Recurrent Pregnancy Loss: When to Investigate and What to Test

Miscarriage is more common than most people realise — approximately 10 to 15% of clinically confirmed pregnancies end in loss, the majority in the first trimester. For most couples who experience a single miscarriage, no investigation is recommended. It is statistically likely to be a chromosomal event in the embryo — random in nature, unlikely to recur.

Recurrent pregnancy loss (RPL) is a different situation. Defined as two or more consecutive pregnancy losses, it affects approximately 1 to 2% of couples trying to conceive — and it demands a structured, systematic investigation. Not because a cause is always found (in approximately 50% of cases, it is not), but because when a treatable cause is present, the difference in outcome can be profound.

Why Does Miscarriage Happen?

The great majority of first-trimester miscarriages — in sporadic and recurrent cases alike — are driven by chromosomal abnormalities in the embryo. An embryo with an incorrect number of chromosomes (trisomy, monosomy, or polyploidy) either fails to implant, or implants and then arrests in early development. This is largely a function of egg quality — which declines with age — and is why miscarriage rates rise so steeply in the mid-to-late thirties.

When miscarriage occurs repeatedly, the questions become: is this continuing to be random chromosomal bad luck? Or is there an underlying maternal, paternal, or uterine factor making loss more likely?

The Most Common Causes of Recurrent Pregnancy Loss

1. Embryonic Chromosomal Abnormality

Even in recurrent pregnancy loss, the most common explanation for each individual loss is chromosomal abnormality in the embryo. In women over 35, the majority of RPL cases are driven by age-related egg aneuploidy — an increasing proportion of eggs carry chromosomal errors, and this produces an increasing proportion of chromosomally abnormal embryos that miscarry.

The most powerful tool for breaking this cycle in the context of IVF is preimplantation genetic testing (PGT-A): chromosomal analysis of blastocysts before transfer, selecting only euploid embryos. PGT-A significantly reduces the miscarriage rate in RPL patients with an identified chromosomal cause.

2. Parental Chromosomal Abnormalities

In approximately 2 to 5% of RPL couples, one partner carries a structural chromosomal rearrangement — most commonly a balanced translocation. This person is healthy (because the rearrangement is balanced), but their eggs or sperm carry an unbalanced complement, producing embryos that miscarry. Karyotyping of both partners is a standard and essential component of the RPL workup.

3. Uterine Structural Abnormalities

Structural abnormalities of the uterine cavity account for approximately 10 to 15% of RPL:

• Uterine septum: A congenital fibrous band dividing the uterine cavity — the most common surgically correctable structural cause of RPL. Blood supply to the septum is poor, causing implanted embryos to fail. Hysteroscopic septum resection is a minimally invasive day procedure with excellent outcomes.
• Submucosal fibroids: Cavity-distorting fibroids impair implantation and early pregnancy support. Hysteroscopic or laparoscopic myomectomy is curative.
• Intrauterine adhesions: Scarring within the cavity (Asherman's syndrome) from previous D&C, infection, or surgery — reduces the functional endometrial surface.
• Bicornuate or unicornuate uterus: Congenital malformations associated with second-trimester loss and preterm birth.

4. Antiphospholipid Syndrome (APS)

APS is the most important treatable immunological cause of RPL, and one of the most rewarding to diagnose. It is an autoimmune condition in which the body produces antibodies (anticardiolipin antibodies, lupus anticoagulant, anti-beta2-glycoprotein I) that promote clot formation in the placental blood vessels, cutting off blood supply to the developing embryo.

APS is diagnosed by two positive antibody tests at least 12 weeks apart. Treatment with low-dose aspirin and low-molecular-weight heparin (LMWH) during pregnancy significantly improves live birth rates — from approximately 10 to 20% untreated to 70 to 75% with treatment in APS-related RPL. It is one of the most important RPL diagnoses to make.

5. Thyroid Disease and Hormonal Factors

Both clinical and subclinical hypothyroidism are associated with increased miscarriage risk. Even women with TSH in the low-normal range but positive thyroid peroxidase antibodies (Hashimoto's thyroiditis) have elevated miscarriage rates. Levothyroxine treatment to maintain TSH below 2.5 mIU/L in pregnancy is the standard approach.

Elevated prolactin (hyperprolactinaemia) — even at mild levels — can impair the luteal phase and early pregnancy support. PCOS-related hormonal imbalance is also associated with early pregnancy loss.

6. Sperm DNA Fragmentation

Emerging evidence implicates sperm DNA fragmentation in recurrent miscarriage — even when semen analysis parameters are entirely normal. Sperm with fragmented DNA may fertilise eggs normally but produce embryos that arrest at various developmental stages or implant and then miscarry. Sperm DNA testing should be included in the RPL investigation of any couple where the losses are chromosomally normal on miscarriage tissue testing.

The Complete RPL Investigation Panel

• Karyotype (chromosomal analysis) of both partners
• Antiphospholipid antibody panel: anticardiolipin IgG/IgM, lupus anticoagulant, anti-beta2-glycoprotein I — on two occasions at least 12 weeks apart
• Thyroid function (TSH, free T4) and thyroid peroxidase antibodies
• Fasting glucose and insulin if PCOS is suspected
• Pelvic ultrasound and/or hysteroscopy for uterine cavity assessment
• Thrombophilia screen: Factor V Leiden, prothrombin gene mutation, protein C and S, antithrombin III — in selected patients based on history
• Sperm DNA fragmentation — should be routinely included
• Miscarriage tissue genetic testing (products of conception) — whenever possible from each loss

When a Cause Is Not Found

In approximately 50% of RPL cases, a complete investigation yields no identifiable cause. This is frustrating — but the prognosis is not as bleak as couples often fear. The live birth rate in subsequent pregnancies with unexplained RPL is approximately 60 to 70% with supportive care — close monitoring, early scan reassurance, and luteal phase progesterone support — even without a specific treatment being given.

For couples with unexplained RPL in the context of IVF, PGT-A to select chromosomally normal embryos is a valuable strategy even without a confirmed genetic cause in the parents, as it addresses the most common underlying mechanism.

Frequently Asked Questions

Q1. After how many miscarriages should I start investigating?

Most guidelines — including ESHRE and RCOG — now define RPL as two or more consecutive losses. Waiting for three, as older guidelines specified, means an additional pregnancy loss before investigation begins. At Solo Clinic, investigation is offered after two consecutive losses, with tissue testing of each miscarriage where possible to build the diagnostic picture progressively.

Q2. Should the miscarried tissue be tested?

Yes — whenever possible. Testing the products of conception (POC) for chromosomal abnormalities tells you directly whether the specific loss was chromosomal in nature. If the tissue is chromosomally normal, this significantly strengthens the case for investigating maternal or paternal structural or immunological factors. If chromosomal, it guides the consideration of PGT-A in subsequent IVF.

Q3. Can I do anything to prevent a miscarriage once I am pregnant?

This depends on the underlying cause. For APS, aspirin and heparin significantly reduce miscarriage risk once started. For thyroid disease, optimising TSH before and throughout pregnancy is protective. Progesterone supplementation in the luteal phase and early pregnancy is commonly used for luteal phase insufficiency, with some evidence for benefit in women with a history of unexplained RPL. There is no evidence that bed rest, activity restriction, or most commercially marketed supplements reduce miscarriage risk.