Triage and care for women with symptoms or diagnosis of pregnancy loss between 14 + 0 and 21 + 6 weeks' gestation.

The priorities when planning forward are to provide contraception to allow a choice about interpregnancy interval; to establish the cause in the interval before the next pregnancy; and to develop a plan of care for the subsequent pregnancy based on the likely cause of the MTL. The overall recurrence rate of MTL is 7%–8% but differs by cause or phenotype, from <5% (in cases of fetal anomaly, multiple gestations, intrauterine fetal death) to 30% (in cases of cervical insufficiency). 7 A systematic review and meta‐analysis of 10 observational studies reporting on outcomes of 12 004 subsequent pregnancies after MTL generated estimated outcome frequencies for women with a previous MTL as follows: live birth 81% (95% CI: 64–94), early pregnancy (first or second trimester) loss 15% (95% CI: 4–30), and preterm birth 13% [95% CI: 6–23]. The pooled odds ratio for preterm birth in subsequent pregnancy after MTL in case–control studies was OR 4.52 (95% CI: 3.03–6.74). However, as the evidence is limited and of very low certainty, larger, higher quality cohort studies are needed to investigate this potential association (Table  10 ). 112 Recurrence risk of mid‐trimester pregnancy loss. Abbreviation: MTL, Midtrimester pregnancy loss. Quality of evidence has been assessed using the GRADE system throughout. ⊕⊕⊕o = quality is moderate.

This guideline was conceptualized after discussion with the Chair of the FIGO Preterm Birth committee. A consensus group in conjunction with the Tommy's National Centre for Miscarriage Research, Tommy's Maternal and Fetal Health Research Centre, Tommy's National Centre for Preterm Birth Research, and the FIGO Preterm Committee developed the guidance. Evidence synthesis was carried out by CEF, RK, ACare, KV, and JC. The original draft was written by CEF, with all authors contributing to subsequent review and editing. LF and AJD formatted the tables and figures. All authors read and approved the final manuscript.

This guidance is intended for the management of symptomatic women, as asymptomatic women with known risk factors should already be identified at pregnancy booking and offered specialist preterm prevention care. This document is directed at multiple stakeholders with the intention of bringing attention to MTL. This document proposes to create a global framework for action to improve the diagnosis and care of women with symptoms or a diagnosis of MTL. The intended target audience includes: Healthcare professionals—all those who are qualified to care for pregnant women and their babies (e.g., obstetricians, gynecologists, neonatologists, general practitioners, midwives, nurses, non‐physician clinicians, and clinical officers). Healthcare delivery organizations and providers—governments, federal and state legislators, healthcare management organizations, health insurance organizations, international development agencies, and nongovernmental organizations. Professional organizations—international, regional, and national professional organizations of obstetricians and gynecologists, midwives, nurses and neonatologists, and worldwide national organizations dedicated to the care of pregnant women. Healthcare professionals—all those who are qualified to care for pregnant women and their babies (e.g., obstetricians, gynecologists, neonatologists, general practitioners, midwives, nurses, non‐physician clinicians, and clinical officers). Healthcare delivery organizations and providers—governments, federal and state legislators, healthcare management organizations, health insurance organizations, international development agencies, and nongovernmental organizations. Professional organizations—international, regional, and national professional organizations of obstetricians and gynecologists, midwives, nurses and neonatologists, and worldwide national organizations dedicated to the care of pregnant women.

As with any assessment, this must start with a comprehensive history of the presenting complaint. This is important to evaluate possible etiology (fetal, placental, uterocervical, or infective) and therefore target investigations and management. Women with threatened MTL might present with subtle symptoms such as increased vaginal discharge or pressure in the vagina. In some circumstances, the woman might be asymptomatic and the diagnosis of MTL is made during a routine ultrasound examination. Extra attention must be given to the details of any previous MTL or extreme preterm birth, particularly if the birth occurred at home, in a different hospital, or was not investigated. It is important to ensure that women are listened to and their fears are acknowledged. This is particularly relevant if they have experienced a previous loss. If a woman feels her symptoms are significant, this needs to be factored into subsequent management decisions. These factors are especially important for women from minority ethnic groups whom we know report difficulties in having their symptoms or concerns taken seriously. Key questions include: Previous pregnancy losses (with the gestational age of occurrence), extreme preterm births or stillbirths (with the gestational age of occurrence), antecedent rupture of membranes, and whether the fetus was born showing signs of life prior to 22 weeks. The presence or absence of vaginal bleeding, the presence and duration of pain, contractions or backache, fevers, history of antibiotic therapy, previous (or current) cerclage or progesterone use, and a history of multiple attendances with recurrent symptoms in pregnancy. 39 Previous pregnancy losses (with the gestational age of occurrence), extreme preterm births or stillbirths (with the gestational age of occurrence), antecedent rupture of membranes, and whether the fetus was born showing signs of life prior to 22 weeks. The presence or absence of vaginal bleeding, the presence and duration of pain, contractions or backache, fevers, history of antibiotic therapy, previous (or current) cerclage or progesterone use, and a history of multiple attendances with recurrent symptoms in pregnancy. 39 A review of the notes, scan reports, and investigation results from the current and previous pregnancies should be undertaken, including scans undertaken elsewhere or in early pregnancy units. A template clinical assessment document incorporating a structured clinical history sheet is provided in Table  S1 (Table  1 ). Initial triage and assessment of women with threatened mid‐trimester pregnancy loss. Abbreviation: MTL, Midtrimester pregnancy loss. Quality of evidence has been assessed using the GRADE system throughout. ⊕⊕⊕⊕ = quality is high, the authors have a lot of confidence that the true effect is similar to the estimated effect, ⊕⊕⊕o = quality is moderate, ⊕⊕oo = quality is low, ⊕ooo = quality is very low. Maternal observations should be recorded at admission (heart rate, blood pressure, temperature, respiratory rate, and oxygen saturations). This should be recorded on a Modified Early Obstetric Warning Score (MEOWS) chart if available and escalated or repeated according to score or concerns. An abdominal examination should be performed to assess for any palpable contractions or tenderness. A perineal examination should be done with collection of a low vaginal swab (LVS) for GBS. Vaginal speculum examination is required to assess for bleeding, cervical dilatation, bulging or rupture of membranes and to collect samples for microbiological culture. If a cervical polyp is seen, best practice is to avoid removal during the pregnancy. If the cervix is not clearly visualized and in the absence of ruptured membranes, a gentle vaginal examination might be considered. However, it might be more appropriate to escalate to a more senior colleague or consider transvaginal ultrasound assessment of cervical length. If the cervix is dilated, particular attention should be paid to avoid rupturing the membranes. Sterile precautions should be adopted prior to any examination where PPROM is suspected. Women with confirmed PPROM are at risk of ascending infection and sepsis. Therefore, speculum or digital examinations should be kept to a minimum and undertaken by experienced practitioners with sterile precautions. In women experiencing vaginal spotting, further investigations might still be needed regardless of the presence or absence of an ectropion. Transvaginal ultrasound scanning provides additional information to speculum examination and should be performed at the bedside when there is a skilled provider available to do so. Transvaginal scanning is superior to transabdominal scanning for cervical length assessment. It is important to note that a “long closed cervix” on speculum cannot rule out funneling at the internal os. See Section  6.2 for further detail regarding the role of ultrasound (Table  2 ). Examination of women with symptoms of threatened mid‐trimester pregnancy loss. Abbreviation: MEOWS, Modified early obstetric warning score. Quality of evidence has been assessed using the GRADE system throughout. ⊕⊕⊕o = quality is moderate, ⊕⊕oo = quality is low, ⊕ooo = quality is very low.

