Habitual miscarriage - Treatment

Habitual miscarriage is defined as a condition in which two or more pregnancy losses occur, but definitions vary: some guidelines use a threshold of two losses, while others retain the "classic" definition of three losses. Clinical evaluation often begins after two losses if a non-random cause is suspected. In practice, the probability of a preventable cause and age are more important than the "number," as the incidence of random chromosomal abnormalities in the embryo increases with age. [1]

The primary goal of treatment is stated simply: to increase the chance of a live birth, not just to reduce anxiety or "calm" the uterus. Therefore, treatment begins with confirmation of the loss and its type (biochemical, clinical, first trimester, second trimester), followed by diagnostic testing, which changes the strategy. This approach reduces unnecessary appointments and helps prevent the overlooking of rare but important causes. [2]

A significant proportion of cases remain unexplained even after proper investigation. This does not mean that "there is nothing to treat": evidence-based strategies in such situations include optimizing risk factors before conception, planning early monitoring in future pregnancies, and avoiding interventions that do not improve outcomes. [3]

It's important to distinguish between "treatment of habitual miscarriage" and "treatment of threatened miscarriage during a current pregnancy." For example, progesterone is not recommended for everyone with unexplained habitual miscarriage, but it may be recommended for early bleeding in women with previous losses, if an intrauterine pregnancy is confirmed. [4]

Diagnostics without which treatment is a matter of chance

Treatment should focus on causes that can be effectively corrected. These include antiphospholipid syndrome, certain congenital uterine anomalies, severe thyroid pathology, and some second-trimester conditions associated with cervical insufficiency. Testing "for everything" is usually ineffective, so the emphasis is on tests that change the treatment strategy. [5]

The key components of treatment selection for recurrent early pregnancy losses include assessment of antiphospholipid antibodies according to criteria, evaluation of the uterine cavity structure, and basic thyroid endocrine screening. For second-trimester losses, the approach shifts: it is more important to rule out structural causes of the cervix and evaluate the history of preterm labor and painless dilation. [6]

If possible, it makes sense to test the fetal sac tissue for chromosomal abnormalities: this helps distinguish random aneuploidies from situations where a maternal factor is more likely, and facilitates informed discussions about further steps, including genetic counseling. Paired karyotyping of the parents is usually considered selectively, especially if unbalanced structural rearrangements are detected in the tissues or the material is unavailable. [7]

Not all popular “additional” tests are useful. Routine infectious screening without clinical signs, extended immunological panels (e.g., natural killer cell tests, cytokines, human leukocyte antigen compatibility) are generally not recommended outside of research settings because they rarely change treatment and often lead to prescriptions without proven benefit. [8]

Table 1. Examinations that most often influence the choice of treatment

What is being revealed	What is confirmed?	How does treatment change?
Antiphospholipid syndrome	Lupus anticoagulant, anticardiolipin antibodies, antibeta-2-glycoprotein I antibodies (repeat according to the rules)	Anticoagulants are added during pregnancy according to the regimens for antiphospholipid syndrome.
Uterine cavity anomaly	3D ultrasound, hysteroscopy according to indications	Surgical correction is considered in certain cases.
Thyroid dysfunction and thyroid autoimmunity	Thyroid-stimulating hormone, free thyroxine as indicated, thyroid peroxidase antibodies	Correction of overt hypothyroidism, individual tactics for subclinical forms
Genetic factor of loss	Tissue loss analysis, genetic consultation	Reassessment of prognosis, sometimes paired karyotyping, discussion of reproductive options
Second trimester losses, suspected cervical insufficiency	History, serial cervicometry	Cervical observation, discussion of cervical suture in selected situations

Treatment for antiphospholipid syndrome and hemostasis disorders

Antiphospholipid syndrome remains one of the few conditions for which drug therapy reliably increases the likelihood of live birth. Guidelines typically recommend a combination of low-dose aspirin and heparin (usually low molecular weight) during pregnancy, as the combination has been shown to have better outcomes than aspirin alone. [9]

The initiation, dosage, and duration of therapy depend on the clinical presentation and obstetric history. Recommendations include the following approach: aspirin is started before conception or immediately after pregnancy is confirmed, heparin is added after confirmation of a viable intrauterine pregnancy, and thrombosis prophylaxis is continued for a limited period after delivery in some high-risk patients. The specific regimen is always determined by a physician, as the balance between benefit and bleeding risk is individualized. [10]

