Recurrent Miscarriage — Causes, Testing & Treatment

Miscarriage is the most common complication of early pregnancy, affecting approximately 10–15% of all clinically recognized pregnancies. When it happens repeatedly, the emotional toll is profound — and the medical questions become urgent: Why does this keep happening? Can it be prevented?

Recurrent pregnancy loss (RPL) is one of the most challenging areas in reproductive medicine because, even after thorough evaluation, a definitive cause is found in only about half of couples. For the remaining half, the diagnosis is "unexplained RPL" — yet even without a clear answer, the prognosis for eventual live birth is often better than patients expect. Many couples with unexplained RPL share characteristics with those diagnosed with unexplained infertility, where standard testing does not identify a definitive cause.

Defining Recurrent Miscarriage: 2 or 3 Losses?

There is an ongoing debate in reproductive medicine about when to begin formal evaluation. Historically, most guidelines (including the older ASRM guideline) defined RPL as three or more consecutive pregnancy losses. This threshold was partly pragmatic — two losses were considered within the range of statistical bad luck — and partly based on the assumption that investigation should only be triggered when probability of a treatable cause was high.

The more recent ASRM RPL guideline (2020) and the ESHRE RPL guideline (2022) now recommend evaluating couples after two consecutive losses. The rationale:

• Two consecutive losses occur in only about 2–3% of couples, making them relatively unusual.
• Many treatable causes (antiphospholipid syndrome, uterine anomalies) can be identified after two losses.
• Delaying evaluation to three losses causes unnecessary distress and time loss, particularly in older patients.

Working definition for this guide: two or more failed clinical pregnancies (confirmed by ultrasound or histology), with or without a prior live birth.

Chromosomal Causes: The Most Common Explanation

The single most common cause of first-trimester miscarriage is embryonic chromosomal aneuploidy — having the wrong number of chromosomes. More than 50% of all first-trimester pregnancy losses are caused by aneuploid embryos, and this proportion rises with maternal age.

Why Aneuploidy Causes Miscarriage

Most chromosomally abnormal embryos arrest in development or are recognized and expelled by the immune system. This is actually a protective mechanism — aneuploid pregnancies that do progress often result in serious fetal anomalies. Trisomy 16 (the most common single-chromosome trisomy in miscarriages) is universally lethal; trisomies 18 and 13 sometimes survive to term but carry severe anomalies.

Chromosomal Analysis of Miscarriage Tissue

When a pregnancy loss occurs, chromosomal analysis of the products of conception (POC) can determine whether the loss was euploid or aneuploid. This information is diagnostically valuable:

• An aneuploid loss is most likely a random event (meiotic error), and the risk of recurrence depends primarily on maternal age.
• A euploid loss suggests that other factors (uterine, immunological, thrombophilic) may be responsible and warrants further investigation.

Modern POC analysis uses microarray or next-generation sequencing rather than traditional karyotype, offering higher detection rates and results even when tissue culture fails.

Parental Chromosomal Abnormalities

In 2–5% of RPL couples, one partner carries a balanced chromosomal rearrangement (most commonly a balanced translocation or inversion). These rearrangements are personally harmless but can cause unbalanced chromosomal combinations in offspring, leading to miscarriage or anomalous pregnancies. Parental karyotyping is recommended as part of the RPL workup.

Uterine Anatomical Causes

Uterine abnormalities are identified in approximately 10–15% of women with RPL. Both congenital Müllerian anomalies and acquired uterine pathology contribute.

Congenital Uterine Anomalies

The most fertility-relevant Müllerian anomaly is the septate uterus — a fibrous midline septum that divides the uterine cavity, either partially (arcuate or subseptate) or completely. The septum has poor blood supply and cannot support placental development, leading to miscarriage when implantation occurs on or near it.

Hysteroscopic metroplasty (surgical removal of the septum) is associated with substantially lower miscarriage rates in case series, though no randomized trial has been conducted. The ASRM considers correction of a significant septum appropriate in RPL patients.

Other anomalies (bicornuate uterus, unicornuate uterus, didelphys) are associated with late pregnancy losses and preterm birth more than first-trimester RPL.

Acquired Uterine Pathology

• Intrauterine adhesions (Asherman's syndrome) — from prior D&C, infection, or surgery — can impair implantation and placentation.
• Submucosal fibroids — distort the cavity and alter the implantation environment.
• Endometrial polyps — small protrusions of endometrial tissue that may interfere with implantation.

All acquired lesions are evaluable by saline infusion sonography (SIS) or hysteroscopy and are treatable by hysteroscopic surgery.

Thrombophilia: Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is the most clinically important and treatable thrombophilic cause of RPL. APS is an acquired autoimmune condition in which antibodies against phospholipid-binding proteins cause vascular thrombosis and pregnancy complications.

