positivity in 16.5% of women experiencing spontaneous abortion compared to 7.3% in controls, suggesting a potential role in recurrent cases. Chronic endometritis itself, often bacterial in origin, affects 7-58% of women with RPL, diagnosed via endometrial biopsy showing plasma cell infiltration. Viral infections may also play a role in RPL through reactivation or primary infection during pregnancy, causing fetal viremia or placental insufficiency. Cytomegalovirus (CMV) and herpes simplex virus (HSV) reactivation have been linked to increased miscarriage risk, while parvovirus B19 can lead to non-immune hydrops fetalis and loss, particularly in early gestation. A study evaluating women with recurrent spontaneous abortions found frequent associations with parvovirus B19 (detected in endometrial samples) and HSV-2 seropositivity, with odds ratios indicating elevated risk compared to fertile controls. Similarly, CMV IgM positivity has been observed more often in RPL cohorts, though causality remains debated due to the virus's ubiquity. Parasitic infections like toxoplasmosis, caused by Toxoplasma gondii, are relevant in endemic regions where seroprevalence exceeds 50%, increasing miscarriage risk via protozoal invasion of the placenta and fetus. In areas with high exposure from contaminated water or undercooked meat, acute maternal infection during pregnancy elevates the odds of loss by 1.5-2 times, with serologic studies showing higher IgG/IgM rates in women with habitual abortion. The 2022 European Society of Human Reproduction and Embryology (ESHRE) guideline advises against routine screening for infectious causes in RPL unless clinical history (e.g., symptoms of pelvic infection or exposure risks) suggests involvement, due to insufficient evidence linking most pathogens to recurrent loss. Laboratory tests, such as endometrial biopsy for chronic endometritis or serology/PCR for viruses and parasites, may be considered in targeted cases. Antibiotic treatment for confirmed bacterial chronic endometritis, using regimens like doxycycline or broad-spectrum combinations, has been associated with improved live birth rates in RPL, rising from approximately 40% to over 70% in treated cohorts compared to untreated.

Lifestyle and environmental factors

Cigarette smoking is a modifiable risk factor for recurrent pregnancy loss (RPL), with smokers exhibiting approximately twice the odds of RPL compared to non-smokers (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.1–4.1). This association is attributed to oxidative stress induced by tobacco smoke, which disrupts placental function and increases cellular damage in reproductive tissues. Similarly, heavy alcohol consumption elevates the risk of RPL; intake of five or more drinks per week (equivalent to approximately 10 units) has been linked to higher miscarriage rates, with dose-dependent effects observed in early pregnancy. Obesity, defined as a body mass index (BMI) greater than 30 kg/m², is associated with a 25–37% increased risk of RPL, independent of other factors. This elevated risk stems from chronic low-grade inflammation in adipose tissue, which promotes pro-inflammatory cytokine production and impairs endometrial receptivity and placental development. Weight loss interventions targeting obesity have shown potential to mitigate this risk in women with RPL. Exposure to environmental toxins also contributes to RPL. Bisphenol A (BPA), a common endocrine disruptor found in plastics, is associated with higher rates of unexplained recurrent miscarriage through mechanisms involving hormonal disruption and increased aneuploidy in oocytes. Pesticides, such as organophosphates, have been linked to RPL by inducing oxidative stress and apoptosis in placental cells, with occupational or residential exposure elevating odds. Caffeine intake exceeding 300 mg per day (roughly three cups of coffee) is associated with a modestly increased risk of repeated miscarriage (OR 2.7, 95% CI 1.1–6.2 in non-smokers), though evidence suggests this effect is minor compared to other factors. Folic acid deficiency has been implicated in RPL, with low serum folate levels correlating to a 50% higher risk of early pregnancy loss; recent analyses indicate that up to 10% of women with RPL may have suboptimal folate status, underscoring the importance of preconception supplementation. Psychological stress acts primarily as a confounder in RPL rather than a direct cause, potentially exacerbating other risk factors through indirect pathways like altered sleep or diet but without independent causation.