This guideline was supported by the Tommy's Charity, who provide funding to the Tommy's National Centre for Miscarriage Research, Tommy's Maternal and Fetal Health Research Centre, and Tommy's National Centre for Preterm Birth Research.

This document serves as a guide for the optimal triage and care of women presenting with symptoms of pregnancy loss between 14 + 0 and 21 + 6 weeks, referred to as mid‐trimester pregnancy loss (MTL) throughout this guideline. This guideline is intended to assist clinical judgment and not to replace it. Although it is not the focus of this guideline, our recommendations might also be appropriate in low‐resource settings for pregnancy losses between 22 and 28 weeks. In this guideline, we use the terms “woman” or “women” throughout. These should be taken to include people who do not necessarily identify as women but are pregnant or have given birth.

The following questions have been identified as important research questions for mid‐trimester pregnancy loss: What is the prevalence of mid‐trimester pregnancy loss (by gestation and cause)? What are the sociodemographic risk factors for MTL? What is the accuracy and value of cervical length measurement between 14 and 18 weeks in women with symptoms? What is the accuracy and value of preterm birth biomarker tests (e.g., fetal fibronectin, Actim Partus, vaginal microbiome) between 14 and 28 weeks in women with symptoms? What treatments can reduce mid‐trimester pregnancy loss? Can treatment with progesterone reduce mid‐trimester pregnancy loss for women who present with symptoms? Can treatment with cerclage reduce mid‐trimester pregnancy loss for women who present with symptoms? Can non‐surgical management of first/mid‐trimester pregnancy loss or termination of pregnancy reduce future mid‐trimester pregnancy loss when compared with surgical management? What is the optimal management of cervical polyps in pregnancy? How do infections contribute to mid‐trimester pregnancy loss, and how should they be managed? What is the relationship between air pollution exposure and mid‐trimester pregnancy loss? What are the consequences of mid‐trimester pregnancy loss in subsequent pregnancies and on maternal physical and mental health? What is the prevalence of mid‐trimester pregnancy loss (by gestation and cause)? What are the sociodemographic risk factors for MTL? What is the accuracy and value of cervical length measurement between 14 and 18 weeks in women with symptoms? What is the accuracy and value of preterm birth biomarker tests (e.g., fetal fibronectin, Actim Partus, vaginal microbiome) between 14 and 28 weeks in women with symptoms? What treatments can reduce mid‐trimester pregnancy loss? Can treatment with progesterone reduce mid‐trimester pregnancy loss for women who present with symptoms? Can treatment with cerclage reduce mid‐trimester pregnancy loss for women who present with symptoms? Can treatment with progesterone reduce mid‐trimester pregnancy loss for women who present with symptoms? Can treatment with cerclage reduce mid‐trimester pregnancy loss for women who present with symptoms? Can non‐surgical management of first/mid‐trimester pregnancy loss or termination of pregnancy reduce future mid‐trimester pregnancy loss when compared with surgical management? What is the optimal management of cervical polyps in pregnancy? How do infections contribute to mid‐trimester pregnancy loss, and how should they be managed? What is the relationship between air pollution exposure and mid‐trimester pregnancy loss? What are the consequences of mid‐trimester pregnancy loss in subsequent pregnancies and on maternal physical and mental health?

Postnatal maternal investigations are carried out to assess maternal well‐being and to aid diagnosis of the cause of MTL. These investigations are similar to those carried out after a stillbirth 101 and should be tailored to the clinical history and examination findings. If the cause of the pregnancy loss is known, for example a short or open cervix, then postnatal investigations should be tailored to this. Investigations are ideally performed at the diagnosis of a mid‐trimester loss (to guide acute management and counseling), with follow‐up testing in the postpartum period if initial workup is inconclusive. Checking the booking FBC report is recommended to exclude severe anemia or hemoglobinopathy. A repeat FBC might be useful if there is excessive bleeding or concerns about maternal infection. 102 A blood group and antibody screen should be performed to exclude hemolytic disease due to maternal sensitization to red cell antigens. A Kleihauer test should be taken to detect feto‐maternal hemorrhage. Other tests to be considered include: Coagulation and plasma fibrinogen if maternal sepsis, placental abruption, or pre‐eclampsia is suspected or diagnosed. Renal and liver function tests might be performed, if abnormalities are suspected, for example, related to severe infection, viral hepatitis, cytomegalovirus, or toxoplasmosis. Maternal serology for TORCH screen and parvovirus B19 might be indicated where fetal infection is suspected. Maternal urine toxicology should be sent if there is any suggestion of recreational drug use. Microbiological tests to be performed if symptoms of infection, to include maternal blood cultures, mid‐stream urine analysis, vaginal/cervical swabs, and placental swabs from the maternal surface. 101 Coagulation and plasma fibrinogen if maternal sepsis, placental abruption, or pre‐eclampsia is suspected or diagnosed. Renal and liver function tests might be performed, if abnormalities are suspected, for example, related to severe infection, viral hepatitis, cytomegalovirus, or toxoplasmosis. Maternal serology for TORCH screen and parvovirus B19 might be indicated where fetal infection is suspected. Maternal urine toxicology should be sent if there is any suggestion of recreational drug use. Microbiological tests to be performed if symptoms of infection, to include maternal blood cultures, mid‐stream urine analysis, vaginal/cervical swabs, and placental swabs from the maternal surface. 101 Where the cause is unknown, and the baby is morphologically normal, investigations for antiphospholipid syndrome (lupus anticoagulant and anticardiolipin antibodies) should be conducted from 6 weeks postnatally. If lupus anticoagulant or anticardiolipin antibodies are positive, they should be repeated after a further 12 weeks. Thyroid function tests (TFTs) (TSH and T4) and thyroid peroxidase antibodies are similarly recommended. There might be a transient thyroiditis following a pregnancy loss, so if TFTs are abnormal just after an MTL, a repeat test is recommended after 2 months. An HbA1c might be useful if risk factors for undiagnosed diabetes are present. Other investigations might be warranted on the basis of the fetal post‐mortem examination (see below). Ultrasound and hysteroscopy can be useful for the assessment of the uterine cavity after MTL. Hysteroscopy is generally used for assessment of the endometrium and uterine cavity, whereas ultrasound, including 3D scanning, can identify congenital uterine anomalies and be used to examine the myometrium and the adnexa. Ultrasound assessment is especially important if there is a suspicion of a uterine anomaly (e.g., with recurrent MTL). The results from a retrospective observational study compared 3D ultrasound to hysteroscopy, and the concordance between the two was very good with a kappa of 0.83. 