Recurrent Pregnancy Loss (RPL): Causes, Investigation & Treatment

Recurrent Pregnancy Loss: Causes, Investigation & Treatment

Recurrent pregnancy loss (RPL) — also called recurrent miscarriage — is defined as two or more pregnancy losses before 20 weeks of gestation (ASRM 2020 definition). It affects approximately 1–2% of couples and is one of the most emotionally devastating experiences in reproductive medicine.

What Causes Recurrent Pregnancy Loss?

Chromosomal abnormalities (50–60% of losses) The majority of individual miscarriages are caused by random chromosomal errors in the embryo — usually aneuploidy (wrong number of chromosomes). In recurrent cases, the most relevant causes are:

• Parental chromosomal translocations: Found in 3–5% of RPL couples. One parent carries a balanced chromosomal rearrangement that appears normal in them but can produce unbalanced embryos. Karyotyping of both partners is essential.
• Embryonic aneuploidy: In older women, the higher aneuploidy rate means RPL is more likely to be random rather than a recurring cause.

Uterine anatomical abnormalities (15–20%)

• Uterine septum: The most clinically significant — associated with a 65–70% miscarriage rate if untreated; hysteroscopic resection reduces risk significantly
• Submucous fibroids (indenting the uterine cavity)
• Uterine polyps
• Asherman's syndrome (intrauterine adhesions — often from prior D&C)
• Unicornuate or bicornuate uterus

Thrombophilias — clotting disorders

• Antiphospholipid Syndrome (APS): The most treatable cause — found in ~15% of RPL cases. Characterised by antiphospholipid antibodies (ACA, anti-β2GPI, lupus anticoagulant) causing placental thrombosis. Treatment: low-dose aspirin + heparin (LMWH) from positive pregnancy test — reduces miscarriage rate from ~90% to ~70–75% live birth rate.
• Hereditary thrombophilias (Factor V Leiden, prothrombin mutation): Association with RPL is weaker than APS. ESHRE 2023 does not recommend routine thrombophilia treatment for hereditary thrombophilias in RPL without confirmed thrombosis.

Hormonal and metabolic factors

• Poorly controlled thyroid disease — TSH should be <2.5 mIU/L in early pregnancy; levothyroxine is safe and effective
• Poorly controlled diabetes
• Polycystic ovary syndrome — elevated LH and androgens may contribute; insulin resistance may impair implantation
• Luteal phase deficiency (progesterone support) — evidence is evolving

Immune and inflammatory factors

• Natural killer cell abnormalities — controversial; routine NK cell testing is not endorsed by ASRM or ESHRE
• Endometritis — chronic endometrial inflammation; diagnosed by hysteroscopy or endometrial biopsy; treated with antibiotics

Unexplained RPL (50% of cases) Even after a complete workup, approximately 50% of RPL couples have no identified cause. This is distressing but carries a reasonably good prognosis: the live birth rate with supportive care alone ("tender loving care") in unexplained RPL is 50–75% in the subsequent pregnancy.

Essential Investigations

Per ASRM 2020 and ESHRE 2023 RPL guidelines:

For both partners:

• Peripheral blood karyotype (chromosomal analysis)

Female:

• Antiphospholipid antibodies: Lupus anticoagulant, anticardiolipin IgG/IgM, anti-β2GPI IgG/IgM (test twice ≥12 weeks apart for diagnosis)
• TSH, T4 (thyroid function)
• Fasting glucose and HbA1c
• AMH (ovarian reserve — guides IVF/PGT-A counselling)
• Uterine assessment: SIS (saline infusion sonography) or hysteroscopy — preferred over HSG for uterine cavity
• Consider: progesterone levels in luteal phase

Conceptus (products of conception) if available:

• Chromosomal microarray or karyotype of miscarriage tissue — identifies whether aneuploidy was the cause and guides counselling

Not routinely recommended (insufficient evidence per ESHRE 2023):

• Thrombophilia screen beyond APS
• Natural killer cell testing
• HLA typing
• Routine sperm DNA fragmentation (though may be considered in unexplained RPL)

Treatment Options

Reference: ASRM Practice Committee — Evaluation and Treatment of Recurrent Pregnancy Loss, 2020. ESHRE Guideline: Recurrent Pregnancy Loss, 2023. PROMISE Trial — Progesterone in Unexplained Recurrent Miscarriage.