Investigation

Clinical history and examination

The clinical history for recurrent miscarriage begins with a detailed assessment of the patient's pregnancy outcomes, including the total number of previous losses, live births, and their sequence, whether consecutive or interspersed with successful pregnancies. This evaluation should specify the gestational age at each loss and the interval between pregnancies to identify patterns that may inform prognosis, as the chance of a live birth decreases with increasing numbers of miscarriages—for instance, approximately 72% after three losses compared to 50% after six or more. Symptoms associated with each miscarriage, such as vaginal bleeding, abdominal pain, or cramping, are documented to contextualize the events and rule out acute complications during prior episodes. The obstetric history encompasses details of all prior pregnancies, including modes of delivery and any complications, while the broader medical history probes for conditions like diabetes, thyroid disorders, or polycystic ovary syndrome that could contribute to losses. Family history is a critical component, focusing on patterns of recurrent miscarriage, genetic disorders, or hereditary thrombophilias among first-degree relatives, which may suggest inherited etiologies. Lifestyle factors for both partners are routinely explored, including smoking, alcohol consumption, diet, occupational exposures, and patterns of physical activity, as these modifiable elements—such as obesity or tobacco use—adversely affect live birth rates. Maternal age is noted as a key prognostic indicator, with advancing age correlating to diminished fertility and higher miscarriage risk. Partner involvement is emphasized throughout the evaluation process, with the male partner's history including age, similar lifestyle risks, and, if indicated, semen analysis to assess sperm quality or DNA fragmentation in selected cases. The physical examination prioritizes anthropometric measures, such as body mass index (BMI), to identify obesity or underweight status, both of which are associated with increased miscarriage risk through mechanisms like insulin resistance. Thyroid palpation is performed to detect goiter or nodules suggestive of dysfunction, guiding subsequent screening. A comprehensive pelvic examination evaluates for uterine abnormalities, such as fibroids or structural anomalies, which may be suspected based on historical symptoms of pain or irregular bleeding. General systemic assessment, including signs of endocrine or autoimmune disorders, completes the initial evaluation to direct further investigations without interpreting diagnostic tests.

Laboratory investigations

Laboratory investigations play a crucial role in evaluating recurrent miscarriage by identifying underlying genetic, hematologic, endocrine, and infectious causes that may be amenable to intervention. These tests are typically initiated after a thorough clinical history and physical examination, which guide the selection of appropriate assessments to avoid unnecessary testing. According to guidelines from the European Society of Human Reproduction and Embryology (ESHRE), evaluation can proceed following two consecutive clinical pregnancy losses, focusing on targeted laboratory panels rather than broad screening. Parental karyotyping, involving chromosomal analysis of both partners' peripheral blood, is recommended to detect balanced structural abnormalities such as reciprocal or Robertsonian translocations, which occur in approximately 2-5% of couples experiencing recurrent pregnancy loss. These rearrangements can lead to unbalanced gametes and subsequent embryonic aneuploidy, explaining the miscarriages. If an abnormality is identified, genetic counseling is advised to discuss reproductive options, including preimplantation genetic testing. The yield of this test underscores its value in a subset of cases, though it is not universally abnormal. Testing for antiphospholipid syndrome (APS) is a cornerstone of laboratory evaluation, particularly after two or more pregnancy losses. The panel includes assays for lupus anticoagulant, anticardiolipin antibodies (IgG and IgM), and anti-β2-glycoprotein I antibodies (IgG and IgM), which should be repeated at least 12 weeks apart to confirm persistence and avoid false positives from transient elevations. Positive results diagnose APS, a condition linked to thrombotic events in the placental vasculature, and warrant consideration of antithrombotic therapy in subsequent pregnancies. This testing is prioritized due to its established association with recurrent loss and proven treatment benefits. Endocrine screening focuses on treatable disorders that may contribute to miscarriage risk. Thyroid function and autoimmunity are assessed via serum thyroid-stimulating hormone (TSH) levels and thyroid peroxidase (TPO) antibodies, with subclinical hypothyroidism (TSH >2.5 mIU/L with normal free T4), for which treatment may be considered to potentially reduce miscarriage risk (conditional recommendation), particularly if TPO antibodies are present. Glycemic control is evaluated using hemoglobin A1c (HbA1c) to detect or , which should be optimized preconceptionally. Prolactin levels are measured only if indicated by symptoms such as or irregular menses, as routine screening is not recommended without clinical suspicion. These tests address endocrine imbalances that affect implantation and early . Beyond APS, routine screening for inherited conditions such as or prothrombin G20210A mutations is not advised by ASRM guidelines, as evidence does not support improved outcomes with anticoagulation in carriers. This recommendation, reaffirmed in recent reviews, avoids over-testing given the low attributable risk in recurrent miscarriage without personal history. For infectious etiologies, endometrial is considered only if chronic is suspected based on persistent symptoms or recurrent infections, using immunohistochemical staining for CD138-positive plasma cells to confirm the . Routine is not recommended, as the prevalence of chronic in unexplained recurrent loss is low and treatment benefits remain unproven in large trials.

