Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/050, May 2022)

Abstract

Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols.

Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out.

Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM).

Key words

guideline - recurrent miscarriage - recurrent pregnancy loss - incidence - diagnosis - therapy

I  Guideline Information

Guidelines program of the DGGG, OEGGG and SGGG

For information on the guidelines program, please refer to the end of this guideline.

Citation format

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures (Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/050, May 2022). Geburtsh Frauenheilk 2022. doi:10.1055/a-1895-9940

Guideline documents

The complete long version of this guideline in German, a slideshow version of this guideline, and a list of the conflicts of interest of all of the authors are available on the homepage of the AWMF: http://www.awmf.org/leitlinien/detail/ll/015-050.html

Guideline authors

See [Tables 1] and [2].

Tab. 1 Lead author and/or coordinating guideline author.

Author	AWMF professional society
Prof. Dr. B. Toth	German Society of Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V.] (DGGG) Austrian Society of Gynecology and Obstetrics [Österreichische Gesellschaft für Gynäkologie und Geburtshilfe] (ÖGGG) German Society of Gynecological Endocrinology and Reproductive Medicine [Deutsche Gesellschaft für Gynäkologische Endokrinologie und Fortpflanzungsmedizin] (DGGEF)

Tab. 2 Contributing guideline authors.

Author Mandate holder	DGGG working group/ AWMF/non-AWMF professional society/ organization/association
Prof. Dr. M. Bohlmann	Immunology Working Group in the DGGG [Arbeitsgemeinschaft Immunologie in der DGGG] (AGIM)
Prof. Dr. K. Hancke	German Society for Reproductive Medicine [Deutsche Gesellschaft für Reproduktionsmedizin] (DGRM)
Prof. Dr. Ruben Kuon	Expert
Prof. Dr. F. Nawroth	Expert
PD Dr. S. von Otte	Professional Association of Gynecologists [Berufsverband der Frauenärzte] (BVF)
Prof. Dr. N. Rogenhofer	Immunology Working Group in the DGGG (AGIM)
Prof. Dr. S. Rudnik-Schöneborn	German Society of Human Genetics [Deutsche Gesellschaft für Humangenetik e. V.] (GfH) Austrian Society of Human Genetics [Österreichische Gesellschaft für Humangenetik] (ÖGH)
Prof. Dr. E. Schleußner	German Society of Ultrasound in Medicine [Deutsche Gesellschaft für Ultraschall in der Medizin e. V.] (DEGUM)
Prof. Dr. C. Tempfer	German Society of Gynecology and Obstetrics (DGGG)
Dr. Dr. Kilian Vomstein	Expert
Prof. Dr. T. Wischmann	German Society for Fertility Counseling [Deutsche Gesellschaft für Kinderwunschberatung] (BKiD)
Prof. Dr. M. von Wolff	Swiss Society of Gynecology and Obstetrics [Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe] (SGGG)
Prof. Dr. W. Würfel	German Society of Gynecology and Obstetrics (DGGG) German Society of Gynecological Endocrinology and Reproductive Medicine (DGGEF)
Prof. Dr. J. Zschocke	German Society of Human Genetics (GfH) Austrian Society of Human Genetics (ÖHG)

The following professional societies/working groups/organizations/associations have stated their interest in contributing to the compilation of the guideline text and participating in the consensus conference and have nominated representatives to attend ([Table 2]).

The guideline was moderated by PD Dr. Helmut Sitter (AWMF-certified guideline advisor/moderator).

Abbreviations

APL: antiphospholipid

APLS: antiphospholipid syndrome

ASRM: American Society for Reproductive Medicine

ASA: acetylsalicylic acid

BMI: body mass index

BV: bacterial vaginosis

DEGUM: German Society of Ultrasound in Medicine [Deutsche Gesellschaft für Ultraschall in der Medizin]

ESHRE: European Society of Human Reproduction

FVL: factor V Leiden

G-CSF: granulocyte colony-stimulating factor

GW: week(s) of gestation

HLA: human leukocyte antigen

HSC: hysteroscopy

IVF: in-vitro fertilization

LBR: live birthrate

LMWH: low molecular weight heparin

PBD: polar body diagnosis

PCOS: polycystic ovary syndrome

PGT: preimplantation genetic testing

PGT-SR: preimplantation genetic testing for structural chromosomal rearrangements

pNK cells: peripheral natural killer cells

PT: prothrombin

RCOG: Royal College of Obstetricians and Gynaecologists

RM: recurrent miscarriage

TPO Ab: thyreoperoxidase antibodies

TSH: thyroid-stimulating hormone

uNK cells: uterine natural killer cells

VEGF: vascular endothelial growth factor

WHO: World Health Organization
 

II  Guideline Application

Purpose and objectives

The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols.

Targeted areas of patient care

• Inpatient care

• Outpatient care

Target user group/target audience

The recommendations of the guideline are aimed at gynecologists, geneticists and specialists for psychosocial counselling of persons wanting to have children who are involuntarily childless.

Other targeted readers (for information) include:

• Colleagues specializing in hemostaseology, laboratory medicine, internal medicine and general medicine

• Nursing staff

• Family members

Adoption and period of validity

The validity of this guideline was confirmed by the board members/representatives of the participating medical professional societies, working groups, organizations and associations as well as by the executive board of the DGGG, SGGG, OEGGG and the DGGG/OEGGG/SGGG guidelines commission in January 2022 and therefore approved in its entirety. This guideline is valid from 1 May 2022 through to 1 May 2025. Because of the contents of this guideline, this period of validity is only an estimate. The guideline can be reviewed and updated if urgently required; if the guideline still reflects the current state of knowledge, its period of validity can be extended.

III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches.

This guideline has been classified as: S2k

Grading of recommendations

The grading of evidence based on the systematic search, selection, evaluation and synthesis of an evidence base which is then used to grade the recommendations is not envisaged for S2k guidelines. The different individual statements and recommendations are only differentiated linguistically, not by the use of symbols ([Table 3]).

Tab. 3 Grading of recommendations (based on Lomotan et al., Qual Saf Health Care 2010).

Description of binding character	Expression
Strong recommendation with highly binding character	must/must not
Regular recommendation with moderately binding character	should/should not
Open recommendation with limited binding character	may/may not

Statements

Expositions or explanations of specific facts, circumstances or problems without any direct recommendations for action included in this guideline are referred to as “statements”. It is not possible to provide any information about the grading of evidence for these statements.

Achieving consensus and level of consensus

At structured NIH-type consensus-based conferences (S2k/S3 level), authorised participants attending the session vote on draft statements and recommendations. The process is as follows. A recommendation is presented, its contents are discussed, proposed changes are put forward, and all proposed changes are voted on. If a consensus (> 75% of votes) is not achieved, there is another round of discussions, followed by a repeat vote. Finally, the extent of consensus is determined, based on the number of participants ([Table 4]).

Tab. 4 Level of consensus based on extent of agreement.

Symbols	Level of consensus	Extent of agreement in percent
+++	Strong consensus	> 95% of participants agree
++	Consensus	> 75 – 95% of participants agree
+	Majority agreement	> 50 – 75% of participants agree
–	No consensus	< 51% of participants agree

When this guideline was compiled, special consideration was given to previous recommendations (first compilation of the guideline in 2006, revisions in 2008, 2013 und 2017), the recommendations of the European Society of Human Reproduction (ESHRE) and Embryology [1], the Royal College of Obstetricians and Gynaecologists [2], the American College of Obstetricians and Gynecologists (ACOG 2002) [3] and the American Society for Reproductive Medicine (ASRM 2012) [4].

Expert consensus

As the term already indicates, this refers to consensus decisions taken specifically with regard to recommendations/statements issued without a prior systematic search of the literature (S2k) or where evidence is lacking (S2e/S3). The term “expert consensus” (EC) used here is synonymous with terms used in other guidelines such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength of the recommendation is graded as previously described in the chapter on the grading of recommendations; it is only expressed semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”) without the use of symbols.

IV  Guideline

1  Introduction

The psychological strain on couples with recurrent miscarriage (RM) is high and this often leads to demands for detailed diagnostic and treatment strategy after a single miscarriage. Therapeutic approaches can also differ greatly because of the lack of relevant studies and the resultant lack of evidence-based therapeutic recommendations.

2  Incidence and Definition

Approximately 1 – 3% of all couples of reproductive age experience recurrent miscarriage, which constitutes a significant problem for their partnership and quality of life [5]. A miscarriage is defined as the loss of a fetus at any time from conception to the 24th week of gestation (GW) or the loss of a fetus weighing < 500 g [6]. The World Health Organization (WHO) definition of recurrent miscarriage is “three and more consecutive miscarriages before the 20th GW” [6]. The American Society of Reproductive Medicine (ASRM) already defines the occurrence of two miscarriages as RM [4], [7]. This definition increases the incidence of RM to 5% of all couples of reproductive age [8].