103 Post‐mortem examination includes a range of procedures, from completely non‐invasive (external examination and imaging), partially or minimally invasive (imaging‐guided autopsy) to full conventional post‐mortem examination. Whether the parents accept a post‐mortem investigation of the baby or not, it is important that histological testing of the placenta, cord, and membranes is offered. Placental swabs should be taken using aseptic technique for aerobic and anaerobic bacterial cultures. In a large cohort of 5000 cases, placental examination gave a cause of death in around 20% of cases. 104 Fetal cytogenetic analysis, most commonly chromosome microarray (CMA), should be offered in all cases of MTL. This might be best performed by sampling placental tissue. If CMA shows an abnormality, then parental testing is recommended. Parents should be given time to consider their options for further testing of their baby. Individual, cultural, and religious beliefs must be respected. The value of post‐mortem in stillbirth is well documented. External examination is a comprehensive external examination of the baby. It might be helpful in diagnosing obvious fetal structural abnormalities, particularly of the body wall, face, hands, or feet. Minimally invasive examination: Comprehensive post‐mortem imaging of the baby can now be used to direct whether an invasive postmortem examination or tissue sampling is needed. 105 Skeletal imaging (e.g., X‐ray) is routinely performed to detect skeletal anomalies, but the yield is low where antenatal imaging is normal and should be reserved for when anomalies are suspected. 106 Cross‐sectional imaging such as comprehensive postmortem ultrasound or magnetic resonance imaging (MRI) can be offered. A diagnostic accuracy of 70%–80% when compared with invasive postmortem can be achieved. 107 , 108 Micro computed tomography and high field MRI can be used but are usually only available in specialist centers. 108 Tissue biopsy can be performed laparoscopically 109 or via the umbilicus 110 if parents do not consent to full autopsy. Post‐mortem examination: Full conventional autopsy examination is the reference standard for maximum diagnostic information following second trimester loss. If endomyocardial fibroelastosis or atrioventricular (AV) node calcification is found post‐mortem, maternal anti‐SSA (anti‐Ro) and anti‐SSB (anti‐La) antibodies should be tested. Maternal alloimmune antiplatelet antibodies should be tested for where fetal intracranial hemorrhage is found or fetal thrombocytopenia detected. Establishing a cause‐and‐effect relationship might be difficult but the use of a careful history to establish the sequence of events and confirm the phenotype of the loss is important. This allows investigations to be tailored to the phenotype. Multidisciplinary team review that includes a pathologist, obstetrician, and neonatologist will offer the best chance of finding a cause. 111 There should be clarity on who is responsible for following up, reviewing and acting upon the tests results. Parents should be made aware that the overall cause of pregnancy loss remains unexplained in up to half of cases. 7 Parents should be advised that a follow‐up appointment with a consultant obstetrician, or another appropriate healthcare provider, will be arranged and results of investigations and implications for care in future pregnancies will be discussed. Appointments should take place away from the maternity setting (Table  9 ). Postnatal investigations and follow‐up. thyroid function tests (TSH and T4) and thyroid peroxidase antibodies. HbA1c External Minimally invasive examination Full autopsy Abbreviation: AV, atrioventricular; FBC, Full blood count; HbA1c, haemaglobin A1c; MTL, midtrimester pregnancy loss, TSH, thyroid stimulating hormone; T4, thyroxine. Quality of evidence has been assessed using the GRADE system throughout. ⊕⊕oo = quality is low, ⊕ooo = quality is very low..

Management in subsequent pregnancies should be individualized and care tailored to the likely cause of MTL. All women should be booked as high‐risk pregnancies and receive consultant‐led care from a consultant with an interest in preterm birth prevention or pregnancy loss. Their first appointment should be arranged for as soon as possible after their first trimester scan, or earlier if early intervention is indicated. A study found that parents with a history of prenatal loss, including MTL, experience increased pregnancy‐related stress and anxiety in subsequent pregnancies. 113 Clinicians should provide the woman and her partner with an opportunity to express their emotional distress and direct them to further psychological support. 113 Acknowledgment of prior experience in subsequent pregnancy care and encouragement to report any concerns are important (Table  11 ). Management of subsequent pregnancies for women who have suffered mid‐trimester pregnancy loss. Abbreviation: MTL, Midtrimester pregnancy loss. Quality of evidence has been assessed using the GRADE system throughout. ⊕ooo = quality is very low.

The authors have no conflicts of interest to report.

The Cochrane Library (including the Cochrane Database of Systematic Reviews), EMBASE, TRIP, Medline, and PubMed (electronic databases) were searched for relevant studies. The date of the last search was August 2025. The databases were searched using the relevant MeSH terms including all subheadings. The search terms included “late abortion”, “late miscarriage”, “mid‐trimester/midtrimester miscarriage” and “second trimester miscarriage”. The search was limited to humans and the English language. The National Library for Health and National Guidelines Clearing House were also searched for relevant guidelines and reviews. The full search strategy is available to view as supporting information. In assessing the quality of evidence and grading of strength of recommendations, the document follows the terminology proposed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group ( www.gradeworkinggroup.org/index.htm ). This system uses consistent language and graphical descriptions for the strength and quality of the recommendations and the evidence on which they are based. The overall quality of evidence was assessed for each of the recommendations and expressed using four levels of quality: very low, low, moderate, and high. Considerations for quality of evidence include primarily the study design and methodology. This utilized the appropriate hierarchy of evidence as relevant to the study type (e.g., diagnostic, intervention/therapy, or prognostic). However, other factors considered in assessing the level of evidence were: risk of bias, study limitations, directness, consistency of results, precision, publication bias, indirectness of evidence, and scarcity of evidence. Each recommendation is denoted with its strength (strong or weak) while considering the balance of desirable and undesirable consequences, quality of evidence, values and preferences, and resource use. Therefore, the quality of evidence is only one possible consideration for the strength of evidence. The decision to apply a possible examination or intervention is also based on potential risk–benefit, cost, and resource allocation. Some recommendations might be based on low‐quality evidence but still represent a benefit that outweighs the risks and burdens and therefore might be strongly recommended. These recommendations are based on published evidence. However, given the limitations in the evidence, a consensus approach was needed to formulate many of the recommendations. The consensus group was multidisciplinary and met both face to face and virtually from 2022. Charity partners included Tommy's and the Miscarriage Association. We also thank our patient experts for their input as well.