Imaging studies

Imaging studies play a crucial role in the investigation of recurrent pregnancy loss (RPL) by identifying structural uterine abnormalities, such as congenital Müllerian anomalies, fibroids, polyps, and adhesions, which may contribute to pregnancy failure. These assessments are recommended for all women with RPL to evaluate uterine anatomy, with non-invasive options prioritized to guide further management. Transvaginal ultrasound, particularly three-dimensional (3D) imaging, serves as the first-line modality for assessing uterine structure due to its high in detecting fibroids, endometrial polyps, and Müllerian anomalies like septate or bicornuate . It effectively differentiates between and bicorporeal , which is essential for accurate , and is preferred over other techniques for its accessibility and non-invasive nature. Two-dimensional (2D) transvaginal ultrasound is also conditionally recommended to rule out in RPL patients, though it has lower sensitivity for intrauterine adhesions. Hysteroscopy remains the gold standard for direct visualization and confirmation of intrauterine pathologies, including polyps, fibroids, and synechiae, with studies reporting a yield of 15-27% for detecting uterine anomalies in women with RPL. Although routine diagnostic hysteroscopy is not universally recommended due to limited evidence of benefit in all cases, it is valuable when initial ultrasound findings suggest abnormalities or for therapeutic intervention in confirmed lesions. Hysterosalpingography (HSG) provides an outline of the and fallopian tubes through contrast , offering moderate sensitivity for pronounced malformations but lower accuracy in distinguishing anomaly types compared to or sonohysterography. It is often used complementarily when tubal patency assessment is needed alongside cavity evaluation. For complex cases, magnetic resonance imaging (MRI) is conditionally advised by the 2022 European Society of Human Reproduction and Embryology (ESHRE) guidelines when 3D ultrasound is unavailable or inconclusive, as it provides detailed soft-tissue imaging of uterine anomalies without radiation exposure. Laparoscopy, typically combined with hysteroscopy, is reserved for suspected endometriosis or to confirm congenital malformations like rudimentary horns, serving as the definitive diagnostic tool in select invasive scenarios. These imaging approaches collectively detect uterine abnormalities in approximately 13% of RPL cases, higher than the general population rate of 5.5%.