Diagnostic Criteria

APS is diagnosed when a patient has both a clinical criterion (thrombosis or specific obstetric morbidity, including three or more unexplained losses before 10 weeks, or one loss at or after 10 weeks of a morphologically normal fetus) and a laboratory criterion (positive antiphospholipid antibodies on two occasions at least 12 weeks apart):

• Lupus anticoagulant (LA)
• Anticardiolipin antibody (aCL), IgG or IgM, at medium or high titer
• Anti-beta-2 glycoprotein-I antibody (anti-β2GPI), IgG or IgM

Single positive tests are insufficient for diagnosis; persistence at 12 weeks is required to exclude transient positivity.

Treatment

Combination therapy with low-dose aspirin (81 mg/day) and heparin (low-molecular-weight heparin, such as enoxaparin, is preferred) is the standard of care. The Rai & Regan Lancet review demonstrated that this combination significantly reduces miscarriage rates compared to aspirin alone (29% vs. 42% in their landmark RCT). Success rates with treatment are approximately 70–80%.

Inherited Thrombophilias

Factor V Leiden, prothrombin gene mutation, protein C/S deficiency, and antithrombin deficiency are inherited conditions that increase clotting risk. Their role in early RPL is controversial — evidence is stronger for their association with late pregnancy losses (second trimester). Routine screening for inherited thrombophilias in early RPL is not universally recommended by ASRM, though many clinicians screen in patients with mid-trimester losses or failed IVF.

Thyroid Disorders

Thyroid abnormalities are common in women with RPL:

• Hypothyroidism — even subclinical hypothyroidism (TSH >2.5 mIU/L in some studies) is associated with increased miscarriage risk. Treatment with levothyroxine to normalize TSH reduces this risk.
• Thyroid autoimmunity — elevated thyroid peroxidase antibodies (TPO-Ab) are associated with increased miscarriage risk even in euthyroid women, possibly through immune dysregulation. Treatment remains controversial; some studies support levothyroxine even in TPO-Ab positive euthyroid women, but evidence from RCTs is mixed.
• Hyperthyroidism — untreated hyperthyroidism increases miscarriage risk and requires treatment.

TSH and TPO antibodies are part of the standard RPL workup.

Exploring Conception Options?

For couples navigating recurrent miscarriage while continuing to try to conceive, exploring every option — including how conception occurs — can be part of a comprehensive approach.

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Luteal Phase Defect

Luteal phase defect (LPD) — insufficient progesterone production after ovulation — has long been proposed as a cause of early pregnancy loss. The evidence is inconsistent: progesterone secretion varies naturally, and what constitutes an "adequate" luteal phase has never been standardized. The ASRM considers LPD a controversial entity and does not recommend empirical luteal phase support as a proven treatment for RPL in the absence of IVF.

However, the picture shifted with the publication of the PRISM trial (NEJM, 2019), a large multicenter RCT that evaluated progesterone supplementation (400 mg vaginal progesterone twice daily) versus placebo in women with early pregnancy bleeding and a history of one or more prior miscarriages. Among women with three or more prior miscarriages, progesterone therapy significantly increased live birth rates (72% vs. 57%), a clinically meaningful 15-percentage-point improvement. Among women with one or two prior losses, the benefit was not statistically significant.

Based on PRISM and related evidence, vaginal progesterone is now commonly offered to women with three or more prior losses who conceive and present with early pregnancy bleeding. Its use from the time of positive pregnancy test (without bleeding) is less well-supported but practiced in many centers.

Preimplantation Genetic Testing for Aneuploidy (PGT-A)

PGT-A allows genetic analysis of embryo biopsies before transfer, selecting only euploid (chromosomally normal) embryos for implantation. For RPL couples where recurrent aneuploidy is the suspected cause — particularly in older patients or those whose POC analysis has confirmed aneuploid losses — PGT-A is a logical strategy.

Evidence. A large randomized trial (STAR trial, NEJM 2018) did not show that PGT-A improved cumulative live birth rates compared to morphology-based selection in unselected IVF patients. However, this trial used older trophectoderm biopsy techniques and did not specifically focus on RPL patients.

In RPL patients, PGT-A is valued not for increasing the live birth rate per cycle relative to unselected transfer, but for:

• Reducing the miscarriage rate per transfer by ensuring only euploid embryos are transferred
• Potentially shortening time to live birth by avoiding aneuploid transfers
• Providing diagnostic information (if all embryos are aneuploid, this points toward egg quality as the underlying cause)

The ASRM RPL guideline acknowledges PGT-A as a reasonable option in RPL patients, particularly those with a history of aneuploid losses or advancing maternal age. See our PGT-A and embryo grading guide for a detailed discussion.

Unexplained RPL: A Diagnosis of Exclusion

After thorough evaluation, approximately 50% of RPL couples have no identifiable cause. This is frustrating, but several points provide some reassurance:

1. Natural conception success rates remain meaningful. Studies show that even without treatment, 60–75% of women with unexplained RPL who try again will eventually have a live birth — though this probability declines with increasing number of prior losses and advancing age.
2. Supportive care may help. The "tender loving care" (TLC) model — frequent early ultrasound monitoring, emotional support, and reassurance during subsequent pregnancies — has been associated with improved outcomes in uncontrolled studies. Whether this reflects a real physiological benefit or simply better monitoring of pregnancies that would have succeeded anyway is debated.
3. Emerging immune therapies. Treatments targeting immune mechanisms (IVIG, intralipid infusion, corticosteroids, tacrolimus) are being investigated, but none has yet been proven in large RCTs and none is currently recommended in standard guidelines for unexplained RPL.