Because of the higher maternal age at first pregnancy, there is an increasing tendency to already carry out detailed diagnostic examinations in patients who have had two miscarriages.

This approach may already be justified after two clinical pregnancies, as proposed in the guideline of the ASRM and further emphasized in a recent meta-analysis [9]. The definition of RM on which this guideline is based corresponds to the definition of the WHO which defines three or more consecutive miscarriages as recurrent miscarriage [6].

When assessing whether a detailed diagnostic workup is called for already after two miscarriages, the medical history of the miscarriage and the overall medical reproductive situation of the affected couples play an important role. Investigations should include all relevant causes for the abortion but should also be therapeutically relevant and cost-effective.

The probability of having a subsequent pregnancy with a live birth after a previous miscarriage varies considerably and depends on a number of different factors. In addition to maternal age, the number of previous miscarriages also affects the likelihood of recurrence. [Table 5] presents data from a Danish registry study [10].

Tab. 5 Probability of a live birth depending on maternal age and the number of previous miscarriages (based on Kolte et al. [10]).

Previous miscarriage(s)	Probability of a live birth
	25 – 29 years	30 – 34 years	35 – 39 years	40 – 44 years
1 miscarriage	~ 85%	~ 80%	~ 70%	~ 52%
2 miscarriages	~ 80%	~ 78%	~ 62%	~ 45%
3 miscarriages	~ 75%	~ 70%	~ 55%	~ 32%
≥ 4 miscarriages	< 65%	< 60%	< 45%	> 25%

Consensus-based recommendation 2.E1
Expert consensus	Level of consensus +++
The risk factors listed in this guideline must be investigated after three consecutive miscarriages.

Consensus-based recommendation 2.E2
Expert consensus	Level of consensus +++
In justified cases, possible risk factors for RM should already be investigated after two consecutive miscarriages.

3  Diagnosis and Treatment of Relevant Risk Factors

3.1  Lifestyle and behavior

A number of different circumstances and individual lifestyle behaviors have been discussed in the literature as possible causative factors for miscarriage. Proposed factors include stress, overweight and underweight, physical activity, caffeine, nicotine and alcohol consumption, as well as other factors [11].

3.1.1  Stress

Numerous studies have shown that infertility and also RM are associated with depression and anxiety in affected women. But it is still unclear whether these symptoms or whether psychological stress can also cause RM (overview in [12]). A critical issue with regard to the majority of existing studies is that retrospectively collected information reported by women with RM about their stress levels prior to a miscarriage may be predisposed to lapses of memory (recall bias).

Consensus-based statement 3-1.S1
Expert consensus	Level of consensus +++
Stress and traumatic experiences during pregnancy may result in a miscarriage, although it is currently not clear whether this is caused by the stressful event itself or the concomitant injurious behavior.

3.1.2  Coffee consumption

A recent meta-analysis compared 4 observational studies on the effects of drinking coffee on RM [11]. The meta-analysis found that caffeine consumption was not associated with a verifiable dose-dependent higher risk of RM (OR 1.35, 95% CI: 0.83 – 2.19).

International guidelines recommend reducing coffee consumption to less than 3 cups per day [13].

Consensus-based statement 3-1.S2
Expert consensus	Level of consensus +++
Recent studies found no correlation between coffee consumption and the probability of miscarriage.

3.1.3  Nicotine consumption

Nicotine consumption is associated with poor obstetric and neonatal outcomes such as ectopic pregnancy, stillbirth, placenta previa, preterm birth, low birthweight, and congenital malformations. The recommendation to all pregnant persons must be to entirely abstain from consuming nicotine during pregnancy [14].

Consensus-based statement 3-1.S3
Expert consensus	Level of consensus +++
In cases with RM, the affected couple must be advised to abstain from nicotine already prior to conception.

3.1.4  Alcohol consumption

After a woman knows she is pregnant, she must not consume alcohol because of the high risk of harmful effects to the embryo and the risk of fetal alcohol syndrome or fetal alcohol spectrum disorder (FASD), which has a prevalence of 0.2 – 8.2 per 1000 livebirths. For more information, please refer to the S3 guideline “Diagnosis of Fetal Alcohol Spectrum Disorders, FASD” (https://www.awmf.org/leitlinien/detail/ll/022-025.html).

Consensus-based recommendation 3-1.E3
Expert consensus	Level of consensus +++
Couples with RM must be informed that consuming alcohol during pregnancy may be associated with severe fetal developmental disorders. Pregnant women must abstain from consuming any alcohol.

3.1.5  Vitamin D deficiency

Recent studies have shown a possible association between vitamin D deficiency and autoimmune or alloimmune disorders in women with RM. However, because the data on this are limited, it is not possible to give any general recommendations about the administration of vitamin D as prophylaxis against miscarriage in cases with RM. The determination of vitamin D levels prior to conception is recommended for high-risk cohorts.

3.1.6  Body mass index

Numerous studies have found an association between higher BMI and an increased risk of miscarriage. In addition to a higher BMI, a low BMI also appears to have a negative impact on the miscarriage rate. In a meta-analysis of 32 studies (n = 265 760), the miscarriage rate was higher – compared with that of normal-weight women (BMI 18.5 – 24.9 kg/m²) – in cases with a higher BMI (BMI 25 – 29.9 kg/m², RR 1.09, 95% CI: 1.04 – 1.13; p < 0.0001; BMI ≥ 30 kg/m², RR 1.21, 95% CI: 1.15 – 1.27; p < 0.00 001) or a low BMI (BMI < 18.5 kg/m², RR 1.08, 95% CI: 1.05 – 1.11; p < 0.0001) [15].

The results of studies on the impact of weight loss on the livebirth rate or miscarriage rate have been inconsistent; therefore, based on existing investigations, it is still unclear whether losing weight will reduce the risk of miscarriage [16], [17]. For further information, please refer to the AWMF guideline 015/081 “Obesity and Pregnancy”.

Consensus-based recommendation 3-1.E4
Expert consensus	Level of consensus +++
Women with RM who are underweight or overweight/obese must strive to normalize their weight.

Consensus-based recommendation 3-1.E5
Expert consensus	Level of consensus +++
Affected women should be advised about suitable measures to reduce their BMI if they have a BMI ≥ 25 kg/m2 or about measures to increase their BMI if they have a BMI < 18.5 kg/m2.

3.2  Genetic factors

3.2.1  Chromosomal disorders

Embryonic/fetal chromosomal anomalies are the most common cause of spontaneous miscarriages. The earlier the miscarriage occurs, the more probable it is that an embryonal/fetal chromosomal disorder is present. Chromosomal anomalies are found in around 50% of miscarriages occurring in the first trimester of pregnancy, while the rate for the second trimester is only around 30% [18]. According to the data from a systematic review [19], the prevalence of chromosomal anomalies in spontaneous miscarriages is 50%; this prevalence decreases slightly to 40% in women who have had at least three previous miscarriages. The risk of embryonic/fetal trisomy caused by chromosomal anomalies increases with higher maternal age. Trisomy 16 is the most common cause of miscarriage, followed by trisomy 22. Polyploidy is present in around 15 – 20% of cytogenetically abnormal miscarriages. Monosomy X is responsible for around 10 – 20% of miscarriages in the first trimester of pregnancy. No correlation with maternal age has been detected for monosomy X, polyploidy or structural chromosomal anomalies. Structural chromosomal aberrations are found in 5 – 10% of miscarriages and are an indication that the parents should be investigated for balanced chromosomal rearrangements. In couples with two or more miscarriages, balanced chromosomal aberration is detected in one of the partners in around 4 – 5% of cases [20].

If a balanced chromosomal aberration is confirmed in one of the partners, the risk of miscarriage or of giving birth to an infant with chromosomal aberration is higher, depending on the chromosomes involved. This has consequences for the provision of prenatal diagnostic services in later pregnancies (see 3.2.5).

Consensus-based recommendation 3-2.E6
Expert consensus	Level of consensus +++
Couples with RM must undergo cytogenetic analysis. This may be carried out using conventional chromosomal investigations in both partners prior to conception or by using the tissue of the miscarried fetus (molecular cytogenetic analysis).

Consensus-based recommendation 3-2.E7
Expert consensus	Level of consensus +++
If a structural chromosomal abnormality is confirmed in the tissue of the miscarried fetus, both partners must undergo cytogenetic examination.

Consensus-based statement 3-2.S4
Expert consensus	Level of consensus +++
The result must be communicated during genetic counselling by a specialist for human genetics or a physician with the relevant qualifications in accordance with statutory national regulations.

