Recurrent Pregnancy Loss

Recurrent pregnancy loss is now defined as two or more pregnancy losses, and a cause is found in only about half of couples. The evaluation starts with one question, whether the losses occur in the first or the second trimester, followed by baseline tests for every couple and further tests only for selected couples. Even after three losses, the chance of a successful pregnancy is 65 to 70%.

Recurrent pregnancy loss is a demoralising problem in reproductive medicine, for couples and for the doctors treating them. Couples arrive anxious for an explanation, and their doctors want to help them find one. Dr. Kanika Singh, Sr. Consultant - Medical Genetics, Artemis Hospitals, Gurugram, India, chose the subject for exactly that reason: so much about why pregnancies fail repeatedly remains poorly understood, and a structured approach is the best way to find an answer where one exists. Her framework rests on three ideas. Ask first whether the losses happen in the first or the second trimester, because the causes differ. Run a small set of tests in every couple and a larger set only in selected couples. And keep the prognosis in view, because it is considerably better than most couples assume.

What is recurrent pregnancy loss? Definition and frequency

The American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) both now define recurrent pregnancy loss, also called recurrent miscarriage, as two or more pregnancy losses. The older threshold of three losses has been abandoned, which brings couples into evaluation one loss earlier.

The background rate matters for counselling. About 15 to 20% of recognised pregnancies end in spontaneous miscarriage, so a single loss is common and usually sporadic. Recurrent loss, particularly in the first trimester, affects about 1% of couples.

What causes recurrent pregnancy loss?

A cause is found in only about half of couples; the rest remain unexplained despite extensive workup. Dr. Singh's slide on aetiology sets out the broad distribution:

• Genetic causes: 2 to 5%
• Anatomical causes: 10 to 15%
• Autoimmune causes: 20%
• Infections: 0.5 to 5%
• Endocrine factors: 17 to 20%
• Unexplained, despite extensive workup: 40 to 50%

Two points follow. First, an unexplained result is the expected outcome for many couples, not a failure of the investigation. Second, the categories are wide, which is why Dr. Singh insists that thinking only about genetic causes is not enough. Couples sometimes need extensive evaluation across several systems before a contributory factor emerges.

The genetic causes, from fetal aneuploidy to parental balanced translocations and single-gene disorders, are covered in depth in the companion article on genetic causes of recurrent pregnancy loss and pre-implantation genetic testing. The anatomical, endocrine, thrombotic, immunological and male factors, and how each is treated, are covered in the article on recurrent pregnancy loss treatment by cause.

First- vs second-trimester miscarriage: why the timing matters

The gestation at which the losses occur is the first thing Dr. Singh establishes from the history, because first- and second-trimester losses have different causes. She broadly sorts couples into one of two lists.

First-trimester losses point towards:

• chromosomal abnormality in the embryo, which must be ruled out first
• antiphospholipid antibody syndrome
• endocrine disorders in the woman
• structural problems of the uterus
• autoimmune causes

Second-trimester losses point towards a different set:

• cervical incompetence
• intrauterine adhesions
• endometriosis
• bacterial vaginosis
• congenital anomalies of the uterus and genital tract

A third pattern carries its own message. When the same ultrasound abnormality appears in pregnancy after pregnancy in the second trimester, Dr. Singh regards a genetic cause, typically a single-gene condition, as the leading explanation.

The trimester split also sets expectations for chromosomal testing: the earlier the loss, the more likely the embryo was chromosomally abnormal, although Dr. Singh still checks chromosomes in later losses.

Taking the history: what the doctor will ask

Dr. Singh's history is designed to surface the clues that redirect the workup. She asks about:

• The number of losses and when they occurred. This sets the trimester pattern and the prognosis.
• Chronic illness in the woman. Systemic lupus erythematosus, alopecia or any other condition suggesting an autoimmune predisposition raises the index of suspicion for immune and antiphospholipid causes.
• Malformations seen on ultrasound in previous pregnancies, and whether they recur.
• Family history of infertility, recurrent pregnancy loss, or a child with developmental delay or a malformation. Any of these suggests an inherited chromosomal or genetic factor.
• Occupation and lifestyle factors.
• Polycystic ovarian disease, diabetes and deep vein thrombosis in the woman.

Recurrent pregnancy loss tests every couple should have

Every couple should have four baseline investigations: chromosomal analysis of the pregnancy tissue, imaging of the uterine cavity, antiphospholipid antibody testing, and a hormonal and metabolic screen. Dr. Singh's baseline panel is short, and every element earns its place.

Chromosomal microarray of the pregnancy tissue

Testing the products of conception (the pregnancy tissue passed or removed after a miscarriage) is, in her words, the best thing a clinician can do, because it answers the most likely question directly. When tissue is retrieved, particularly at a surgical evacuation, it should go for chromosomal microarray rather than conventional karyotyping. Karyotyping detects only large deletions, duplications and missing or extra chromosomal segments. Microarray detects far smaller imbalances and has a higher diagnostic yield, so it is now the first-line test.

