Recurrent pregnancy loss — what can be done?

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Definition: what counts as a miscarriage

Recurrent pregnancy loss means two or more spontaneous losses, each occurring before 20–24 weeks of gestation.

The following all count as a loss:

• A pregnancy confirmed on a urine or blood test that later becomes negative
• A blighted ovum (anembryonic pregnancy)
• Fetal demise — the heartbeat stops
• The cervix opens and the pregnancy is passed spontaneously

Recurrent pregnancy loss affects roughly 1–2% of women who conceive (ESHRE guideline, 2022).

Risk factors that cannot be changed

Lifestyle and body-weight risk factors

• Smoking — 1.2× risk
• Low caffeine intake (50–149 mg/day) — no increase in risk
• Moderate caffeine (150–349 mg/day) — 1.16× risk
• High caffeine (350–699 mg/day) — 1.4× risk
• Underweight, BMI < 19 kg/m² — 1.2× risk
• Overweight, BMI > 25 kg/m² — 1.2× risk
• Alcohol — 3.7× risk

Conditions that can be treated

APS (antiphospholipid antibody syndrome)

• Lupus anticoagulant (LA) — 7.79× risk
• Anticardiolipin IgM (ACL) — 5.6× risk
• Anticardiolipin IgG — 3.6× risk
• Anti-β2GP-I (anti-beta-2-glycoprotein-I) — 2.1× risk

Inherited thrombophilia

• Factor V Leiden — 2× in the first trimester, 7.8× in the second
• Prothrombin mutation — 1.8× risk
• Protein S deficiency — 14.7× risk

Genetic factors

• Parental chromosome rearrangement — 2.2× risk
• A previous euploid loss — 2.6× risk

Uterus and thyroid

• Congenital uterine malformation — 1.3–3× risk
• Uterine fibroids — 1.16× risk
• Thyroid autoantibodies — 1.86× risk

Which tests are worth doing

Given the risk factors above, the recommended work-up is:

Uterine structure

• Three-dimensional ultrasound (3D-TVUS) is the main investigation
• Alternatives: MRI, or 2D ultrasound with saline infusion sonography (SIS)
• HSG is not recommended

Immune testing

• Test for antiphospholipid syndrome (APS)
• Inherited thrombophilia is not recommended as routine testing — Factor V Leiden, prothrombin mutation, protein S deficiency

Endocrine testing

• TSH ± anti-TPO
• Prolactin
• Screening for diabetes

Genetic testing

• Karyotype of the products of conception
• Parental karyotype, when the products of conception cannot be tested

Tests not recommended as routine

• Sperm DNA fragmentation
• Chronic endometritis

Treatment

Recurrent loss has many causes. In any one couple the work-up may find a single cause, several causes, or none at all.

Lifestyle changes

• Vitamin B6 and folic acid supplements
• Stop smoking
• Keep weight in range — BMI 18–25, and 19–25 kg/m² is better still
• Keep alcohol to a minimum
• Exercise regularly — 1–3 hours a week for women, 4–6 hours a week for men

Endocrine treatment

• Hypothyroidism must be treated
• Subclinical hypothyroidism — TSH > 4 mIU/L with a normal fT4 — should also be treated
• Raised anti-TPO with normal thyroid hormones is not yet an indication to treat, unless another autoimmune disease also needs treating
• For high prolactin, bromocriptine is recommended
• Metformin and growth factors are not recommended

The uterus

• Congenital abnormalities such as a dysmorphic or septate uterus should be corrected surgically
• Submucous fibroids distorting the cavity should be removed hysteroscopically

Antiphospholipid syndrome

Treatment is aspirin combined with unfractionated or low-molecular-weight heparin, as appropriate. In some cases aspirin with heparin, or IVIG, is used.

Genetic causes

• Where a parent carries a segmental rearrangement, PGT-SR on the embryos can reduce miscarriage
• Where neither parent has a chromosome abnormality, PGT-A does not reduce miscarriage

When no cause is found (unexplained)

The chance of carrying a future pregnancy successfully is high — please do not lose heart. IVF with PGT-A before transfer may help in some cases.

In summary

Recurrent loss is a particular and complex problem. It needs an appropriate, targeted work-up and targeted treatment to prevent it happening again. I wish you every success.

A video explanation is available on YouTube.

References

1. Hennessy M, Dennehy R, Meaney S, Linehan L, Devane D, Rice R, O'Donoghue K. Clinical practice guidelines for recurrent miscarriage in high-income countries: a systematic review. Reproductive BioMedicine Online. 2021;42(6):1146-1171.
2. Suker A, Li Y, Robson D, Marren A; Australasian CREI Consensus Expert Panel on Trial Evidence (ACCEPT) group. Australasian recurrent pregnancy loss clinical management guideline 2024, part I. Aust N Z J Obstet Gynaecol. 2024 Oct;64(5):432-444.
3. Suker A, Li Y, Robson D, Marren A; ACCEPT group. Australasian recurrent pregnancy loss clinical management guideline 2024, part II. Aust N Z J Obstet Gynaecol. 2024 Oct;64(5):445-458.
4. ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Mcheik S, Peramo B, Quenby S, Nielsen HS, van der Hoorn ML, Vermeulen N, Goddijn M. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023 Mar 2;2023(1):hoad002.
5. Regan L, Rai R, Saravelos S, Li TC; Royal College of Obstetricians and Gynaecologists. Recurrent miscarriage. Green-top Guideline No. 17. BJOG. 2023 Nov;130(12):e9-e39.