Management

Supportive care

Supportive care for recurrent pregnancy loss (RPL) emphasizes general, non-targeted strategies to optimize health and provide reassurance during preconception and subsequent pregnancies. Preconception counseling is a key component, where individuals are advised to initiate folic acid supplementation at a dose of 400 micrograms daily to reduce the risk of neural tube defects, a recommendation applicable to all women of reproductive age planning pregnancy, including those with a history of RPL. This supplementation should begin at least one month prior to conception and continue through the first trimester. Lifestyle modifications form another cornerstone of preconception care, with evidence indicating that , limiting alcohol intake to less than 1 unit per day, reducing to under 200 mg daily, and achieving a healthy body weight (BMI 18.5–24.9 kg/m²) can positively influence pregnancy outcomes in couples affected by RPL. and status have been associated with increased RPL risk, underscoring the importance of through balanced diet and moderate exercise prior to conception. These adjustments not only mitigate modifiable risk factors but also enhance overall potential. A multidisciplinary approach is recommended, involving referral to specialized RPL clinics that integrate expertise from reproductive endocrinologists, geneticists, hematologists, and psychologists to deliver coordinated care. These clinics provide comprehensive evaluation, ongoing support, and tailored monitoring without focusing on unproven interventions. In subsequent pregnancies, early monitoring—typically starting at 6–7 weeks and repeated as needed—helps confirm viability and detect issues promptly, offering reassurance and enabling timely intervention if required. General measures such as adequate hydration and are advised during early to support maternal well-being, particularly if symptoms like spotting occur, though is not routinely recommended absent complications. Psychological support can be integrated into this care framework to address the emotional toll of RPL, with brief counseling sessions helping to alleviate anxiety.

Cause-specific interventions

Once a specific cause of recurrent loss (RPL) has been identified through investigation, targeted interventions can be implemented to address the underlying and improve subsequent outcomes. For genetic causes, such as parental balanced chromosomal rearrangements (e.g., translocations), fertilization (IVF) combined with preimplantation for structural rearrangements (PGT-SR) is offered to carriers to select euploid embryos for transfer, thereby reducing the risk of miscarriage due to unbalanced gametes. The European Society of Human Reproduction and Embryology (ESHRE) 2022 guidelines conditionally recommend discussing PGT-SR with affected couples, noting a cumulative live of 67.5% across cycles, though it is not routinely advised due to limited high-quality evidence on overall benefit compared to natural conception attempts. In a cohort of 300 couples with balanced rearrangements undergoing PGT-SR, the cumulative live reached 55.8%, with complex translocations and identified as factors lowering success. Uterine anomalies, particularly a , are addressed through hysteroscopic metroplasty to resect the and potentially enhance implantation and reduce loss rates. Although the ESHRE 2022 guidelines do not recommend this procedure due to insufficient evidence of benefit ( for live birth 2.3, 95% CI 0.86-5.9), multiple meta-analyses indicate improved reproductive outcomes post-resection in women with RPL. A reported live birth rates increasing to 50.2% after hysteroscopic metroplasty, with a corresponding reduction in spontaneous rates from 38.6% to lower levels in treated groups. The American Society for Reproductive Medicine (ASRM) 2024 guideline supports metroplasty for symptomatic septate uteri, citing live birth rates of 34.1% at 12 months post-procedure in RPL patients. Endocrine disorders require correction of hormonal imbalances to mitigate RPL risk. Overt is treated with to normalize function, as untreated cases are associated with higher rates; ESHRE guidelines strongly recommend this intervention, with one study showing rates dropping from 20.6% to 4.7% post-treatment. For subclinical , is conflicting, but a 2024 found reduced loss risk by 31% (risk ratio 0.69, 95% CI 0.52-0.92) in affected women. In (PCOS)-related RPL, metformin is used to improve insulin sensitivity and , with a 2025 demonstrating a 40% reduction in first-trimester risk when administered preconceptionally and continued into early . ESHRE guidelines note insufficient for routine metformin use but suggest it for PCOS management in RPL contexts. Coagulation disorders, notably (APS), are managed with a combination of (LMWH) and low-dose aspirin to prevent thrombotic events in the uteroplacental circulation. ESHRE 2022 guidelines conditionally recommend preconceptional aspirin (75-100 mg/day) plus prophylactic LMWH from confirmation in women with APS and three or more losses, reporting live birth rates of 85.7% versus 67.5% without treatment (an absolute improvement of 18.2%). A 2021 confirmed this approach improves live birth rates by 20-30% in APS-associated RPL, though aspirin alone shows no benefit. Infectious causes like chronic are treated with targeted s following endometrial biopsy confirmation, as untreated may impair implantation and increase loss risk. Although ESHRE 2022 guidelines highlight a lack of randomized controlled trials and do not routinely recommend screening, observational studies demonstrate improved outcomes post-treatment; a 2020 cohort reported live birth rates rising from 42% to 75% after 14-day regimens in RPL patients with endometritis. A 2023 further supported this, showing a 25% increase in live birth rates and reduced rates after eradication. The ESHRE 2022 guidelines specify that progesterone supplementation is not routinely recommended for RPL unless there are three or more prior losses accompanied by in the current , where vaginal progesterone may conditionally improve live birth rates ( 1.28).