One practical step is frequently missed. The mother's blood sample (in an EDTA tube) should be sent with the tissue. Products of conception are often heavily mixed with maternal tissue, and a laboratory can return a reassuring "normal" result that in fact describes the mother's chromosomes. With the paired maternal sample, the laboratory can exclude maternal cell contamination and confirm that the result genuinely reflects the pregnancy.

Imaging the uterine cavity

The cavity is assessed by three-dimensional ultrasound, hysterosalpingography (an X-ray of the uterus and tubes taken with contrast dye) or, increasingly, saline infusion sonography (ultrasound with saline instilled into the cavity). The aim is to identify a developmental anomaly of the uterus, a fibroid, a polyp or adhesions.

Antiphospholipid antibody tests

Antiphospholipid antibodies are the markers of antiphospholipid syndrome, an autoimmune condition that makes the blood prone to clot. Three antibodies are checked: anti-beta-2 glycoprotein I, anticardiolipin and lupus anticoagulant. Timing matters: testing should be done at least six weeks after a miscarriage, because the physiological changes that follow a pregnancy loss can produce false-positive results.

Thyroid, diabetes and PCOS screening

• Thyroid profile. Thyroid peroxidase (TPO) antibodies are recommended alongside TSH by ESHRE, though not by every guideline, and Dr. Singh adds them routinely, because a positive result indicates an autoimmune predisposition that informs the rest of the evaluation.
• HbA1c and fasting blood sugar for diabetes.
• Assessment for polycystic ovarian disease, which Dr. Singh treats as mandatory given how prevalent it has become.

Additional tests for selected couples

A second tier of tests is reserved for couples whose baseline workup is normal, or whose history points in a particular direction.

Parental karyotype. When testing of the pregnancy tissue is not feasible, both partners should have a karyotype, a count and structural check of the full set of chromosomes. Here the choice of test reverses: microarray is the wrong tool for the parents. A balanced translocation, in which segments of two chromosomes have swapped places, involves no net gain or loss of genetic material, so microarray, which detects only imbalances, cannot see it. In the parents the question is not whether chromosome numbers are abnormal (they are known to be normal) but whether a balanced rearrangement is present, and only a karyotype answers it.

Sperm DNA fragmentation. Not ordered often, but worth considering when the couple also has infertility and all other investigations are normal.

Chronic endometritis. Chronic endometritis is persistent inflammation of the lining of the uterus. The guidelines mention endometrial biopsy. It is not routine, but the history may justify investigating and treating it, alongside a standard vaginal swab.

Fasting prolactin. Recommended only where there is galactorrhoea or a history of anovulatory cycles.

Inherited thrombophilias. These are genetic tendencies to blood clotting. They are no longer recommended for testing by the guidelines, but are tested by Dr. Singh in defined circumstances, notably a history of deep vein thrombosis or second-trimester losses.

Immune markers. TNF-alpha, B cells and natural killer cells, measured in blood. The guidelines do not support this testing; Dr. Singh orders it selectively, for reasons set out in the article on treatment by cause.

Chances of a successful pregnancy after recurrent miscarriage

After a single loss, the chance of success in the next pregnancy is 80 to 90%, and even after three losses it remains 65 to 70%. Prognosis depends on the underlying cause, the number of previous losses and the woman's age. The chance of a successful pregnancy does fall with each loss, but far less steeply than couples fear, and after three or four losses there is still a good chance of a successful term pregnancy.

That message changes the tone of the consultation. A couple with three losses is still more likely than not to have a successful pregnancy, so careful evaluation and genuine reassurance are complementary rather than competing tasks.

Where Dr. Singh's practice departs from the ESHRE and ASRM guidelines

Dr. Singh's management framework combines the ESHRE and ASRM guidelines, and she is explicit where her practice departs from them. She tests for inherited thrombophilias and immune markers selectively, although the guidelines advise against. She considers immunotherapy for a narrow group of women. Each departure is confined to a defined clinical context: an autoimmune history, a second-trimester pattern, or a normal first-line workup. That discipline, testing broadly only when the first line is unrevealing and the history justifies it, is what separates a structured evaluation from an exhaustive and expensive one.

For couples whose losses are chromosomal, reproductive options extend from natural conception with prenatal diagnosis to IVF with pre-implantation genetic testing, discussed in the genetics article linked above. For couples with antiphospholipid syndrome, thyroid disease, polycystic ovary syndrome or a uterine lesion, specific treatment exists, discussed in the article on treatment by cause. Dr. Singh's answers to referring doctors on metformin timing in PCOS and on sperm quality in men over 50 are recorded in the masterclass Live Discussion.