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]).
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Previous miscarriage(s)
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Probability of a live birth
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25 – 29 years
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30 – 34 years
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35 – 39 years
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40 – 44 years
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1 miscarriage
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~ 85%
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~ 80%
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~ 70%
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~ 52%
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2 miscarriages
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~ 80%
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~ 78%
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~ 62%
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~ 45%
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3 miscarriages
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~ 75%
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~ 70%
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~ 55%
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~ 32%
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≥ 4 miscarriages
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< 65%
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< 60%
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< 45%
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> 25%
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Consensus-based recommendation 2.E1
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Expert consensus
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Level of consensus +++
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The risk factors listed in this guideline must be investigated after three consecutive miscarriages.
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Consensus-based recommendation 2.E2
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Expert consensus
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Level of consensus +++
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In justified cases, possible risk factors for RM should already be investigated after two consecutive miscarriages.
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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).
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Consensus-based statement 3-1.S1
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Expert consensus
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Level of consensus +++
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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.
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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].
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Consensus-based statement 3-1.S2
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Expert consensus
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Level of consensus +++
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Recent studies found no correlation between coffee consumption and the probability of miscarriage.
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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].
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Consensus-based statement 3-1.S3
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Expert consensus
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Level of consensus +++
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In cases with RM, the affected couple must be advised to abstain from nicotine already prior to conception.
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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).
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Consensus-based recommendation 3-1.E3
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Expert consensus
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Level of consensus +++
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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.
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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”.
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Consensus-based recommendation 3-1.E4
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Expert consensus
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Level of consensus +++
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Women with RM who are underweight or overweight/obese must strive to normalize their weight.
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Consensus-based recommendation 3-1.E5
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Expert consensus
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Level of consensus +++
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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.
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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).
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Consensus-based recommendation 3-2.E6
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Expert consensus
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Level of consensus +++
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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).
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Consensus-based recommendation 3-2.E7
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Expert consensus
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Level of consensus +++
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If a structural chromosomal abnormality is confirmed in the tissue of the miscarried fetus, both partners must undergo cytogenetic examination.
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Consensus-based statement 3-2.S4
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Expert consensus
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Level of consensus +++
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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.
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Consensus-based statement 3-2.S5
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Expert consensus
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Level of consensus +++
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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.
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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.
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Consensus-based recommendation 3-2.E8
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Expert consensus
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Level of consensus +++
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If there is evidence that the miscarriage was caused by a monogenic disorder, genetic counselling must include genetic testing.
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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.
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Consensus-based recommendation 3-2.E9
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Expert consensus
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Level of consensus +++
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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.
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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.
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Consensus-based recommendation 3-2.E10
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Expert consensus
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Level of consensus +++
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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.
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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].
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Consensus-based recommendation 3-3.E11
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Expert consensus
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Level of consensus +++
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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.
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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.
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Consensus-based recommendation 3-3.E12
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Expert consensus
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Level of consensus ++
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Women with RM and uterine septum must be informed following a benefit-risk analysis about the option of expectant management versus hysteroscopic septum resection.
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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.
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Consensus-based recommendation 3-3.E13
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Expert consensus
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Level of consensus +++
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Hysteroscopic adhesiolysis may be offered to women with RM and intrauterine adhesions for miscarriage prophylaxis.
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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).
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Consensus-based recommendation 3-3.E14
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Expert consensus
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Level of consensus +++
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Women with RM and submucosal fibroids may be offered surgical resection for miscarriage prophylaxis.
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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].
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Consensus-based recommendation 3-3.E15
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Expert consensus
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Level of consensus +++
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Women with RM and persistent polyps may be offered hysteroscopic resection for miscarriage prophylaxis.
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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.
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Consensus-based recommendation 3-4.E16
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Expert consensus
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Level of consensus +++
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Infection screening using vaginal swab specimens must not be carried out in asymptomatic women with RM.
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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.
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Consensus-based recommendation 3-4.E17
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Expert consensus
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Level of consensus +++
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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.
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Consensus-based recommendation 3-4.E18
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Expert consensus
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Level of consensus +++
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Repeat biopsy may be carried out to diagnose chronic endometritis which persists even after antibiotic treatment.
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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]).
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Consensus-based recommendation 3-4.E19
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Expert consensus
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Level of consensus +++
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Examination of the vaginal or endometrial microbiome must not be carried out in women with RM outside clinical studies.
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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.
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Consensus-based recommendation 3-4.E20
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Expert consensus
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Level of consensus +++
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Antibiotic therapy for miscarriage prophylaxis may be administered to women with RM and chronic endometritis.
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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.
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Consensus-based recommendation 3-5.E21
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Expert consensus
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Level of consensus ++
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The associated endocrine and metabolic pathologies of women with RM and PCOS should be investigated.
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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].
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Consensus-based recommendation 3-5.E22
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Expert consensus
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Level of consensus +++
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TSH levels must be determined in women with RM. Further diagnostic tests must be carried out if the TSH value is abnormal.
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Consensus-based recommendation 3-5.E23
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Expert consensus
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Level of consensus +++
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TSH concentrations should be monitored during early pregnancy in women with RM and TPO antibodies.
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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.
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Consensus-based recommendation 3-5.E24
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Expert consensus
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Level of consensus +++
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Associated endocrine and metabolic pathologies in women with RM and PCOS must be treated.
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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.
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Consensus-based recommendation 3-5.E25
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Expert consensus
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Level of consensus +++
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Manifest hypo- or hyperthyroidism must be treated prior to conception.
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Consensus-based recommendation 3-5.E26
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Expert consensus
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Level of consensus ++
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No substitution therapy should be given to women with RM and latent hypothyroidism.
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Consensus-based recommendation 3-5.E27
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Expert consensus
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Level of consensus +++
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No thyroid hormone substitution therapy should be administered if TPO antibodies are present and TSH values are normal.
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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].
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Consensus-based recommendation 3-6.E28
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Expert consensus
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Level of consensus +++
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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).
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Consensus-based recommendation 3-6.E29
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Expert consensus
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Level of consensus +++
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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.
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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.
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Consensus-based statement 3-6.S6
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Expert consensus
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Level of consensus +++
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|
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].
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Clinical criteria
|
|
≥ 1 venous or arterial thrombosis
|
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1 or 2 unexplained miscarriages of a morphologically normal fetus > 10 GW
|
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≥ 3 miscarriages < 10th GW
|
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≥ 1 late miscarriage or preterm birth < 34th GW due to placental insufficiency or preeclampsia
|
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Laboratory criteria (confirmed by 2 tests carried at an interval of 12 weeks between tests)
|
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Anticardiolipin antibodies (IgM, IgG) moderate-to-high titer
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Anti-β2 glycoprotein 1 antibodies (IgM, IgG) high titer
|
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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.
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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).
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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.
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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.
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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.
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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.
|