Consensus-based statement 3-2.S5
Expert consensus	Level of consensus +++
If a balanced chromosomal aberration is confirmed in one of the partners, the risk of miscarriage or of giving birth to an infant with chromosomal aberration is higher, depending on the chromosomes involved. This has consequences for the provision of prenatal diagnostic workups in later pregnancies and for polar body or preimplantation diagnostics.

3.2.2  Monogenic disorders

X-linked dominant disorders which are lethal for males have a higher risk of miscarriage. But autosomal dominant and recessive disorders with severe malformations may also result in increased intrauterine mortality. In such cases, genetic testing with pathological examination of the fetus should be carried out, particularly if the disorder was not identified prenatally.

Consensus-based recommendation 3-2.E8
Expert consensus	Level of consensus +++
If there is evidence that the miscarriage was caused by a monogenic disorder, genetic counselling must include genetic testing.

3.2.3  Results of association studies

Numerous studies have pointed to possible maternal, paternal or fetal genetic factors which have only a limited impact on the risk of miscarriage. A meta-analysis of the impact of paternal age showed a slight increase in the risk of miscarriage (OR 1.04 – 1.43) with increasing paternal age [21]. A meta-analysis was carried out of 428 case-control studies (from 1990 to 2015) which investigated 472 genetic variants in 187 genes in women with three and more miscarriages [22]. Without exception, the relative increase in risk caused by genetic variants was low (OR 0.5 – 2.3). Uniform study conditions and larger cohorts will be needed in future, and analysis should include genome-wide association studies of both partners and of the tissue from the miscarried fetus.

Consensus-based recommendation 3-2.E9
Expert consensus	Level of consensus +++
Molecular genetic analysis of gene variants which were previously detected in the context of association studies must not be carried out in couples with RM.

3.2.4  Prenatal diagnostic options

It is not possible to treat the causes of chromosomal aberrations. If a chromosomal aberration is confirmed in one of the parents, prenatal chromosomal analysis after chorionic villous sampling or amniocentesis is usually offered in subsequent (spontaneously occurring) pregnancies. According to the DEGUM recommendations, the associated risk of miscarriage is generally considered to be between 0.5% and 1% [23]. In facilities with extensive experience, consistent ultrasound support during chorionic villous sampling or amniocentesis, which takes maternal risk factors into account, can probably reduce the risk of miscarriage to 0.2% or 1 in 500 [24], [25].

3.2.5  Preimplantation diagnosis

In couples with confirmed balanced chromosomal rearrangement, it is possible to prevent miscarriage by selecting cytogenetically normal gametes or embryos after preimplantation diagnosis (PGT, preimplantation genetic testing). In cases with maternal chromosomal aberrations, polar body diagnosis (PBD) may be carried out in specialized centers. This does not take account of the male set of chromosomes. PBD and PGT are permitted in Germany, Austria and Switzerland in specific, legally regulated, circumstances.

Numerous studies have found no improvement in the livebirth rate (LBR) of women with RM after in-vitro fertilization (IVF) with PGT-SR (compared to spontaneous pregnancies), not even in couples where one partner has a balanced chromosomal aberration. A systematic review (n = 20 studies) also found no improvements in the LBR after PGT-SR [26]. But couples who become pregnant spontaneously have a significantly higher miscarriage rate compared to couples who become pregnant after PGT-SR. The few studies which directly compared spontaneous pregnancies with IVF and PGT-SR pregnancies reported a long period until the couple had a livebirth after PGT-SR [26]. The LBR for both groups was comparable, while the rate of miscarriages was around 20 – 40% higher with spontaneous pregnancies [27], [28]. The authors of the review concluded that PGT-SR offers no benefits compared to spontaneous conception in couples with RM caused by balanced chromosomal rearrangement [26]. Neither the ESHRE and RCOG guidelines nor the ASRM statements currently recommend PGT in couples with RM.

Consensus-based recommendation 3-2.E10
Expert consensus	Level of consensus +++
Preimplantation genetic testing may be offered to couples with RM and confirmed familial chromosomal disorders to reduce the miscarriage rate, even though currently it was not found to improve the rate of livebirths.

3.3  Anatomical factors

3.3.1  Diagnosis of anatomical factors

Hysteroscopic examinations (HSC) of patients with 2, 3 and ≥ 4 consecutive miscarriages found no difference in the prevalence of congenital (uterine malformation) or acquired (adhesions, polyp, submucosal fibroids) intrauterine pathologies [29].

3.3.2  Congenital malformations

The reported incidence in the literature of uterine anomalies in cases with RM ranges between 10% and 25% (compared to 5% for controls) [30] and between 3% and 7% for controls [31]. Women with subseptate uterus have a 2.6 times higher risk of early miscarriage (RR 2.65, 95% CI: 1.39 – 5.06) [32]. Arcuate uterus is considered a normal variant and has no clinical importance [33]. Women with bicornuate uterus have a higher risk of early (RR 2.32, 95% CI: 1.05 – 5.13) and late miscarriage (RR 2.90, 95% CI: 1.56 – 5.41) [34].

3.3.3  Acquired malformations

Intrauterine adhesions

Two reviews reported on intrauterine adhesions after miscarriage detected by HSC in 19% (95% CI: 12.8 – 27.5%) [35] and 22% (95% CI: 18.3 – 27%) [36] of patients, respectively.

The risk of adhesions rises with the number of miscarriages and appears to be associated with the frequency of curettage performed for miscarriage [35]. To prevent adhesion formation, it is important to carefully weigh up the necessity of carrying out curettage.

Fibroids

An evaluation of retrospective and prospective data of patients with RM found an incidence of submucosal fibroids of 2.6% (25/966) for fibroids [37]. A meta-analysis of 19 observational studies (4 prospective and 15 retrospective studies) showed that intramural fibroids without submucosal involvement are not associated with significantly higher rates of miscarriage (relative risk [RR] 1.24; 95% CI: 0.99 – 1.57). A subsequent successful pregnancy without surgical intervention was reported for 70.3% of women without cavity-distorting fibroids [37].

Polyps

It is not clear to what extent polyps as intracavitary pathologies also affect the risk of miscarriage analogous to submucosal fibroids. The presence of diffuse micropolyps (polyps < 1 mm) is common in cases with chronic endometritis [38].

Consensus-based recommendation 3-3.E11
Expert consensus	Level of consensus +++
3D-transvaginal sonography and/or hysteroscopy must be carried out in women with RM to exclude uterine malformation, submucosal fibroids and polyps. Hysteroscopy must be carried out to exclude intrauterine adhesions.

3.3.4  Treatment of anatomical factors

3.3.4.1  Congenital malformations

Surgical intervention is not indicated for arcuate uterus, bicornuate uterus or uterus didelphys [31], [39], [40].

A retrospective European cohort study of 257 women with septate uterus and a prior history of subfertility, miscarriage or preterm birth compared resection of the uterine septum in 151 women with expectant management in 106 women over a median of 46 months and found no difference in the rate of miscarriage (46.8% vs. 34.4%; OR 1.58 [0.81 – 3.09]) or LBR (53.0% vs. 71.7%; HR 0.71, 95% CI: 0.49 – 1.02) [41]. The first randomized controlled study was published in April 2021 and included 80 women with uterine septum who were randomized either to hysteroscopic septum resection (n = 40 initially, n = 36 at the end of the study) or expectant management (n = 40 initially, n = 33 at the end of the study) [42]. The LBR in both groups was the same, and the authors therefore no longer recommend hysteroscopic septum resection to improve the LBR. However, when interpreting the data, it is important to take into account that the multicenter study (originally planned as a single-center study) was only able to include a small study cohort over a very long period of time (2010 – 2018). Moreover, different diagnostic methods were used. In addition, the inclusion criteria changed over the long course of the study, so that a relevant percentage of patients with subfertility or who were status post preterm birth were included in the evaluation.

Patients with RM and confirmed uterine septum must therefore be informed that the evidence is still not clear and should ideally be enrolled in a randomized study.

Consensus-based recommendation 3-3.E12
Expert consensus	Level of consensus ++
Women with RM and uterine septum must be informed following a benefit-risk analysis about the option of expectant management versus hysteroscopic septum resection.

3.3.4.2  Acquired malformations

Whether intrauterine adhesions generally affect the risk of miscarriage, how extensive such adhesions are and whether adhesiolysis reduces the risk is not clear. The treatment of choice for intrauterine adhesions is hysteroscopic adhesiolysis [43]. Some retrospective studies appear to have better reproductive outcomes after surgical HSC [44], [45]. Controlled randomized studies are lacking.

Consensus-based recommendation 3-3.E13
Expert consensus	Level of consensus +++
Hysteroscopic adhesiolysis may be offered to women with RM and intrauterine adhesions for miscarriage prophylaxis.