It is important to explain to women how they should collect an uncontaminated midstream specimen of urine (MSU). A high vaginal swab (HVS) should be collected if a speculum examination is performed. An LVS should be sent in all cases as this is more sensitive for GBS detection. It is important to put the indication on any microbiology request as the microbiologist might give different advice depending on the clinical situation (at a minimum, it is necessary to specify threatened pregnancy loss and gestation). Ideally, urine and swabs should be collected before giving any antibiotics. If samples are collected after giving antibiotics, there is a chance of a false negative result. In this situation, the timing and type of antibiotic given should be documented on the microbiology request. Testing for sexually transmitted infections is important as most infections are asymptomatic. This might be focused on at‐risk groups (e.g., under 25‐year‐olds) or routine practice depending on local prevalence. Testing, treatment, and follow‐up should follow local guidelines. This might involve allied services such as genitourinary medicine. The sensitivity and specificity of leukocytosis and raised C‐reactive protein in the prediction of chorioamnionitis is poor. Thus, these investigations should be used in conjunction with clinical features when diagnosing chorioamnionitis (Table  3 ). 5 Recommended laboratory tests for women with symptoms of threatened mid‐trimester pregnancy loss. Abbreviation: GBS, group B Streptococcus; MSU, Midstream urine; MTL, midtrimester pregnancy loss; MC&S, mocroscopy, culture and sensitivity; NAAT, nucleic acid amplification test; PPROM, preterm prelabor rupture of membranes; UTI, urinary tract infection. Quality of evidence has been assessed using the GRADE system throughout. ⊕⊕⊕o = quality is moderate, ⊕⊕oo = quality is low, ⊕ooo = quality is very low.. It is recommended that women receive both transabdominal TA and transvaginal ultrasound if possible, as bedside tests (see Section  5 ). A scan to assess fetal viability should be performed as soon as possible and is recommended as part of the initial assessment to guide onward management. Transvaginal cervical length measurement is recommended but it is critical that this is performed and interpreted by someone with adequate training. Transvaginal scans provide more accurate measurement; transabdominal scans might not view or accurately assess the cervix resulting in inappropriate management. Cervical length measurements should follow the ISUOG guidelines. An assessment of liquor volume might be indicated as oligohydramnios is associated with a poorer prognosis, particularly in PPROM. However, a normal liquor volume does not exclude PPROM. A placental location scan should also be performed to assess for the presence of a subchorionic hematoma or low‐lying placenta. This will assist onward care planning, particularly in the case of confirmed MTL. A detailed ultrasound should be performed by fetal medicine specialists if there are concerns regarding fetal anomaly or liquor volume in the absence of PPROM (Table  4 ). Recommended ultrasound investigations for women with symptoms of threatened or confirmed mid‐ trimester loss. Abbreviation: PPROM, Preterm prelabour rupture of membranes. Quality of evidence has been assessed using the GRADE system throughout. ⊕ooo = quality is very low..

Mid‐trimester pregnancy loss (MTL) is generally defined as a pregnancy loss between 14‐ and 24‐weeks' gestation. 1 The terminology and definitions used in the published literature in relation to MTL, however, vary considerably. When referring to any pregnancy loss, the term “abortion” should be avoided as it can cause distress at an already difficult time. Qualitative work into the use of appropriate terminology has shown that parents felt “mid‐trimester pregnancy loss” as opposed to “mid‐trimester miscarriage” or “late miscarriage,” best represented their experience, and therefore is the term recommended for use in this guideline. 2 For consistency, therefore, where previous studies have used the term miscarriage but not defined which trimester this relates to, this is referred to as early pregnancy loss. The true incidence of MTL is difficult to ascertain; however, it is estimated to affect 2%–3% of recognized pregnancies. 3 In published literature, MTL has often been merged with first trimester pregnancy losses, preterm birth (PTB), and preterm pre‐labor rupture of membranes (PPROM). These conditions might represent a continuum with shared underlying etiologies. The distinction between MTL and PTB remains at the gestation thought to represent fetal viability (currently 24 weeks' gestation). It should be noted, however, that with advances in neonatal care management, survival‐focused care can be offered from 22 weeks' gestation depending on available resources, and this is why this guidance uses 21 + 6 as its cut‐off. 4 It is acknowledged that in low‐resource settings, this guideline might be applicable to births up to 28 weeks or babies weighing less than 1 kg. Women with a history of MTL represent a heterogeneous group, demonstrating a wide range of presenting symptoms as well as etiologies. Contributing factors might include cervical insufficiency, infection, thrombophilia, and congenital uterine anomalies. Although an underlying causative factor can be identified in approximately 50% of women with MTL, it remains unknown for a significant proportion of cases. 5 Additionally, there might also be more than one contributing factor toward an MTL. The presence of dual or even triple pathology is thought to dramatically increase the risk of subsequent MTL. When reviewing the evidence for MTL risk factors, we prioritized studies involving unselected cohorts or naturally conceived pregnancies to ensure findings are broadly applicable to the general obstetric population. However, several available studies were derived from in vitro fertilization (IVF) cohorts, and as such might differ in baseline characteristics, such as maternal age, comorbidities as well an underlying infertility diagnosis. Consequently, the generalizability of findings from IVF population studies to spontaneously conceived pregnancies is limited, and we acknowledge that such studies should be interpreted with caution in the context of wider clinical practice. There is heterogenity in the reporting of study outcomes. Where possible, we have reported the adjusted estimates. Advancing maternal age has been associated with an overall increase in the risk of early pregnancy loss. Sporadic early pregnancy loss related to embryo aneuploidy occurs most commonly in the first trimester and is, therefore, not strongly implicated in MTL. Nonetheless, maternal age is still considered a risk factor for MTL. In a large Canadian population‐based study of 1040 miscarriages between 15 and 21 weeks' gestation, wherein fetal chromosomal or structural abnormalities were excluded, maternal age appeared to show a U‐shaped relationship with MTL risk. 3 Using age 27 as the reference (odds ratio [OR] = 1.0), the odds of loss were elevated in both the youngest (≤16 years: OR = 3.0) (95% confidence interval [CI] 0.3–1.6) and oldest (≥44 years: OR = 8.9) (95% CI 1.1–4.9) mothers. Risk declined from the age of 16 to mid‐20s, reaching its lowest point at 27 years, then rose progressively from the late 20s onward, with a marked increase after age 35. The authors concluded that both very young ages as well as advanced maternal age were independent risk factors for MTL. A large retrospective single‐center study, of 15 210 IVF‐conceived pregnancies found that women aged between 35 and 40 years were at a higher risk of late miscarriage, compared to women under 35, with an OR of 1.16 (95% CI 0.87–1.55). Women aged above 40 years had a further increased risk of late miscarriage, compared to women under 35 with an OR of 2.79 (95% CI 1.64–4.77). 