Approaches for unexplained cases

Approximately 40-50% of cases of recurrent loss (RPL) remain unexplained after comprehensive . For these idiopathic cases, expectant —close monitoring without specific interventions—is the primary approach, with subsequent pregnancies achieving live birth rates of 60-70% in the absence of identifiable risk factors. Empiric therapies are sometimes considered for unexplained RPL, though evidence is limited and recommendations are cautious. The European Society of Human Reproduction and (ESHRE) provides a conditional recommendation for vaginal progesterone supplementation (typically 400 mg daily) in women with three or more prior miscarriages, based on moderate-quality evidence suggesting a potential improvement in live birth rates, though it does not benefit those with fewer losses. This intervention is initiated from the time of positive until 12-16 weeks of and is thought to support endometrial receptivity and uterine quiescence. Low-dose aspirin (81 mg daily) combined with (e.g., enoxaparin 40 mg subcutaneously daily) has been used empirically in unexplained RPL outside of (APS), but recent meta-analyses, including a 2024 Cochrane review, demonstrate no significant benefit in live birth rates and highlight potential risks such as complications. Guidelines therefore advise against routine use in non-APS cases due to lack of efficacy. Intravenous immunoglobulin (IVIG) and corticosteroids, such as , are not recommended for unexplained RPL owing to insufficient evidence of efficacy and associated risks including , , , and . A 2023 randomized trial found (20 mg daily) did not improve live birth rates compared to and increased adverse outcomes. Similarly, multiple systematic reviews conclude IVIG provides no reproducible benefit over in idiopathic cases.

Prognosis

Live birth outcomes

Women with a history of two prior miscarriages have a live birth rate of approximately 70% in their subsequent , while those with three prior losses experience rates of 50-60%. These figures reflect baseline prognosis without targeted interventions and vary based on factors such as maternal age. Live birth outcomes differ significantly by underlying cause. For anatomical abnormalities, such as a , surgical correction yields live birth rates of around 80-83% in subsequent . In contrast, untreated genetic causes, including parental balanced chromosomal translocations, are associated with lower rates of 30-50% per pregnancy due to recurrent . Recent registry-based studies from 2025 indicate that cumulative live birth rates exceed 90% after four pregnancy attempts in women with recurrent miscarriage, highlighting the value of persistence. Assisted reproductive technologies, particularly when combined with preimplantation for , can boost cumulative live birth rates to approximately 70% in affected couples.

Influencing factors

Several factors influence the of recurrent miscarriage, with the number of prior losses being one of the most significant. Each additional miscarriage increases the risk of subsequent loss. For instance, the of a live birth decrease by about 32% per additional loss (OR 0.68, 95% CI 0.51-0.92). After three losses, the live birth rate is substantially lower, roughly halving compared to fewer losses, dropping from around 72% after three losses to 50% or less after six or more. Maternal age also plays a critical role in modifying outcomes, as advancing age is associated with higher rates of chromosomal abnormalities leading to . Women under 30 years have live birth success rates of 70-80% (specifically 81.3% within five years), while those over 40 experience rates below 40% (41.7%). This age-related decline is independent of other factors and underscores the importance of timely evaluation. A history of prior live birth may exert a protective effect on , with women experiencing secondary recurrent miscarriage (after at least one live birth) showing similar or slightly improved live birth rates compared to primary cases. This benefit likely reflects underlying and health factors. Similarly, elevated maternal BMI greater than 30 kg/m² reduces live birth chances by approximately 20%, with an associated increased miscarriage risk (OR 1.73, 95% CI 1.06-2.83). According to the 2022 ESHRE guidelines, paternal factors such as age and lifestyle have only a minor influence on prognosis, with no strong evidence linking sperm parameters or DNA fragmentation to recurrent outcomes beyond general fertility assessments.