The RPL Diagnostic Workup: What to Test

A comprehensive RPL evaluation typically includes:

The yield of inherited thrombophilia panels and immune tests (NK cell assays, HLA typing) outside of research settings is debated, and most major guidelines do not recommend them routinely.

Key Takeaways

• RPL evaluation is appropriate after two consecutive losses; waiting for three is no longer standard.
• Aneuploidy accounts for more than 50% of first-trimester losses; POC analysis can confirm whether a specific loss was chromosomal.
• Antiphospholipid syndrome is the most important treatable cause, addressed with aspirin plus heparin.
• Uterine anomalies — particularly septate uterus — are correctable by hysteroscopic surgery.
• Progesterone supplementation (PRISM trial) benefits women with three or more prior losses who experience early pregnancy bleeding.
• PGT-A can reduce miscarriage rates per transfer in RPL patients undergoing IVF by ensuring only euploid embryos are transferred.
• Unexplained RPL carries a reasonable prognosis for eventual live birth with continued attempts.

References

1. American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103–1111. Updated 2020.
2. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535):601–611.
3. Coomarasamy A, et al. A randomized trial of progesterone in women with bleeding in early pregnancy (PRISM trial). N Engl J Med. 2019;380(19):1815–1824.
4. ESHRE Early Pregnancy Guideline Development Group. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2023.
5. Rubio C, et al. In vitro fertilization with preimplantation genetic testing for aneuploidies in cases of unexplained implantation failure. Fertil Steril. 2013;99(2):381–388.

Frequently Asked Questions

How many miscarriages define recurrent pregnancy loss?

The ASRM defines recurrent pregnancy loss (RPL) as two or more clinical pregnancy losses before 20 weeks gestation. The European Society of Human Reproduction and Embryology (ESHRE) uses the same definition but includes biochemical pregnancies in some guidelines. Previously, the threshold was three losses, but most specialists now recommend evaluation after two consecutive losses, particularly in women over 35.

What causes recurrent miscarriage?

Identifiable causes are found in approximately 50% of RPL cases. Common causes include:

• Chromosomal abnormalities in the embryo (most common; accounts for 50–60% of early losses)
• Uterine structural abnormalities — septate uterus, submucous fibroids, Asherman's syndrome (intrauterine adhesions)
• Antiphospholipid syndrome (APS) — an autoimmune clotting disorder; treatable with aspirin and heparin
• Parental chromosomal abnormalities — balanced translocations in either partner
• Endocrine disorders — poorly controlled thyroid disease, diabetes, elevated prolactin
• Thrombophilias — hereditary blood clotting disorders

In approximately 50% of cases, no cause is found (unexplained RPL).

Can PGT-A testing prevent recurrent miscarriage?

PGT-A (preimplantation genetic testing for aneuploidy) allows selection of chromosomally normal embryos for transfer, which significantly reduces the risk of miscarriage due to embryo chromosomal errors. Studies show PGT-A reduces per-transfer miscarriage rates from approximately 20–30% to 2–5% in women with RPL. However, PGT-A does not address non-chromosomal causes of miscarriage (uterine factors, immune issues), and requires IVF, which may not be appropriate for all couples.

Should I take aspirin or heparin for recurrent miscarriage?

Only if you have been diagnosed with antiphospholipid syndrome (APS) — a specific autoimmune condition identified through blood tests (anticardiolipin antibodies, lupus anticoagulant, anti-beta-2 glycoprotein). For confirmed APS, low-dose aspirin plus low-molecular-weight heparin (LMWH) starting from a positive pregnancy test dramatically improves live birth rates (from ~10% to 70–80%). These medications are NOT recommended for recurrent miscarriage without confirmed APS — evidence does not support their use for unexplained RPL.

Is recurrent miscarriage genetic?

Chromosomal abnormalities are the most common cause of individual miscarriages, but parental chromosomal abnormalities (such as balanced translocations or inversions) cause only about 2–5% of RPL cases. If a parental chromosomal abnormality is identified, a genetic counselor can advise on the probability of affected pregnancies and whether IVF with PGT-A is indicated. Most couples with RPL have normal parental chromosomes, and the chromosomal errors are in the embryos themselves (de novo, random events).

What is the prognosis for couples with unexplained recurrent miscarriage?

Despite the emotional burden, the prognosis for couples with unexplained RPL is generally favorable. Studies show that 65–75% of couples with unexplained RPL will have a successful live birth in their next pregnancy without any specific treatment. Supportive care — including early pregnancy monitoring, progesterone supplementation, and psychological support — may improve outcomes in some couples. After 3 or more losses, approximately 65% will achieve a live birth in subsequent pregnancies.