It is important to note that anticoagulants are not a "universal treatment for recurrent miscarriage." In unexplained recurrent miscarriage, heparin and aspirin do not improve live birth rates, so they are not recommended as a "just in case" treatment. This is one of the key areas where the modern evidence base diverges from popular treatments from older sources. [11]

Inherited thrombophilias have a weaker association with recurrent losses than antiphospholipid syndrome, and approaches to testing and treatment are more cautious. Some guidelines allow selective testing for second-trimester losses, but routine anticoagulation in the absence of antiphospholipid syndrome is not supported. [12]

Table 2. Antiphospholipid syndrome: what is usually included in treatment

Element of therapy	When considering	What is important to control
Low dose acetylsalicylic acid (usually 75-150 mg)	Confirmed antiphospholipid syndrome, high risk	Risks of bleeding, associated contraindications
Low molecular weight heparin in a prophylactic dose	Confirmed antiphospholipid syndrome with pregnancy loss	Platelets, signs of bleeding, delivery schedule
Extension of prophylaxis after childbirth in some patients	With an increased risk of thrombosis	Postpartum risk of thrombosis, individual factors

Table 3. Anticoagulants for habitual miscarriage: where indicated and where not

Situation	Anticoagulants	Comment
Confirmed antiphospholipid syndrome	Yes, according to obstetric schemes	The most proven drug option
Unexplained habitual miscarriage	No	They do not increase the live birth rate
Hereditary thrombophilia without antiphospholipid syndrome	Usually no	The decision is individual, the evidence base is limited

Treatment for anatomical causes and pathology of the cervix

If a congenital uterine cavity anomaly is detected, the treatment strategy depends on its type. For uterine septum, hysteroscopic correction is discussed: some meta-analyses show a reduction in the rate of losses, but the impact on the live birth rate is less clear. Therefore, in a number of guidelines, the recommendation is formulated cautiously and often with the caveat that it should be performed in experienced centers and with audited results. [13]

Other anatomical causes that may require treatment include significant intrauterine adhesions, significant submucosal nodes, or endometrial polyps if they distort the uterine cavity. The decision to intervene is usually made after visualization of the cavity and discussion of alternatives, as the finding itself does not always indicate loss. [14]

Cervical insufficiency is a separate issue for second-trimester losses. Modern management often begins not with a "prophylactic suture for everyone," but with serial ultrasound monitoring of cervical length in subsequent pregnancies. Cervical insufficiency is considered in women with repeated second-trimester losses likely associated with cervical insufficiency, but it is emphasized that evidence of its impact on neonatal survival is limited. [15]

It's important to distinguish between treating the underlying cause and symptomatic treatment. In cases of anatomical factors, "one-size-fits-all" regimens of sedatives, antispasmodics, and hemostatic agents do not resolve the problem and may delay appropriate referral for further evaluation and specialized intervention. A more effective strategy is one in which the underlying cause is confirmed and intervention is targeted. [16]

Table 4. Anatomical causes and treatment options

Cause	As confirmed	What are they doing?
Uterine septum	3D ultrasound, hysteroscopy	Hysteroscopic correction is discussed in individual cases.
Adhesions of the uterine cavity	Hysteroscopy	Consider dissection of adhesions, then control of the cavity
Submucous node, polyp with cavity deformation	Ultrasound, hysteroscopy according to indications	Removal according to indications depending on the impact on the cavity
Suspected cervical insufficiency	History, serial cervicometry	Observation and discussion of cervical suture in selected cases

Treatment for endocrine, metabolic, infectious and genetic factors

Of the endocrine conditions, the thyroid gland is the most practical. Screening for thyroid-stimulating hormone and thyroid peroxidase antibodies is recommended for women with recurrent miscarriage; in cases of overt hypothyroidism, levothyroxine treatment is considered standard treatment, as normalizing hormonal status is important for pregnancy development. In cases of subclinical hypothyroidism and isolated antibodies, the evidence supporting treatment benefits is weaker, so treatment decisions are often individualized. [17]