6 Importantly, patients who had pre‐implantation genetic testing were excluded, thereby adding to the generalisability of the findings to an unselected or natural conception population. A history of MTL has been associated with an increased risk of recurrence in future pregnancies. The estimated overall recurrence risk of MTL is thought to be 7% based on birth registry data. 7 If there is a known cause detected for the first MTL, several studies have found that a woman's risk of a recurrent MTL can be further stratified depending on the underlying phenotype of the initial MTL, with studies showing rates up to 30%. Danish birth registry data followed 9602 women with either an MTL or extreme preterm birth (16 + 0 to 27 + 6 gestational weeks) in their first pregnancy. The overall recurrence rate was 7.3% (n = 452), a rate that differed by phenotype from <5% (fetal anomaly, multiple gestations, and intrauterine fetal death) to 21% (cervical insufficiency). 7 A similar variation in recurrence risk by phenotype was seen in a single‐center cohort of 1072 IVF patients with an index MTL. Subsequent pregnancy outcomes were compared across four groups defined by the attributed cause of the index MTL: unexplained ( n  = 458), fetal ( n  = 146), cervical ( n  = 412), and trauma related ( n  = 56). Although “cervical” and “trauma related” were not defined in detail, the risk of another MTL in the next pregnancy was higher when the index loss was unexplained (9.4%) or cervical (15.5%) than when it was due to fetal or trauma‐related causes (4.2%): unexplained versus fetal/trauma, adjusted OR 1.9 (95% CI 1.2–2.9), P  = 0.003; cervical versus fetal/trauma, adjusted OR 2.7 (95% CI 1.8–4.0), P  < 0.001. 8 Future risk of MTL might also be influenced by a shortened interpregnancy interval. One retrospective cohort study found that an interpregnancy interval (IPI) of ≤3 months was associated with an increased risk of recurrent MTL. A total of 4290 women who naturally conceived within 2 years following a loss at 14–23 weeks' gestation (miscarriage, termination, or perinatal death) were followed up to determine the risk of MTL in a subsequent pregnancy. The findings showed that following the loss of an index pregnancy of 14–19 weeks' gestation, an IPI of ≤3 months was associated with an increased rate of recurrent MTL compared with an IPI of >9–12 months (adjusted relative risk [aRR] = 2.02, 95% CI 1.44–2.83). This elevated risk was not observed for women who had a spontaneous index loss in the first trimester or between 20 and 23 weeks. 9 There is a paucity of data available on the relationship between ethnicity and overall risk of early pregnancy loss, including specifically the risk of MTL. One large retrospective study undertaken in the UK found that compared to white Europeans, the odds of a spontaneous miscarriage were increased in Black African (adjusted OR [aOR] 1.20; 95% CI 1.12–1.29) and Black Caribbean women (aOR 1.31; 95% CI 1.21–1.41). A previous history of spontaneous miscarriage was associated with preterm birth in all races but was strongest in Black African women (aOR 1.47; 95% CI 1.29–1.67), which led to the authors calling for further study of risk factors, specifically related to ethnicity. 10 A prospective cohort study of 4070 women, conducted in the USA, studied MTL risk according to ethnicity and found that self‐reported race was independently associated with risk of early pregnancy loss, and the higher risk for Black women ( n  = 932) was concentrated in gestational weeks 10–20. 11 Overall, the cumulative risk of pregnancy loss after 5 weeks' gestation was 21.3%. Black women had an increased risk of early pregnancy loss, after adjustment for age and alcohol use, compared to white women (adjusted hazard ratio = 1.57, 95% CI 1.27–1.93). When only pregnancy loss after 10 weeks gestation was considered, there was a further increase in the risk difference for Black women (adjusted hazard ratio = 1.93, 95% CI 1.48–2.51). Smoking has been shown to increase the overall risk of spontaneous pregnancy loss, 16 and a high‐quality meta‐analysis of studies from first trimester data shows that active smoking specifically during the pregnancy in which miscarriage risk was documented increases overall miscarriage risk (summary relative risk ratio = 1.32, 95% CI 1.21, 1.44; n  = 25 studies). The risk of miscarriage increased with the amount smoked (1% increase in relative risk per cigarette smoked per day). 12 Evidence isolating smoking‐related risk for MTL is limited and mixed. In a Danish prospective cohort of 24 608 pregnancies with exposure recorded before outcomes, maternal smoking was not associated with either first‐trimester loss ( n  = 104) or second‐trimester loss ( n  = 217) after adjustment. 13 By contrast, a US case–control study (626 cases, 1300 controls; miscarriage endpoint ≤20 weeks) reported a stronger association for later losses, with moderate active smoking (11–20 cigarettes/day) being linked to MTL (crude OR 1.8; 95% CI 1.1–2.9), attenuating after adjustment (OR 1.5; 95% CI 0.9–2.6; model without environmental tobacco smoke). Environmental tobacco smoke exposure of ≥1 h/day was more strongly related to late than early losses (adjusted OR 1.9 vs 1.3). 14 In relation to MTL, one study using outcomes from a Norwegian birth registry appeared to show that in utero exposure to tobacco smoke associated with a higher risk of MTL. 15 The adjusted hazard ratio of late miscarriage was 1.23 (95% CI 0.72–2.12) in women with in utero exposure to maternal tobacco smoke when compared with non‐exposed women. Heavy alcohol consumption is associated with an increased risk of MTL and early sPTB (spontaneous preterm birth). The threshold of risk is not easily defined but there does appear to be a dose‐dependent relationship. In a dose–response meta‐analysis, the association between alcohol consumption and binge drinking and the risk of pregnancy loss in the first and second trimesters was evaluated. Adjusted data from 458 154 women in the second trimester analysis showed the risk of MTL increased by 3% (OR 1.03, 95% CI 0.99–1.08) for each additional drink per week but not to a statistically significant degree. 16 However, the study that carried the greatest weight within this meta‐analysis found there was an increased risk of MTL for women consuming three or more alcoholic drinks daily, independent of age, parity, race, marital status, smoking, or previous abortions. 17 Life‐table analysis showed that the age‐adjusted relative risks of second‐trimester losses (15–27 weeks) were 1.03 (not significant), 1.98 ( P <  0.01), and 3.53 ( P <  0.01) for women taking less than 1, 1–2, and 3 or more drinks daily, compared with non‐drinkers. 17 Obesity has become a major health problem worldwide and is also associated with adverse pregnancy outcomes. Evidence examining the association between obesity and MTL is limited, as most studies report miscarriage risk across all gestations or focus on preterm birth outcomes. One prospective population‐based cohort study including 3604 women showed that obesity in women was associated with increased odds of miscarriage, independent of fertility treatment. Compared with normal weight in women, being overweight (body mass index [BMI] 25.0–29.9; OR 1.49; 95% CI 1.12–1.98) as well as obesity (≥30.0) (OR 1.44; 95% CI 1.00–2.08) were associated with increased odds of miscarriage. 18 In relation to MTL risk, one study examining risk following an IVF cycle showed that obesity, defined as a BMI of 30 kg/m 2 or above, was associated with a higher risk of MTL, with an OR of 1.80 (95% CI 1.33–2.44), compared to BMI between 18.5 and 25 kg/m 2 . 6 The association between environmental risk factors and MTL is mainly extrapolated from studies that have examined the potential role of environmental exposures in increasing the risk of early pregnancy loss. These studies have generally focused on factors like air pollution, chemicals, and heavy metals. A systematic review including 35 human studies suggested that environmental factors such as air pollution might increase the risk of both spontaneous early pregnancy loss as well as still birth. 