A recent Cochrane analysis found no significant reduction in the risk of miscarriage after fibroid enucleation (intramural: OR 1.33, 95% CI: 0.26 – 6.78, submucosal: OR 1.27, 95% CI: 0.27 – 5.97), although the quality of the investigated studies was poor [46]. Whether fibroid enucleation is indicated in women with RM depends on the clinical picture (hypermenorrhea, size and length of the fibroids).

Consensus-based recommendation 3-3.E14
Expert consensus	Level of consensus +++
Women with RM and submucosal fibroids may be offered surgical resection for miscarriage prophylaxis.

There are no randomized studies on the effect of HSC in women with endometrial polyps or intrauterine synechiae [47]. A meta-analysis showed that hysteroscopic resection of intrauterine polyps visible on ultrasound carried out prior to intrauterine insemination can increase the clinical pregnancy rate [48].

Consensus-based recommendation 3-3.E15
Expert consensus	Level of consensus +++
Women with RM and persistent polyps may be offered hysteroscopic resection for miscarriage prophylaxis.

3.4  Microbiological factors

3.4.1  Diagnosis of microbiological factors

As the association between infections and RM is not clear, general screening for vaginal infections outside the usual tests carried out as part of prenatal care is not recommended.

Consensus-based recommendation 3-4.E16
Expert consensus	Level of consensus +++
Infection screening using vaginal swab specimens must not be carried out in asymptomatic women with RM.

3.4.1.1  Chronic endometritis

Chronic endometritis confirmed by plasma cells in the biopsied endometrial specimen is present in 7% to 67% of otherwise asymptomatic women with RM and 30% to 66% of women with repeated implantation failure [49], [50], [51], [52], [53]. A recent meta-analysis of 12 studies estimated the prevalence of chronic endometritis in women with RM to be 29.67% (95% CI: 20.81 – 38.53; p > 0.0001) [54]. The cure rate after first-line antibiotic therapy is around 90% [54]. Repeat biopsy in a subsequent cycle for therapy control may therefore be discussed with the patient.

Consensus-based recommendation 3-4.E17
Expert consensus	Level of consensus +++
Endometrial biopsy to exclude chronic endometritis (based on immunohistochemical staining for the plasma cell-specific antigen CD138) may be carried out in women with RM.

Consensus-based recommendation 3-4.E18
Expert consensus	Level of consensus +++
Repeat biopsy may be carried out to diagnose chronic endometritis which persists even after antibiotic treatment.

3.4.1.2  Microbiome diagnostic testing

An abnormal vaginal microbiome or bacterial vaginosis (BV) leads to a significantly decreased pregnancy rate with IVF (prospective multicenter study [55]). If Lactobacillus species are not the dominant bacterial species on the endometrium, the probability of implantation after embryo transfer is significantly lower and the probability of miscarriage increases (prospective case-controlled study of vaginal and/or endometrial microbiome [56]) [57]. A recent prospective multicenter observational study of the endometrial microbiome came to a similar conclusion [58]. If Lactobacillus dominance, which was previously non-existent, is restored with the help of antibiotics/application of Lactobacilli, no differences in pregnancy rates were found (prospective case-controlled study [59]).

Consensus-based recommendation 3-4.E19
Expert consensus	Level of consensus +++
Examination of the vaginal or endometrial microbiome must not be carried out in women with RM outside clinical studies.

3.4.2  Treatment of microbiological factors

Antibiotic therapy with doxycycline (e.g., 200 mg 1 – 0 – 0 for 14 days) may be administered prior to pregnancy in cases with chronic endometritis and cases with persistent endometritis and the continued presence of detectable plasma cells (e.g., with ciprofloxacin with/without metronidazole) [49]. A meta-analysis of 12 studies reported a success rate of 87.9% for patients treated with antibiotics after being diagnosed with chronic endometritis [54]. If no treatment was administered, plasma cells were detected in around 90% of cases; the spontaneous cure rate is clearly low [60], [61]. Prospective randomized controlled studies to confirm these results are still needed.

Consensus-based recommendation 3-4.E20
Expert consensus	Level of consensus +++
Antibiotic therapy for miscarriage prophylaxis may be administered to women with RM and chronic endometritis.

3.5  Endocrine factors

3.5.1  Diagnosis of endocrine factors

3.5.1.1  Progesterone

Luteal phase insufficiency is being discussed as a possible cause of recurrent miscarriages. However, according to current knowledge, luteal insufficiency is a clinical (and not a laboratory) diagnosis and is based on the clinical symptoms of cycle disorders. There is no cut-off value for serum progesterone levels to define this diagnosis [62]. For this reason, routine ovulation control of women with eumenorrhea is not recommended [63], [64].

3.5.1.2  PCO syndrome

The question whether PCOS is per se associated with a higher risk of miscarriage cannot be answered based on current studies as the symptoms are very heterogeneous and can include hyperandrogenemia, metabolic syndrome with insulin resistance, and obesity.

Consensus-based recommendation 3-5.E21
Expert consensus	Level of consensus ++
The associated endocrine and metabolic pathologies of women with RM and PCOS should be investigated.

3.5.1.3  Thyroid dysfunction disorders

Because of the limited data, a recent Cochrane review was unable to come to any clear conclusions about the benefits of thyroid hormone substitution in euthyroid women with positive TPO Ab or women with subclinical hypothyroidism [65].

This is supported by double-blinded, placebo-controlled, randomized controlled study, in which 952 euthyroid women with prior miscarriage or infertility and confirmed higher levels of TPO Ab received either 50 µg levothyroxine or placebo [66]. Neither the miscarriage rate nor the LBR were affected by the therapy. This also applied to women with ≥ 3 previous miscarriages. However, 10% of these women developed thyroid function disorder during pregnancy as evidenced by pathological thyroid function tests [67].

Consensus-based recommendation 3-5.E22
Expert consensus	Level of consensus +++
TSH levels must be determined in women with RM. Further diagnostic tests must be carried out if the TSH value is abnormal.

Consensus-based recommendation 3-5.E23
Expert consensus	Level of consensus +++
TSH concentrations should be monitored during early pregnancy in women with RM and TPO antibodies.

3.5.2  Treatment of endocrine factors

3.5.2.1  Progesterone

Data on the effect of progesterone or progestogen treatment in the first trimester of pregnancy are controversial and mainly focus on idiopathic RM. A more detailed discussion is therefore given in Chapter 3.9.

3.5.2.2  PCO syndrome

PCOS often results in a higher BMI, which is associated with a higher rate of miscarriages. There are also other reasons why reducing weight prior to starting a pregnancy can be medically beneficial for women with a higher BMI (see the S3 guideline on Gestational Diabetes, AWMF guideline 057/008) [68]. The endocrine and metabolic changes underlying PCOS probably affect the risk of miscarriage.

Consensus-based recommendation 3-5.E24
Expert consensus	Level of consensus +++
Associated endocrine and metabolic pathologies in women with RM and PCOS must be treated.

3.5.2.3  Thyroid function disorders

Manifest hyper- or hypothroidism must be diagnosed and treated, especially if the patient wishes to become pregnant. Latent thyroid function disorders should be investigated to allow a possible deterioration to be treated in early pregnancy. Based on current data, it is not clear whether thyroid hormone substitution can reduce the risk of miscarriage.

Consensus-based recommendation 3-5.E25
Expert consensus	Level of consensus +++
Manifest hypo- or hyperthyroidism must be treated prior to conception.

Consensus-based recommendation 3-5.E26
Expert consensus	Level of consensus ++
No substitution therapy should be given to women with RM and latent hypothyroidism.

Consensus-based recommendation 3-5.E27
Expert consensus	Level of consensus +++
No thyroid hormone substitution therapy should be administered if TPO antibodies are present and TSH values are normal.

3.6  Psychological factors

3.6.1  Diagnosis of psychological factors

Evidence-based medicine has not found that RM is caused by psychological factors such as stress alone [1], [69], [70], [71]. According to current information, the impact of indirect influences such as behavioral changes by the pregnant woman (e.g., taking legal stimulants or inadequate diets) needs to be considered [72] as well as the behavior of her partner [1]. Because of their theoretical presuppositions, the explanations for spontaneous miscarriages or RM proposed in older literature sources cannot be tested in empirical studies or could not be replicated to date [73]. The psychological impact of RM should, however, not be underestimated [74] [75] [76].

Consensus-based recommendation 3-6.E28
Expert consensus	Level of consensus +++
Women with a prior history of mental illness, women who are involuntarily childless, and women who lack or have only limited social resources or are struggling with feelings of guilt related to processing their experience of RM must be offered information about psychosocial assistance and support (including self-help groups and internet forums).

Consensus-based recommendation 3-6.E29
Expert consensus	Level of consensus +++
A psychotherapist/psychiatrist must be called in if there is a suspicion that the patient is suffering from reactive depression after RM to assess whether the affected patient/couple require(s) further treatment.