Metabolic factors aren't treated with a "miscarriage pill," but correcting them does improve the overall pregnancy prognosis: achieving a healthier body mass index, quitting smoking, and limiting alcohol and caffeine. This doesn't sound like a "strong treatment," but guidelines include these recommendations because the association with the risk of loss and complications is supported by epidemiological data, and the interventions are relatively safe. [18]

The infectious factor is often overestimated. In recurrent miscarriage, routine testing and treatment for asymptomatic "hidden infections" is generally not recommended, just as most immunological screenings are not recommended, because evidence of improved outcomes is limited. Exceptions include situations with clinical signs of infection and standard obstetric indications, where the specific infection, rather than the "miscarriage," is treated. [19]

Genetic causes are divided into two broad groups: random embryonic aneuploidies and rare parental rearrangements. When structural rearrangements are confirmed, reproductive assistance options are discussed, but routine preimplantation genetic testing for aneuploidies in unexplained recurrent miscarriage is not considered standard due to a lack of data on the benefits and potential risks and costs. [20]

Table 5. Endocrine and metabolic factors: what they actually do

Factor	Pre-pregnancy tactics	Pregnancy tactics
Overt hypothyroidism	Levothyroxine to target thyroid stimulating hormone levels	Monitoring thyroid stimulating hormone, dose adjustment
Subclinical hypothyroidism, thyroid peroxidase antibodies	Individually, discussion of benefits and risks	Observation, decision on therapy based on the clinical situation
Overweight	Weight loss plan, nutrition, physical activity	Weight gain control, prevention of complications
Smoking, alcohol, high caffeine	Complete cessation of smoking, limitation of alcohol and caffeine to 200 mg per day	Support for refusal and restrictions

Table 6. Interventions without proven routine benefit for unexplained recurrent miscarriage

Method	Why is it not recommended routinely?	Potential risks
Heparin or acetylsalicylic acid without antiphospholipid syndrome	They do not increase the live birth rate	Bleeding, hematomas, complications of therapy
Progesterone for everyone with unexplained habitual miscarriage	There is no compelling benefit as a universal strategy	Side effects, false sense of “control”
Immune therapies without clear indications (eg, prednisolone, intravenous immunoglobulin)	The data is heterogeneous, and research is often needed	Side effects, pregnancy complications
Expanded immunological panels as a basis for treatment	They do not improve outcomes and often lead to unnecessary prescriptions.	Overdiagnosis, unnecessary interventions

Management of unexplained pregnancy loss and prevention in future pregnancies

If no cause is found, the mainstay of treatment is a supportive and monitoring strategy, rather than a "multiple medications just in case." Guidelines emphasize that avoiding unnecessary anticoagulants and other interventions is just as important as prescribing what is truly indicated. However, the prognosis often remains favorable, especially with a good monitoring plan and risk factor management. [21]

A practical plan for a new pregnancy typically includes early confirmation of pregnancy location, viability monitoring, and repeated consultations in the first trimester. This helps promptly distinguish normal pregnancy from complications and reduces the likelihood of late detection of problems. This "monitoring organization" in recurrent miscarriage clinics is considered an important part of care. [22]

Regarding progesterone: it is not recommended as a routine treatment for unexplained recurrent miscarriage. However, for early bleeding in women with previous losses, some recommendations suggest vaginal micronized progesterone 400 mg twice daily up to 16 weeks with a confirmed intrauterine pregnancy, as large studies and expert committees have shown a benefit in terms of live births in this specific clinical situation. [23]

Prevention of recurrent pregnancy loss in subsequent pregnancies involves a combination of targeted therapy for the identified cause and mitigation of underlying risks: weight management, smoking cessation, limiting alcohol and caffeine, correcting thyroid disease, and, in the case of antiphospholipid syndrome, strictly adhering to an anticoagulant regimen under supervision. If losses occurred in the second trimester, the plan is supplemented by serial cervicometry and discussion of cervical interventions in selected cases. [24]

Table 7. Example of a practical plan for monitoring the next pregnancy

Timeframe and stage	Target	What do they usually do?
Early period after a positive test	Confirm intrauterine pregnancy	Ultrasound as indicated, symptom assessment
1st trimester	Early detection of complications	Monitoring according to plan, correction of therapy for antiphospholipid syndrome
2nd trimester with previous losses of this period	Cervical assessment	Serial cervicometry, discussion of the suture when indicated
The entire period of pregnancy	Prevention of complications	Control of concomitant diseases and risk factors