19 Extrapolation of these findings could imply that MTL risk might also be elevated. However, these results are limited by several factors such as difficulties in controlling for confounding factors, reporting of data on degree of exposure and measurements of toxin dose. Cervical insufficiency is a well‐established risk factor for MTL. As there is currently no reliable test that can identify women with cervical insufficiency in the non‐pregnant state, the true incidence of cervical insufficiency remains unknown. The diagnosis of cervical insufficiency is based on a history of painless cervical dilation after the first trimester with subsequent expulsion of the pregnancy in the second trimester, typically before 24 weeks of gestation, without contractions or labor and in the absence of other clear pathology (e.g., bleeding, infection, or ruptured membranes). One prospective study aimed to determine the value of a cervical length measurement at 11–14 weeks in predicting the risk of a MTL occurring between 16 and 24 weeks; 11 (0.4%) women miscarried between 16 and 24 weeks, whereas 2825 delivered after 34 weeks. CL was significantly shorter (Mann–Whitney U ‐test, P  = 0.001) in women who had a MTL in comparison to those who delivered after 34 weeks (median CL 28 mm vs 32 mm, respectively). 20 First trimester cervical length was predictive of an MTL (AUC = 0.7838, P <  0.001). Meta‐analysis data have shown that surgical treatment for cervical intraepithelial neoplasia (including loop electrosurgical excision procedure) is associated with a significantly increased risk of pregnancy loss in the second trimester. 21 MTL was assessed in eight studies ( n  = 16 558 women). In this pooled analysis, MTL risk was higher for treated than for untreated women (1.6% and 0.4%, relative risk [RR] 2.60, 95% CI 1.45–4.67). Emerging evidence has also shown an association between MTL and women who had cesarean section in labor, particularly at full dilatation (FDCS), in a previous term birth. Disruption and scarring near or within cervical tissue might result in cervical weakness in future pregnancies. A cohort study compared the outcomes of pregnant women with a preterm birth in their second pregnancy and either a prior FDCS or a prior term vaginal birth for their first. The main outcome for the study was gestational age at birth and birth <30 weeks in the next (third) pregnancy. Sixty‐six women were included in the analysis, of which 29 women had delivered with a previous history of FDCS. The results appeared to show that the women with a prior history of term FDCS had a threefold increased relative risk of recurrent MTL or preterm birth compared with those women with a history of vaginal births (12/29 vs 5/37, P =  0.02, Fisher's exact test, RR 3.06, 95% CI 1.22–7.71). 22 A cohort of 600 patients with a history of dilation and evacuation (D&E) for MTL was followed into subsequent pregnancies. Of 96 pregnancies identified, 77 resulted in term deliveries. The authors concluded that second‐trimester D&E did not increase the risk of MTL or spontaneous preterm birth. 23 There is a considerable body of evidence describing congenital uterine anomalies (CUA) and early pregnancy loss rates; however, only a minority of studies differentiate between first trimester and MTL. It is important to note that owing to improvements in diagnostic methods, the incidence of CUA is showing an apparent increase, due to previously undiagnosed cases now being ascertained. A systematic review with meta‐analysis, published in 2014, has estimated the prevalence of CUA to be 5.5% (95% CI 3.5%–8.5%) in unselected women, 8.0% (95% CI 5.3%–12%) in infertile women, 13.3% (95% CI 8.9%–20.0%) in women with recurrent early pregnancy loss, and 24.5% (95% CI 18.3–32.8) in women with infertility and early pregnancy loss. The risk of sporadic MTL was not significantly increased in women with didelphys (RR 1.71, 95% CI 0.63–4.59; four studies) and unicornuate uteri (RR 2.27, 95% CI 0.64–7.96; four studies) versus normal controls. However, women with septate (RR 2.95, 95% CI 1.51–5.77; five studies) and bicornuate uteri (RR 2.90, 95% CI 1.56–5.41; four studies) had a significantly increased risk of sporadic MTL versus controls. 24 A study from 2023, comparing the reproductive outcomes of women with a unicornuate uterus to women without a CUA, did however seem to indicate an increased risk of MTL. A total of 326 women with a diagnosis of a unicornuate uterus were included and compared with 326 controls. When specifically assessing the risk of MTL between 15 and 22 weeks, there was an increased aOR of 5.19, 95% CI 1.47–18.33. 25 Additionally, within the aforementioned 2014 systematic review, an arcuate uterus was also thought to increase the risk of sporadic MTL (RR 1.98, 95% CI 1.06–3.69; five studies); however, following this, a large prospective study using only gold standard three‐dimensional (3D) ultrasound for diagnosis did not corroborate this finding, with similar pregnancy and live birth rates noted compared to normal controls. 26 Myomas, depending on size and location within the uterus, are thought to have an impact on fertility and reproductive outcomes to varying degrees. Several potential mechanisms by which myomas affect embryo implantation and ongoing pregnancy have been proposed. These mechanisms include chronic endometrial inflammation, abnormal vascularization, increased uterine contractility, and abnormal local endocrine patterns. 27 A study performed within a recurrent early pregnancy loss population found that women with myomas were at a higher risk of a MTL compared with women with unexplained recurrent early pregnancy loss. The risk was greatest in women with submucosal myomas ( n  = 13/60, 21.7%) compared to intramural/subserosal ( n  = 22/125, 17.6%), compared with ( n  = 52/651, 8%) risk in the unexplained recurrent early pregnancy loss group ( P  < 0.01). 28 Further, when women underwent a surgical resection of submucosal myomas, this appeared to significantly reduce MTL risk ( n  = 13/60 (21.7%) to n  = 0/25 (0%); P  < 0.01). The lack of a control group limited the strength of the study, and in fact, the women in the intramural/subserosal group were found to have an equivalent live birth rate to the unexplained group in the subsequent pregnancy. 28 The presence of adenomyosis has also been shown to potentially increase the risk of adverse pregnancy outcomes through various pathogenic mechanisms, including disruption of the uterine junctional zone (JZ) and, thus, of uterine peristalsis; 29 increased intrauterine oxidative stress that might lead to maternal endothelial dysfunction and abnormal placentation, 30 and an increased inflammatory environment that might alter myometrial decidualization, resulting in an abnormal trophoblastic JZ invasion during pregnancy. 31 A Japanese retrospective case–control study compared obstetric complications in 49 singleton pregnancy cases in women with known adenomyosis compared to controls without adenomyosis ( n  = 245). Cases were matched by age, parity, and the need for assisted reproductive technology for conception. Women with adenomyosis were significantly more likely to have an MTL (12.2% vs 1.2%, OR: 11.2, 95% CI 2.2–71.2). 32 Placental insufficiency can impair the transfer of nutrients and oxygen, thereby raising the risk of miscarriage. However, it is important to recognize that certain placental characteristics, such as infarction and calcification, might also occur in uncomplicated pregnancies and are not reliable indicators of poor outcomes. High‐quality prospective cohort evidence of placental factors specific to MTL risk is sparse. One large population‐based prospective study conducted in South Africa followed 7010 singleton pregnancies with 66 late second‐trimester miscarriages (<22 weeks) investigated. When placental histology was available, the most common findings were abruption (either alone or in combination with maternal vascular malperfusion) and acute chorioamnionitis, followed by isolated maternal vascular malperfusion, and less frequently, chronic villitis (including CMV‐associated cases). 