3.6.2  Treatment of psychological factors

A consistently empathic and supportive approach when dealing with the patient (and their partner [77]) as part of patient-centered care (provision of individualized information and offer of emotional support) in the doctor-patient relationship and during treatment by other medical staff is what affected women would like [78] and is also recommended [79], [80], [81]. The expectation is that the doctor must be sympathetic and empathic during conversations, should listen to the patient and take her seriously, provide her with information about the possible further course, and ask about her potential emotional needs [1], [78]. The patient with RM should be able to have frequent low-threshold contact (in person, by telephone, online) during any subsequent pregnancy.

Consensus-based statement 3-6.S6
Expert consensus	Level of consensus +++
The effectiveness of tender loving care as a therapeutic intervention to prevent miscarriage in women with RM has not been confirmed. However psychological interventions after miscarriage can help to stabilize the patientʼs psychological well-being and thereby reduce the risk of stress-related complications of pregnancy in subsequent pregnancies. A consistently empathic and supportive approach when dealing with the patient (and her partner) is absolutely recommended.

3.7  Immune factors

Immune dysfunction is discussed as a possible causative factor, especially in couples with idiopathic RM. As existing studies are extremely heterogeneous (with regard to inclusion criteria for patients and the diagnostic methods used) and the case numbers are often very small, the data are inconsistent [82], [83], [84], [85].

3.7.1  Diagnosis of immune factors

3.7.1.1  Alloimmune factors

Consensus-based recommendation 3-7.E30
Expert consensus	Level of consensus +++
Alloimmune testing, e.g., determining the Th1/Th2 ratio, the T4/T8 index, analysis of pNK and/or uNK cells, NK toxicity testing, lymphocyte function tests, molecular genetic analysis to look for non-classical HLA groups (class Ib) or KIR receptor families and HLA typing should not be carried out in women with RM outside clinical trials if there is no evidence of any pre-existing autoimmune disorder.

3.7.1.2  Autoimmune factors

Antiphospholipid syndrome (APLS) is only present if both the clinical and laboratory criteria defined in [Table 6] are met. Between 2% and 15% of women with RM have an APL syndrome [86]. The diagnostic criteria are more than 20 years old and an increasing number of studies has begun to assume that the actual incidence is low (< 5%) [87], [88]. When making the diagnosis, it is important to confirm that the APL antibody titer is still moderately high or high at the control examination carried out at 12 weeks after the initial determination, which means that the titer is in the > 99th percentile compared to test subjects with unremarkable levels [89].

Clinical criteria

≥ 1 venous or arterial thrombosis

1 or 2 unexplained miscarriages of a morphologically normal fetus > 10 GW

≥ 3 miscarriages < 10th GW

≥ 1 late miscarriage or preterm birth < 34th GW due to placental insufficiency or preeclampsia

Laboratory criteria (confirmed by 2 tests carried at an interval of 12 weeks between tests)

Anticardiolipin antibodies (IgM, IgG) moderate-to-high titer

Anti-β2 glycoprotein 1 antibodies (IgM, IgG) high titer

Lupus anticoagulant

Different clinical and laboratory criteria can be present either in combination or individually. The definition requires that at least one clinical and one laboratory criterion must be met to make a diagnosis of antiphospholipid syndrome.

Consensus-based recommendation 3-7.E31
Expert consensus	Level of consensus +++
In women with RM, antiphospholipid syndrome must be investigated using clinical and laboratory parameters ([Table 6]).

As previously described in the S2k guideline “Diagnosis and Therapy before ART” [90], triple-positive APLS (i.e., all 3 APL antibodies are simultaneously present) is associated with poor maternal or infant outcomes (see laboratory criteria in [Table 6]). These patients require interdisciplinary care and therapy planning already prior to conception.

Individual studies have also indicated that non-criteria APL syndrome may also be present in women with RM, especially if clinical manifestations (such as livedo reticularis, ulcerations, renal microangiopathy, neurological disorders and cardiac manifestations) are observed and the diagnostic criteria for a classical APL syndrome are not or are only partially present (e.g., low APL antibody titer or status post 2 miscarriages) [89] or non-conventional APL antibodies can be detected [91].

Consensus-based recommendation 3-7.E32
Expert consensus	Level of consensus +++
Interdisciplinary care must be initiated already prior to conception in women with RM and an autoimmune disorder or triple-positive antiphospholipid syndrome because of the high maternal risk.

Consensus-based recommendation 3-7.E33
Expert consensus	Level of consensus +++
Women with RM should be investigated for non-criteria APLS based on clinical and laboratory parameters, especially in cases with manifest clinical symptoms (livedo reticularis, ulcerations, renal microangiopathies, neurological disorders and cardiac manifestations).

3.7.2  Treatment of immune factors

Recent publications have noted that many therapeutic studies are carried out in patients with (idiopathic) RM without a previous specific immunological diagnosis to guide treatment. This means that a clear identification of patients with immune disorders is lacking, which may result in a lack of stratification [82], [83], [84], [85].

The recent ESHRE guideline on RM has emphasized that the study data on immunomodulatory therapies in patients with identified underlying immunological abnormalities suggest that the effects can be beneficial [1]. However, the overall data are inconsistent. Further studies which group patients according to defined immunological abnormalities (targets) are urgently required.

3.7.2.1  Treatment of alloimmune factors

Consensus-based recommendation 3-7.E34
Expert consensus	Level of consensus +++
Glucocorticoids as prophylaxis against miscarriage must not be given to women with RM and no evidence of pre-existing autoimmune disorders outside clinical studies.

3.7.2.2  Intravenous immunglobulins

Consensus-based recommendation 3-7.E35
Expert consensus	Level of consensus +
Intravenous immunoglobulins as prophylaxis against miscarriage must not be given to women with RM outside clinical studies.

3.7.2.3  Lipid infusions

Consensus-based recommendation 3-7.E36
Expert consensus	Level of consensus +++
Lipid infusions as prophylaxis against miscarriage must not be given to women with RM outside clinical studies.

3.7.2.4  Allogeneic lymphocyte immunotherapy (LIT)

Consensus-based recommendation 3-7.E37
Expert consensus	Level of consensus +
Allogeneic lymphocyte immunotherapy as prophylaxis against miscarriage must not be administered to women with RM outside clinical studies.

3.7.2.5  TNFα receptor blockers

Consensus-based recommendation 3-7.E38
Expert consensus	Level of consensus ++
TNFα receptor blockers must not be given to women with RM outside clinical studies.

3.7.2.6  Treatment of autoimmune factors

RM patients with APLS benefit from taking aspirin (50 – 150 mg/d) and low weight molecular heparin [92], [93], [94], [95], [96]. Treatment with aspirin can already be initiated prior to conception or from the day of the positive pregnancy test and should be continued up to week 34 + 0 of gestation [97]. The administration of LMWH should start from the day of the positive pregnancy test and continued for at least 6 weeks postpartum.

In contrast to LMWH with aspirin, other therapeutic approaches such as glucocorticoids, immunoglobulins or aspirin alone have not been found to result in any significant improvement of the LBR of RM patients with APLS [92].

According to recent studies, treatment for non-criteria APLS should be the same as for APLS, as the few existing studies have found a possible benefit from administering LMWH and ASA [98] – [103].

Consensus-based recommendation 3-7.E39
Expert consensus	Level of consensus +++
Low dose acetylsalicylic acid and low weight molecular heparin must be given to women with RM and antiphospholipid syndrome. In addition to acetylsalicylic acid (which must be continued until week 34 + 0 of gestation), heparin must be administered from the day of the positive pregnancy test and continued for at least 6 weeks postpartum.

Consensus-based recommendation 3-7.E40
Expert consensus	Level of consensus ++
Women with RM and non-criteria antiphospholipid syndrome must be treated with low dose acetylsalicylic acid and low weight molecular heparin. In addition to acetylsalicylic acid (which must be continued until week 34 + 0 of gestation), heparin must be administered from the day of the positive pregnancy test and continued for at least 6 weeks postpartum.

3.8  Coagulation

3.8.1  Diagnosis of congenital thrombophilic factors

In recent decades, many studies have discussed possible associations between maternal (and also paternal [104], [105]) thrombophilia and RM. Numerous pro-coagulation factors have been studied: factor V Leiden mutation (FVL; c.1601G>A in F5, rs6025), prothrombin G20210A mutation (PT; c.*97G>A in F2, rs1799963), factor XIII polymorphisms, antithrombin, protein C, protein S, protein Z and factor XII deficiency, elevated factor VIII levels, high lipoprotein(a) levels [106], [107], [108] and changes found during thrombelastography [109]. Uteroplacental thrombosis has been proposed as a thrombophilia-related pathomechanism and possible cause of miscarriage as it affects placental and embryonic/fetal blood supply [110].