Psychological and Social Impact

Emotional consequences

Recurrent miscarriage often triggers intense emotional responses, including profound grief, anxiety, and depression among affected individuals and couples. Women, in particular, frequently report feelings of loss and emptiness, with grief manifesting as sadness, guilt, and anger toward the body or circumstances. Research indicates that 30-50% of women may develop PTSD-like symptoms, such as intrusive memories, hypervigilance, and emotional numbness, following recurrent losses, with prevalence rates reaching up to 39% in some cohorts. These reactions are compounded for couples, where men may experience similar but often less intense grief, leading to mismatched coping styles that exacerbate emotional distress. Long-term psychological effects include an elevated risk of chronic anxiety, with odds ratios of approximately 1.5-2 compared to women without pregnancy loss history, persisting into subsequent pregnancies and daily life. Depression rates can remain high, affecting 20-55% of women over time, contributing to ongoing emotional burden. Relationship strain is prevalent in 20-40% of couples, often involving communication breakdowns, reduced intimacy, and feelings of isolation between partners, as differing expressions heighten tensions. Recent 2025 studies highlight that emotional impacts of recurrent pregnancy loss include heightened distress, such as intensified fears of further loss and amplified . Cultural stigma surrounding further worsens isolation, as societal silence and taboos discourage open discussion, leading to and heightened for affected individuals. These factors underscore the need for emotional consequences to be addressed alongside medical evaluations in RPL care.

Support strategies

Support strategies for addressing psychological distress following recurrent miscarriage encompass a range of therapeutic, medical, and community-based interventions tailored to individual needs. Given the high prevalence of emotional consequences such as anxiety and depression in affected individuals, these strategies aim to mitigate long-term impacts through evidence-based care. The 2022 European Society of Human Reproduction and (ESHRE) guideline emphasizes considering the emotional burden of recurrent pregnancy loss (RPL) and providing supportive care in specialist settings, including access to multidisciplinary teams with expertise in psychological support. Counseling plays a central role, with (CBT) demonstrating effectiveness in reducing symptoms of anxiety and depression among women with RPL. A preliminary open-label study involving 14 women found that individual CBT, averaging 8.9 sessions, significantly lowered state anxiety scores from 49.0 to 38.0 on the (P=0.016) and depression scores from 13.6 to 5.2 on the Beck Depression Inventory-II (P=0.001). groups specifically for RPL offer a vital community outlet, allowing individuals to share experiences and coping mechanisms in a non-judgmental environment. Organizations like RESOLVE: The National Association provide virtual and in-person support groups focused on pregnancy loss, incorporating elements such as expressive arts and trauma processing to foster emotional recovery. Medical interventions, including , are recommended for cases involving clinical depression, particularly when symptoms persist despite counseling. The American College of Obstetricians and Gynecologists (ACOG) highlights that antidepressant medication can help manage severe stress and anxiety post-pregnancy loss, with careful consideration of risks during subsequent pregnancies. Multidisciplinary clinics integrate psychological care with medical evaluation, offering holistic management that includes routine assessment of distress and coordinated referrals. The ESHRE guideline advocates for such clinics to ensure compassionate, couple-centered support, including clear communication and tailored emotional resources. Online resources further enhance accessibility to support, with platforms like Tommy's providing dedicated communities for and recurrent loss. Tommy's operates moderated groups and informational hubs that connect users with peers and expert advice on coping with and anxiety. These digital tools, alongside professional interventions, align with guideline recommendations for proactive emotional care, such as those in the 2022 ESHRE update, which stress the importance of information provision and listening skills in RPL management.

References

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