33 Some histological findings might reflect sequelae of an underlying condition rather than representing a direct placental factor contributing to miscarriage risk. Placental inflammation might well be the downstream consequence of chorioamnionitis. Histologic chorioamnionitis on placental exam, demonstrated by inflammatory cell infiltrates in the chorion, amnion, villi, or intervillous space, after MTL suggests infection as an underlying cause, even if there were no overt maternal signs. In a case–control study of 90 spontaneous second‐trimester losses and 17 controls, Srinivas et al. (2008) 34 found histologic chorioamnionitis (neutrophil infiltration of the chorion/amnion) in 67% of losses, compared with none of the controls ( P  < 0.001). Importantly, many affected women had no documented clinical diagnosis of chorioamnionitis, indicating that subclinical infection or inflammation could be an under‐recognized contributor to mid‐trimester loss. Both inherited and acquired thrombophilias can cause micro‐ and macro‐thrombosis within the spiral arteries and intervillous space. Maternal vascular malperfusion (MVM) is the predominant placental pathology in stillbirth, particularly in the early third trimester, but potentially if the malperfusion is severe or occurs early enough, might lead to MTL. MVM, which presents as multiple placental infarcts, distal villous hypoplasia, and decidual arteriopathy, has been observed in patients with Factor V Leiden or antiphospholipid syndrome (APS) who have had a MTL. 35 One notable pathology is massive perivillous fibrin deposition (MPFD), characterized by extensive fibrin accumulation around chorionic villi. This disruption of placental function can cause fetal growth restriction and miscarriage, with nearly one‐third of affected pregnancies ending in loss. Notably, the recurrence risk can reach up to 18%. 36 Placental hematomas are associated with adverse pregnancy outcomes. Data regarding the significance of subchorionic hematoma show a variable relationship with pregnancy outcome, but studies demonstrating subchorionic hematoma in the second trimester suggest a stronger relationship with adverse pregnancy outcome than those identified in the third trimester. 37 An Austrian retrospective case–control study compared pregnancy outcomes of 32 women with an intraplacental hematoma (located in the intervillous cavity of the placenta), 199 women with a retroplacental hematoma, and a control group consisting of 113 age‐matched women with no signs of placental abnormalities. The presence of an intraplacental hematoma had a higher associated rate of MTL than retroplacental hematoma ( P  < 0.01). 38 Studies have found that ascending infection from the lower genital tract is implicated in 10%–25% of MTL. 39 Women with a prior history of MTL are thought to be at increased risk of preterm birth and vice versa. The risk of infection‐driven MTL appears to be inversely related to gestational age. In a retrospective study of placental histology of 7705 spontaneous births, the prevalence of histological chorioamnionitis was found to be 94.4% in births occurring between 21 and 24 weeks, compared to 40% in births at 25–28 weeks and 10.7% in births at 33–36 weeks. 40 Chorioamnionitis is a polymicrobial condition. The organisms involved can include anaerobic streptococci, enterococci, coliforms, staphylococci, fusobacterium, mycoplasma, urea plasma, and group B hemolytic streptococci. It is thought that the symptoms of chorioamnionitis are most associated with the ascent of micro‐organisms via the cervix into the uterine cavity. Histological examination of placental tissue in births occurring between 16‐ and 24‐weeks' gestation has shown localized choriodecidual inflammation, generalized chorioamnionitis, intervillositis, and funisitis. 41 The causative micro‐organisms that are implicated with preterm birth appear to also be linked to MTL. One theory is that the deleterious effects caused by these micro‐organisms, if rapidly progressive, might result in MTL, and if more slowly progressive, could lead to a later viable but extremely preterm birth. 42 In healthy women, the normal genital tract flora consists for the most part of Lactobacillus species bacteria. 41 Potentially virulent microbes, such as Gardnerella vaginalis , can displace lactobacilli as the predominant organisms in the vagina, a condition known as bacterial vaginosis (BV). Vaginal dysbiosis (with or without symptoms of BV) has been proposed as a mechanism that can induce local inflammation and invasion by infectious agents, potentially increasing pregnancy loss risk. Although this process has been implicated in early pregnancy loss overall, the data available in relation to MTL is ambiguous. 43 Meta‐analysis data, reviewing all women screened positive for BV either by clinical criteria or by criteria based on gram‐stain findings, were noted to show an increase in the risk of MTL with asymptomatic bacterial vaginosis (OR 6.32, 95% CI 3.65–10.94), as well for preterm birth and maternal infection. 43 A 2013 Cochrane review aimed to assess the effects of antibiotic treatment of BV in pregnancy. The review included 21 trials, totaling 7847 women diagnosed with bacterial vaginosis or intermediate vaginal flora. Antibiotic treatment was found to reduce the risk of MTL (RR 0.20; 95% CI 0.05–0.76; two trials, 1270 women, fixed effect, I 2  = 0%). 44 The largest randomized controlled trial that has been conducted since this review, however, appeared to show that the treatment of BV did not decrease MTL risk. The PREMEVA trial screened 84 530 pregnant women before 14 weeks gestation. Of the 5630 women noted to have BV, 2869 were randomly assigned to receiving a single course of clindamycin, a triple course of clindamycin, or placebo. The primary outcome was a composite of MTL (16–21 weeks) or spontaneous very preterm birth (22–32 weeks), which was assessed in all patients with birth data (modified intention to treat). The primary outcome occurred in 22 (1.2%) of 1904 participants receiving clindamycin and 10 (1.0%) of 956 participants receiving placebo (RR 1.10, 95% CI 0.53–2.32; P =  0.82). 45 Women with a history of MTL (from 16 to 21 weeks + 6 days) or preterm birth (from 22 to 36 weeks + 6 days) were eligible for inclusion into a separate high‐risk subtrial and were randomly assigned (1:1) to either single‐course or triple‐course clindamycin. For these 236 high‐risk pregnancies, the primary outcome occurred in five (4.4%) participants in the triple‐course clindamycin group and 8 (6.0%) participants in the single‐course clindamycin group (RR 0.67, 95% CI 0.23–2.00; P =  0.47). A more recent clinical trial published in 2023, evaluating a screen and treat policy for BV compared to standard practice, also appeared to show no difference in pregnancy loss <22 weeks in the low‐risk population. 46 Pertaining to the impact of BV on MTL loss, as the diagnostic criteria for dysbiosis remain unclear, with the lack of standardized screening and detection methods, it remains unclear whether a screen and treat should be implemented. The relationship of urinary tract infections (UTIs) with MTL is difficult to determine due to limited data. However, it is important to acknowledge that there is data on the association between UTI and PTB, and this might be relevant in the context of MTL. UTIs are classified based on the site of infection: lower urinary tract (urethritis cystitis) or upper urinary tract (pyelonephritis). A number of observational studies have demonstrated the relationship between maternal symptomatic UTI and the risk of sPTB and low birth weight. 47 , 48 Preterm deliveries are significantly higher in mothers with pyelonephritis. However, there is substantial heterogeneity between the studies and possible bias, which makes it difficult to establish the overall contribution of UTIs to preterm birth. 49 GBS bacteriuria is considered a marker for genital tract colonization with GBS, which poses a significant risk of PPROM, sPTB, and early‐onset severe neonatal infection. 50 , 51 Asymptomatic bacteriuria (ASB) is the presence of one or more species of bacteria growing in the urine at specified quantitative counts (≥105 colony‐forming units [CFU]/mL or ≥108 CFU/L), irrespective of the presence of pyuria, in the absence of signs or symptoms attributable to UTIs. It can occur in 2%–10% of pregnancies; 45 however, the effect on perinatal outcomes is unclear. 