A meta-analysis published in 2010 [111] found a statistically slightly higher risk of miscarriage in women who were heterozygous for FVL mutation but not PT mutation. A meta-analysis published in 2012 found slightly higher miscarriage rates (OR approx. 2) in carriers of the FVL or PT mutation. As the efficacy of prophylactic heparin to prevent miscarriage has not been confirmed and in view of the potential side-effects of heparin administration in women with RM, the authors have come to the conclusion that testing for the FVL or PT variant – which could potentially result in the administration of heparin to prevent miscarriage – currently results in more harm than benefit [112].

Recent publications have come to the same conclusion with regard to investigating hereditary thrombophilia in women with RM [108], [113], [114].

Consensus-based recommendation 3-8.E41
Expert consensus	Level of consensus +++
Testing for thrombophilia to prevent miscarriage should not be carried out.

Consensus-based recommendation 3-8.E42
Expert consensus	Level of consensus +++
Women with RM who are at risk of thromboembolism must be tested for thrombophilia. This includes determination of antithrombin activity and plasma protein C/S levels as well as molecular genetic analysis for factor V Leiden mutation and prothrombin G20210A mutation.

3.8.2  Treatment for women at risk of thrombophilic events

There is no evidence that the administration of heparin prior to or after conception to prevent further miscarriages has a beneficial effect.

Further studies such as the multinational ALIFE2 study which has been recruiting since 2013 will be necessary to determine to what extent subgroups of patients – e.g., patients with confirmed hereditary thrombophilia – actually benefit from the administration of heparin in subsequent pregnancies [115], [116]. An indivdualized meta-analysis published in 2016 of prospective randomized studies (n = 8) on miscarriage prophylaxis which included 483 women was unable to detect any benefit with regard to the LBR from the administration of low weight molecular heparin [117].

A general administration of heparin only for the purpose of miscarriage prevention is therefore currently not indicated outside clinical studies, even in thrombophilic women with RM (but no evidence of APLS) [118], [119].

Consensus-based recommendation 3-8.E43
Expert consensus	Level of consensus +++
Women with RM must not be given heparin only for the purpose of preventing miscarriage. This also applies to women with hereditary thrombophilia.

Consensus-based recommendation 3-8.E44
Expert consensus	Level of consensus +++
Thrombosis prophylaxis treatment is indicated during pregnancy for women with RM and a high risk of thrombosis.

3.8.2.1  Acetylsalicylic acid (ASA)

The use of ASA during pregnancy for miscarriage prophylaxis is an off-label use. The administration of low doses of ASA starting in the first trimester of pregnancy reduces the risk of placenta-related complications in pregnancy [120], but a protective effect on the miscarriage rate has not been confirmed.

Consensus-based recommendation 3-8.E45
Expert consensus	Level of consensus +++
Acetylsalicylic acid therapy must not be used as miscarriage prophylaxis in women with RM.

3.8.3  Monitoring during pregnancy – D-dimers

Consensus-based recommendation 3-8.E46
Expert consensus	Level of consensus +++
Monitoring of plasma coagulation markers (D-dimers, prothrombin fragments, etc.) must not be carried out during pregnancy in women with RM. Determining these parameters does not mean that prophylactic treatment against miscarriage is indicated.

3.9  Idiopathic RM

Idiopathic RM is present when the criteria for RM are present and genetic, anatomical, endocrine, and established immune and hemostatic factors have been excluded. The percentage of women with idiopathic RM out of the overall population of women with RM is high and ranges from 50 to 75% [3].

3.9.1  Diagnosis of idiopathic RM

Consensus-based recommendation 3-9.E47
Expert consensus	Level of consensus +++
The term idiopathic RM must only be used if diagnostic investigations carried out in accordance with the relevant guidelines were unable to find the cause of RM.

3.9.2  Treatment of idiopathic RM

The LBR of women with idiopathic RM is between 35% and 85% without treatment [121], [122]. In a meta-analysis of randomized therapeutic studies, the LBR of women with idiopathic RM in control and placebo groups was found to be between 60% and 70% [123]. Empirical therapies are often routinely used to treat women with idiopathic RM. This is understandable because affected couples often strongly demand some form of therapy and are very frustrated after investigations into the causes of RM are inconclusive. Nevertheless, these couples should also receive evidence-based counselling and treatment.

A recent Cochrane meta-analysis of 7 studies with 5682 subjects found that the administration of vaginal micronized progesterone (RR 1.03; 95% CI: 1.00 – 1.07) had a marginally verifiable effect [124]. A strong effect was found in women with one or more prior miscarriages and bleeding due to impending abortion (RR 1.03; 95% CI: 1.02 – 1.15). This meta-analysis found no increased rate of malformations after treatment with vaginal progesterone in the first trimester of pregnancy (RR 1.00; 95% CI: 0.68 – 1.46) [125].

Based on the combined data from the PROMISE and PRISM trials in women with RM, vaginal progesterone therapy may be offered up until the 16th week of gestation if bleeding due to impending miscarriage is diagnosed [126]. Based on data from the recent Cochrane meta-analysis, this recommendation can be expanded to include women with bleeding due to impending miscarriage and one or two prior spontaneous miscarriages [124].

Consensus-based recommendation 3-9.E48
Expert consensus	Level of consensus +++
Women with idiopathic RM may be treated with natural micronized progesterone or with synthetic gestagens as miscarriage prophylaxis in the first trimester of pregnancy.

Consensus-based recommendation 3-9.E49
Expert consensus	Level of consensus +++
Vaginal therapy with natural micronized progesterone should be administered as miscarriage prophylaxis to women with RM and impending miscarriage up until the 16th week of gestation.

Consensus-based recommendation 3-9.E50
Expert consensus	Level of consensus +++
Women with idiopathic RM must not be prescribed G-CSF as miscarriage prophylaxis unless treatment is given as part of a clinical study.

Consensus-based recommendation 3-9.E51
Expert consensus	Level of consensus +++
Women with idiopathic RM must not be prescribed acetylsalicylic acid with or without heparin as miscarriage prophylaxis.

• References

• 1 ESHRE Guideline Group on RPL. Bender Atik R, Christiansen OB. et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018: hoy004
• 2 RCOG. The investigation and treatment of Couples with recurrent first-trimester and second-trimester miscarriage. RCOG Green-top Guideline No 17: Royal College of Obstetricians & Gynaecologists; 2011. Accessed August 08, 2022 at: https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/the-investigation-and-treatment-of-couples-with-recurrent-miscarriage-green-top-guideline-no-17
• 3 American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. (Replaces Technical Bulletin Number 212, September 1995). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002; 78: 179-190
• 4 Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98: 1103-1111
• 5 Carrington B, Sacks G, Regan L. Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 2005; 17: 591-597
• 6 WHO. WHO: recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths. Modifications recommended by FIGO as amended October 14, 1976. Acta Obstet Gynecol Scand 1977; 56: 247-253
• 7 Practice Committee of tAmerican Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 90 (5 Suppl): S60
• 8 Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-611
• 9 van Dijk MM, Kolte AM, Limpens J. et al. Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis. Hum Reprod Update 2020; 26: 356-367
• 10 Kolte AM, Westergaard D, Lidegaard O. et al. Chance of live birth: a nationwide, registry-based cohort study. Hum Reprod 2021; 36: 1065-1073
• 11 Ng KYB, Cherian G, Kermack AJ. et al. Systematic review and meta-analysis of female lifestyle factors and risk of recurrent pregnancy loss. Sci Rep 2021; 11: 7081
• 12 Rooney KL, Domar A. The relationship between stress and infertility. Dialogues Clin Neurosci 2018; 20: 41-47
• 13 Hong Li Y, Marren A. Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Aust J Gen Pract 2018; 47: 432-436
• 14 Leung LW, Davies GA. Smoking Cessation Strategies in Pregnancy. J Obstet Gynaecol Can 2015; 37: 791-797
• 15 Balsells M, Garcia-Patterson A, Corcoy R. Systematic review and meta-analysis on the association of prepregnancy underweight and miscarriage. Eur J Obstet Gynecol Reprod Biol 2016; 207: 73-79
• 16 Boedt T, Vanhove AC, Vercoe MA. et al. Preconception lifestyle advice for people with infertility. Cochrane Database Syst Rev 2021; (04) CD008189
• 17 Best D, Avenell A, Bhattacharya S. How effective are weight-loss interventions for improving fertility in women and men who are overweight or obese? A systematic review and meta-analysis of the evidence. Hum Reprod Update 2017; 23: 681-705
• 18 van den Berg MM, van Maarle MC, van Wely M. et al. Genetics of early miscarriage. Biochim Biophys Acta 2012; 1822: 1951-1959
• 19 Zhang T, Sun Y, Chen Z. et al. Traditional and molecular chromosomal abnormality analysis of products of conception in spontaneous and recurrent miscarriage. BJOG 2018; 125: 414-420
• 20 De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 1990; 5: 519-528
• 21 du Fosse NA, van der Hoorn MP, van Lith JMM. et al. Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Hum Reprod Update 2020; 26: 650-669
• 22 Pereza N, Ostojic S, Kapovic M. et al. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril 2017; 107: 150-159.e2
• 23 Kähler C, Gembruch U, Heling KS. et al. DEGUM. [DEGUM guidelines for amniocentesis and chorionic villus sampling]. Ultraschall Med 2013; 34: 435-440
• 24 Kozlowski P, Burkhardt T, Gembruch U. et al. DEGUM, OGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures. Ultraschall Med 2019; 40: 176-193
• 25 Salomon LJ, Sotiriadis A, Wulff CB. et al. Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta-analysis. Ultrasound Obstet Gynecol 2019; 54: 442-451
• 26 Iews M, Tan J, Taskin O. et al. Does preimplantation genetic diagnosis improve reproductive outcome in couples with recurrent pregnancy loss owing to structural chromosomal rearrangement? A systematic review. Reprod Biomed Online 2018; 36: 677-685
• 27 Franssen MT, Musters AM, van der Veen F. et al. Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review. Hum Reprod Update 2011; 17: 467-475
• 28 Ikuma S, Sato T, Sugiura-Ogasawara M. et al. Preimplantation Genetic Diagnosis and Natural Conception: A Comparison of Live Birth Rates in Patients with Recurrent Pregnancy Loss Associated with Translocation. PLoS One 2015; 10: e0129958
• 29 Seckin B, Sarikaya E, Oruc AS. et al. Office hysteroscopic findings in patients with two, three, and four or more, consecutive miscarriages. Eur J Contracept Reprod Health Care 2012; 17: 393-398
• 30 Salim R, Regan L, Woelfer B. et al. A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum Reprod 2003; 18: 162-166
• 31 Sugiura-Ogasawara M, Ozaki Y, Katano K. et al. Uterine anomaly and recurrent pregnancy loss. Semin Reprod Med 2011; 29: 514-521
• 32 Venetis CA, Papadopoulos SP, Campo R. et al. Clinical implications of congenital uterine anomalies: a meta-analysis of comparative studies. Reprod Biomed Online 2014; 29: 665-683
• 33 Oppelt P, Binder H, Birraux J. et al. Diagnosis and Therapy of Female Genital Malformations (Part 1). Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/052, May 2019). Geburtshilfe Frauenheilkd 2021; 81: 1307-1328 DOI: 10.1055/a-1471-4781.
• 34 Turocy JM, Rackow BW. Uterine factor in recurrent pregnancy loss. Semin Perinatol 2019; 43: 74-79
• 35 Hooker AB, Lemmers M, Thurkow AL. et al. Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reprod Update 2014; 20: 262-278
• 36 Hooker AB, Aydin H, Brolmann HA. et al. Long-term complications and reproductive outcome after the management of retained products of conception: a systematic review. Fertil Steril 2016; 105: 156-164.e1-2
• 37 Saravelos SH, Yan J, Rehmani H. et al. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod 2011; 26: 3274-3279
• 38 Cicinelli E, Resta L, Nicoletti R. et al. Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis. Hum Reprod 2005; 20: 1386-1389
• 39 Jaslow CR. Uterine factors. Obstet Gynecol Clin North Am 2014; 41: 57-86
• 40 Bailey AP, Jaslow CR, Kutteh WH. Minimally invasive surgical options for congenital and acquired uterine factors associated with recurrent pregnancy loss. Womens Health (Lond) 2015; 11: 161-167
• 41 Rikken JFW, Verhorstert KWJ, Emanuel MH. et al. Septum resection in women with a septate uterus: a cohort study. Hum Reprod 2020; 35: 1578-1588
• 42 Rikken JFW, Kowalik CR, Emanuel MH. et al. Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial. Hum Reprod 2021; 36: 1260-1267
• 43 Conforti A, Alviggi C, Mollo A. et al. The management of Asherman syndrome: a review of literature. Reprod Biol Endocrinol 2013; 11: 118
• 44 Roy KK, Baruah J, Sharma JB. et al. Reproductive outcome following hysteroscopic adhesiolysis in patients with infertility due to Ashermanʼs syndrome. Arch Gynecol Obstet 2010; 281: 355-361
• 45 Chen L, Zhang H, Wang Q. et al. Reproductive Outcomes in Patients With Intrauterine Adhesions Following Hysteroscopic Adhesiolysis: Experience From the Largest Womenʼs Hospital in China. J Minim Invasive Gynecol 2017; 24: 299-304
• 46 Metwally M, Raybould G, Cheong YC. et al. Surgical treatment of fibroids for subfertility. Cochrane Database Syst Rev 2020; (01) CD003857
• 47 Bosteels J, van Wessel S, Weyers S. et al. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev 2018; (12) CD009461
• 48 Bosteels J, Weyers S. Outpatient treatment for uterine polyps. BMJ 2015; 350: h1469
• 49 Johnston-MacAnanny EB, Hartnett J, Engmann LL. et al. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril 2010; 93: 437-441
• 50 Zolghadri J, Momtahan M, Aminian K. et al. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion. Eur J Obstet Gynecol Reprod Biol 2011; 155: 217-220
• 51 Cicinelli E, Matteo M, Tinelli R. et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reprod Sci 2014; 21: 640-647
• 52 McQueen DB, Bernardi LA, Stephenson MD. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise. Fertil Steril 2014; 101: 1026-1030
• 53 Yang R, Du X, Wang Y. et al. The hysteroscopy and histological diagnosis and treatment value of chronic endometritis in recurrent implantation failure patients. Arch Gynecol Obstet 2014; 289: 1363-1369
• 54 Pirtea P, Cicinelli E, De Nola R. et al. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis. Fertil Steril 2021; 115: 546-560
• 55 Haahr T, Jensen JS, Thomsen L. et al. Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients. Hum Reprod 2016; 31: 795-803
• 56 Moreno I, Codoner FM, Vilella F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol 2016; 215: 684-703
• 57 Fu M, Zhang X, Liang Y. et al. Alterations in Vaginal Microbiota and Associated Metabolome in Women with Recurrent Implantation Failure. mBio 2020; 11: e03242-19
• 58 Moreno I, Garcia-Grau I, Perez-Villaroya D. et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. medRxiv 2021; DOI: 10.1101/2021.02.05.21251207.
• 59 Kyono K, Hashimoto T, Kikuchi S. et al. A pilot study and case reports on endometrial microbiota and pregnancy outcome: An analysis using 16S rRNA gene sequencing among IVF patients, and trial therapeutic intervention for dysbiotic endometrium. Reprod Med Biol 2019; 18: 72-82
• 60 Cicinelli E, Resta L, Loizzi V. et al. Antibiotic therapy versus no treatment for chronic endometritis: a case-control study. Fertil Steril 2021; 115: 1541-1548
• 61 Song D, He Y, Wang Y. et al. Impact of antibiotic therapy on the rate of negative test results for chronic endometritis: a prospective randomized control trial. Fertil Steril 2021; 115: 1549-1556