52 , 53 Available evidence does not demonstrate a direct association between ASB and MTL. Most trials and observational studies on ASB in pregnancy focus on the benefits of early detection and treatment in preventing pyelonephritis, with mixed and low‐certainty evidence for reducing preterm birth and none reporting MTL as a specific outcome. Registry and surveillance data likewise record infection as a broad category in relation to MTL, without specifying ASB. Although ascending infection from the urinary tract is considered a recognized pathway to MTL, there remains no high‐quality, gestation‐specific evidence that ASB alone, when identified and treated, alters MTL risk in unselected obstetric populations. In severe maternal infection, such as with influenza, HIV, dengue fever, and malaria, the maternal immune response might result in MTL instead of a direct placental infection effect. Pathogens such as Plasmodium parasites and Dengue fever's flavivirus have been known to be detected in fetal tissue and placenta. 54 Specifically, regarding viral infections, a case–control study was performed to determine if placental viral infection was associated with spontaneous MTL. 55 Eighty‐four patients with spontaneous MTL (15–23.6 weeks) were included in multivariable model analysis. The study found that the presence of any human papilloma virus was significantly associated with MTL loss (OR = 5.64, CI 1.35, 23.56), as was cytomegalovirus (CMV) (OR = 5.04, CI 1.03–24.45). When histological chorioamnionitis was added to the multivariate model, however, only CMV remained a statistically significant predictor of MTL (OR = 4.62, CI = 1.02–20.89). Parvovirus B19 (B19V) is also able to cross the placenta and result in a fetal infection. This might lead to severe fetal anemia (similar to pregnancies affected by red cell alloimmunization), hydrops fetalis, early pregnancy loss, or intrauterine fetal death. A systematic review and meta‐analysis, exploring the outcomes of 611 fetuses affected by B19V, found that the occurrence of hydrops was associated with a higher risk of pregnancy loss both up to 20 weeks (OR 11.5; 95% CI 2.7–49.7) and after 20 weeks or up to 28 days postpartum (OR 4.2; 95% CI 1.6–11.0). 56 Antiphospholipid syndrome is characterized by the association between adverse pregnancy or vascular thrombosis outcomes and the presence of antiphospholipid antibodies, anticardiolipin antibodies, or anti‐beta‐2‐glycoprotein‐I antibodies. One or more morphologically normal fetal losses after the tenth week of gestation is considered adequate to meet the criteria for an adverse pregnancy outcome in APS. The hypothesis behind APS and pregnancy loss is largely based on the development of a prothrombotic environment. APS‐associated MTL is thought to be related to poor vascularization, leading to impaired placental function, probably secondary to inflammation and thrombosis. Abnormal histologic findings in the spiral arteries have included narrowing, intimal thickening, acute atherosis, and fibrinoid necrosis. 57 Meta‐analysis data, including a total of 25 studies examining APS and recurrent fetal loss, showed that the presence of lupus anticoagulant (OR 7.79, 95% CI 2.30–26.45) and IgM anticardiolipin antibodies (OR 5.61, 95% CI 1.26–25.03) was associated with late recurrent fetal loss. IgG anticardiolipin antibodies, when combining all titers, were associated with both early (OR 3.56, 95% CI 1.48–8.59) and late recurrent fetal loss (OR 3.57, 95% CI 2.26–5.65). 58 Over the past several decades, progress has been made in the identification and understanding of inherited hypercoagulable disorders that promote thrombosis, collectively termed inherited thrombophilia. Meta‐analysis data appears to show that the significance of the association between inherited thrombophilias and fetal loss depends largely on the type of thrombophilia and timing of fetal loss. It is thought that there is a more consistent association between MTL and inherited thrombophilias, with the presumed mechanism being thrombosis of the uteroplacental circulation. Of 31 studies included, Factor V Leiden was associated with early (OR 2.01, 95% CI 1.13–3.58) and late (OR 7.83, 95% CI 2.83–21.67) recurrent fetal loss and late non‐recurrent fetal loss (OR 3.26, 95% 1.82–5.83). Prothrombin G20210A mutation was associated with early recurrent (OR 2.56, 1.04–6.29) and late non‐recurrent (OR 2.30, 95% CI 1.09–4.87) fetal loss. Protein S deficiency was associated with recurrent fetal loss (OR 14.72, 95% CI 0.99–218.01) and late non‐recurrent fetal loss (OR 7.39, 95% CI 1.28–42.63). 59 A literature review of causes of stillbirth found that the chromosomal causes for pregnancy loss reduced from approximately 50% in the first trimester to approximately 5%–15% in the third trimester; an inference can be made that the rate of second trimester chromosomal cause is likely to be between these ranges. 60 One study estimated a 25% chance of a chromosomal cause in MTL, which included aneuploidy (trisomy and monosomy) and polyploidy (triploidy and tetraploidy). 61 Clinical overviews based on cytogenic cohorts have shown that trisomies 13/18/21 and monsomy X are the most common abnormalities observed. 62 Systemic maternal endocrine disorders such as diabetes mellitus and thyroid disease have been associated with early pregnancy loss. Studies have shown that overt hypothyroidism is associated with a substantial risk of early pregnancy loss. 63 There is controversy as to whether subclinical hypothyroidism (SCH) has the same effect. In an Irish prevalence study from a single pregnancy loss clinic, reviewing results from 262 women, undiagnosed overt or subclinical hypothyroidism was found more often in women with MTL compared with those with recurrent early pregnancy loss (14.6% vs 7.1%). 64 A systematic review and meta‐analysis sought to evaluate the relationship between SCH and the risk of early pregnancy loss before 20 weeks of pregnancy. The American Thyroid Association recommended criteria of TSH >2.5 mIU/L in early pregnancy for defining SCH was used in five studies ( n  = 25 158 women); compared with euthyroid pregnant women ( n  = 22 528), patients with non‐treated SCH ( n  = 2630) had a higher prevalence of early pregnancy loss (RR = 2.07, 95% CI 1.70–2.53, P  < 0.01). 65 Polycystic ovary syndrome (PCOS) has been linked to an overall increased risk of early pregnancy loss, but the exact mechanism remains unclear. 66 A retrospective cohort study conducted in China, including 15 210 pregnancies following IVF treatment, noted that PCOS was found to be an independent risk factor for MTL (aOR 1.58, 95% CI 1.28–1.96). The odds ratio was adjusted for the type and duration of infertility, previous spontaneous pregnancy loss (gestation not specified), and stage of the embryo. 6 A post‐hoc analysis was conducted on three prospective, double‐blind studies involving 791 pregnant women with PCOS, who were randomized to receive either metformin or placebo from the first trimester until delivery. Women diagnosed with gestational diabetes (GDM) at baseline in the first trimester had a statistically significantly higher risk of late miscarriage compared to those without (GDM) ( P  < 0.01). 67 Although there appears to be an association between sperm DNA fragmentation and overall risk of early pregnancy loss, there is currently a lack of available evidence in relation to male factors contributing specifically to mid‐trimester loss. 68 The long‐term consequences following MTL are yet to be well studied. It is important to note that studies from women with recurrent pregnancy losses have demonstrated an increased risk of maternal cardiovascular risk and venous thrombosis. 69 There is a strong association with psychological conditions including anxiety, depression, and suicide with pregnancy loss. A multicenter, prospective cohort study of 537 women following a first trimester pregnancy loss found that 9 months after the loss, 18% of women met the criteria for post‐traumatic stress (PTS), 17% for moderate of severe anxiety, and 6% for moderate or severe depression. 70 A systematic review and meta‐analysis of PTS and PTS disorder reported that losses at progressively later gestational ages were associated with higher levels of PTS/PTSD. 71

Table S1.