• 62 Practice Committee of the American Society for Reproductive Medicine. Current clinical irrelevance of luteal phase deficiency: a committee opinion. Fertil Steril 2015; 103: e27-e32
• 63 DeVilbiss EA, Sjaarda LA, Mumford SL. Routine assessment of ovulation is unlikely to be medically necessary among eumenorrheic women. Fertil Steril 2020; 114: 1187-1188
• 64 Chinta P, Rebekah G, Kunjummen AT. et al. Revisiting the role of serum progesterone as a test of ovulation in eumenorrheic subfertile women: a prospective diagnostic accuracy study. Fertil Steril 2020; 114: 1315-1321
• 65 Akhtar MA, Agrawal R, Brown J. et al. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism. Cochrane Database Syst Rev 2019; (06) CD011009
• 66 Dhillon-Smith RK, Middleton LJ, Sunner KK. et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med 2019; 380: 1316-1325
• 67 Sarne DH. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med 2019; 381: 190-191
• 68 Schafer-Graf UM, Gembruch U, Kainer F. et al. Gestational Diabetes Mellitus (GDM) – Diagnosis, Treatment and Follow-Up. Guideline of the DDG and DGGG (S3 Level, AWMF Registry Number 057/008, February 2018). Geburtshilfe Frauenheilkd 2018; 78: 1219-1231
• 69 Kentenich H, Wischmann T, Stöbel-Richter Y. Hrsg. Fertilitätsstörungen – psychosomatisch orientierte Diagnostik und Therapie. Leitlinie und Quellentext (Revision). Gießen: Psychosozial-Verlag; 2013
• 70 Catherino WH. Stress relief to augment fertility: the pressure mounts. Fertil Steril 2011; 95: 2462-2463
• 71 Li W, Newell-Price J, Jones GL. et al. Relationship between psychological stress and recurrent miscarriage. Reprod Biomed Online 2012; 25: 180-189
• 72 Schilling K, Toth B, Rosner S. et al. Prevalence of behaviour-related fertility disorders in a clinical sample: results of a pilot study. Arch Gynecol Obstet 2012; 286: 1307-1314
• 73 Läpple M. Streß als Erklärungsmodell für Spontanaborte (SA) und rezidivierende Spontanaborte (RSA). Zentralblatt für Gynäkologie 1988; 110: 325-335
• 74 Rohde A, Dorn A. Gynäkologische Psychosomatik und Gynäkopsychiatrie. Stuttgart: Schattauer; 2007
• 75 El Hachem H, Crepaux V, May-Panloup P. et al. Recurrent pregnancy loss: current perspectives. Int J Womens Health 2017; 9: 331-345
• 76 Farren J, Mitchell-Jones N, Verbakel JY. et al. The psychological impact of early pregnancy loss. Hum Reprod Update 2018; 24: 731-749
• 77 Koert E, Malling GMH, Sylvest R. et al. Recurrent pregnancy loss: couplesʼ perspectives on their need for treatment, support and follow up. Hum Reprod 2019; 34: 291-296
• 78 Musters AM, Koot YE, van den Boogaard NM. et al. Supportive care for women with recurrent miscarriage: a survey to quantify womenʼs preferences. Hum Reprod 2013; 28: 398-405
• 79 Newbatt E, Beckles Z, Ullman R. Guideline Development Group. Ectopic pregnancy and miscarriage: summary of NICE guidance. BMJ 2012; 345: e8136
• 80 Homer HA. Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol 2019; 59: 36-44
• 81 Dimitriadis E, Menkhorst E, Saito S. et al. Recurrent pregnancy loss. Nat Rev Dis Primers 2020; 6: 98
• 82 Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2014; (2014): CD000112
• 83 Odendaal J, Quenby S, Sammaritano L. et al. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?. Fertil Steril 2019; 112: 1002-1012
• 84 Carp H. Immunotherapy for recurrent pregnancy loss. Best Pract Res Clin Obstet Gynaecol 2019; 60: 77-86
• 85 Achilli C, Duran-Retamal M, Saab W. et al. The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril 2018; 110: 1089-1100
• 86 Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J Med 2010; 363: 1740-1747
• 87 Vomstein K, Voss P, Molnar K. et al. Two of a kind? Immunological and clinical risk factors differ between recurrent implantation failure and recurrent miscarriage. J Reprod Immunol 2020; 141: 103166
• 88 Branch DW. Whatʼs new in obstetric antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 2019; 2019: 421-425
• 89 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295-306
• 90 Toth B, Baston-Bust DM, Behre HM. et al. Diagnosis and Therapy Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015–085, February 2019) – Part 1, Basic Assessment of the Woman. Geburtshilfe Frauenheilkd 2019; 79: 1278-1292
• 91 Zhu H, Wang M, Dong Y. et al. Detection of non-criteria autoantibodies in women without apparent causes for pregnancy loss. J Clin Lab Anal 2019; 33: e22994
• 92 Empson M, Lassere M, Craig J. et al. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005; 2005 (02) CD002859 DOI: 10.1002/14651858.CD002859.pub2.
• 93 Empson M, Lassere M, Craig JC. et al. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol 2002; 99: 135-144
• 94 Mak A, Cheung MW, Cheak AA. et al. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 2010; 49: 281-288
• 95 Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol 2010; 115: 1256-1262
• 96 ACOG Practice Bulletin No. 118: antiphospholipid syndrome. Obstet Gynecol 2011; 117: 192-199
• 97 Derksen RH, de Groot PG. Clinical consequences of antiphospholipid antibodies. Neth J Med 2004; 62: 273-278
• 98 Gardiner C, Hills J, Machin SJ. et al. Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus 2013; 22: 18-25
• 99 Cohn DM, Goddijn M, Middeldorp S. et al. Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. J Thromb Haemost 2010; 8: 2208-2213
• 100 Alijotas-Reig J, Ferrer-Oliveras R. EUROAPS Study Group. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a preliminary first year report. Lupus 2012; 21: 766-768
• 101 Mekinian A, Loire-Berson P, Nicaise-Roland P. et al. Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels. J Reprod Immunol 2012; 94: 222-226
• 102 Arachchillage DR, Machin SJ, Mackie IJ. et al. Diagnosis and management of non-criteria obstetric antiphospholipid syndrome. Thromb Haemost 2015; 113: 13-19
• 103 Lo HW, Chen CJ, Tsai EM. Pregnancy outcomes for women with non-criteria antiphospholipid syndrome after anticoagulant therapy. Eur J Obstet Gynecol Reprod Biol 2020; 244: 205-207
• 104 Toth B, Vocke F, Rogenhofer N. et al. Paternal thrombophilic gene mutations are not associated with recurrent miscarriage. Am J Reprod Immunol 2008; 60: 325-332
• 105 Rogenhofer N, Engels L, Bogdanova N. et al. Paternal and maternal carriage of the annexin A5 M2 haplotype are equal risk factors for recurrent pregnancy loss: a pilot study. Fertil Steril 2012; 98: 383-388
• 106 Ormesher L, Simcox LE, Tower C. et al. ‘To test or not to test’, the arguments for and against thrombophilia testing in obstetrics. Obstet Med 2017; 10: 61-66
• 107 Joksic I, Mikovic Z, Filimonovic D. et al. Combined presence of coagulation factor XIII V34 L and plasminogen activator inhibitor 1 4 G/5 G gene polymorphisms significantly contribute to recurrent pregnancy loss in Serbian population. J Med Biochem 2020; 39: 199-207
• 108 Vomstein K, Herzog A, Voss P. et al. Recurrent miscarriage is not associated with a higher prevalence of inherited and acquired thrombophilia. Am J Reprod Immunol 2021; 85: e13327
• 109 Wang P, Yang H, Wang G. et al. Predictive value of thromboelastography parameters combined with antithrombin III and D-Dimer in patients with recurrent spontaneous abortion. Am J Reprod Immunol 2019; 82: e13165
• 110 Toth B, Jeschke U, Rogenhofer N. et al. Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 2010; 85: 25-32
• 111 Rodger MA, Betancourt MT, Clark P. et al. The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med 2010; 7: e1000292
• 112 Bradley LA, Palomaki GE, Bienstock J. et al. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med 2012; 14: 39-50
• 113 Alecsandru D, Klimczak AM, Garcia Velasco JA. et al. Immunologic causes and thrombophilia in recurrent pregnancy loss. Fertil Steril 2021; 115: 561-566
• 114 Liu X, Chen Y, Ye C. et al. Hereditary thrombophilia and recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod 2021; 36: 1213-1229
• 115 de Jong PG, Quenby S, Bloemenkamp KW. et al. ALIFE2 study: low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia–study protocol for a randomized controlled trial. Trials 2015; 16: 208
• 116 Hamulyak EN, de Jong PG, Scheres LJJ. et al. Progress of the ALIFE2 study: A dynamic road towards more evidence. Thromb Res 2020; 190: 39-44
• 117 Skeith L, Carrier M, Kaaja R. et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016; 127: 1650-1655
• 118 Tan WK, Lim SK, Tan LK. et al. Does low-molecular-weight heparin improve live birth rates in pregnant women with thrombophilic disorders? A systematic review. Singapore Med J 2012; 53: 659-663
• 119 Bates SM, Greer IA, Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e691S-e736S
• 120 Rolnik DL, Wright D, Poon LC. et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med 2017; 377: 613-622
• 121 Kaandorp SP, Goddijn M, van der Post JA. et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362: 1586-1596
• 122 Liddell HS, Pattison NS, Zanderigo A. Recurrent miscarriage–outcome after supportive care in early pregnancy. Aust N Z J Obstet Gynaecol 1991; 31: 320-322
• 123 Jeng GT, Scott JR, Burmeister LF. A comparison of meta-analytic results using literature vs. individual patient data. Paternal cell immunization for recurrent miscarriage. JAMA 1995; 274: 830-836
• 124 Devall AJ, Papadopoulou A, Podesek M. et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev 2021; (04) CD013792
• 125 Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev 2019; 2019 (11) CD003511
• 126 Coomarasamy A, Devall AJ, Brosens JJ. et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol 2020; 223: 167-176

Publication History

Received: 28 June 2022

Accepted after revision: 05 July 2022

Article published online:
25 November 2022