Recurrent Pregnancy Loss Treatment: APS, Thyroid, Fibroids

Recurrent pregnancy loss treatment depends on the cause found once the chromosomes have been examined. Antiphospholipid syndrome is treated with low-dose aspirin and prophylactic heparin, thyroid disease with levothyroxine to keep TSH below 2.5, and cervical incompetence with surveillance and cerclage. The evidence is weaker for treating polyps, inherited thrombophilias and sperm DNA damage, and contested for immune therapies such as IVIG.

Once the chromosomes have been examined, the evaluation of recurrent pregnancy loss widens to the uterus, the hormones, the clotting and immune systems and the male partner. These causes are more varied than the genetic ones and, unlike most of them, many are directly treatable. Dr. Kanika Singh, Sr. Consultant - Medical Genetics, Artemis Hospitals, Gurugram, India, built her management framework from the ESHRE and ASRM guidelines, and she is precise about where the evidence is firm, where it is doubtful, and where her own practice goes further than the guidelines. That three-way distinction runs through every cause below. The genetic causes that precede this evaluation are covered in the article on genetic causes of recurrent pregnancy loss and PGT.

Antiphospholipid syndrome and thrombophilias in pregnancy

Antiphospholipid antibody syndrome (APS) is an acquired, autoimmune tendency to blood clotting, and it is treated in recurrent loss with low-dose aspirin and prophylactic heparin. It belongs to the thrombophilias, conditions that make the blood prone to clot, which fall into two groups. The heritable thrombophilias are genetic: factor V Leiden, the prothrombin gene mutation, and deficiencies of protein C, protein S and antithrombin. The acquired thrombophilias have no genetic basis but an autoimmune one, and the important example is APS.

How is antiphospholipid syndrome diagnosed?

APS is not diagnosed on a blood test alone. It requires at least one clinical criterion and one laboratory criterion.

The clinical criteria are:

• Vascular thrombosis, such as a deep vein thrombosis or a comparable thrombotic event elsewhere in the body, or
• Pregnancy morbidity: three or more unexplained consecutive losses before 10 weeks; one or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks; or a preterm birth before 34 weeks caused by severe pre-eclampsia or placental insufficiency.

The laboratory criteria rest on three antibodies: anticardiolipin, lupus anticoagulant and anti-beta-2 glycoprotein I, with the anticardiolipin and anti-beta-2 glycoprotein I antibodies measured as IgG and IgM. Levels must be significantly raised, above the 99th percentile, and the test must be positive on at least two occasions 12 weeks apart.

When to test for antiphospholipid antibodies

The first test should be done at least six weeks after a pregnancy loss. Timing is a detail Dr. Singh emphasises: the physiological upheaval that follows a loss can produce false-positive results. The sequence is therefore:

1. Wait six weeks after the loss.
2. Test for the three antibodies.
3. Confirm persistence 12 weeks later.

APS treatment in pregnancy: aspirin and heparin

When APS is diagnosed or suspected, low-dose aspirin is started before conception, from the point at which the couple begins trying. Once the pregnancy test is positive, prophylactic heparin is added.

Should inherited thrombophilias be tested?

The guidelines have removed the heritable thrombophilias as a cause of recurrent pregnancy loss, and routine testing is no longer advised. Dr. Singh still tests case by case: when nothing else has been found, when the woman has a history of deep vein thrombosis, or when the losses occur in the second trimester. The studies that do support a link find it concentrated in second-trimester losses.

She is sceptical of empirical anticoagulation. Heparin or low-dose aspirin given prophylactically, when no cause has been found, is of doubtful benefit, although an individual case may still justify it.

Uterine causes: septum, fibroids, polyps and adhesions

A uterine septum, a band of tissue dividing the cavity of the uterus, is an established anatomical cause of recurrent loss, alongside other Müllerian (developmental) anomalies of the uterus. The role of an arcuate uterus, a mild indentation at the top of the cavity, is unclear. Other structural lesions can contribute:

• intrauterine adhesions, scar tissue inside the cavity
• uterine fibroids, usually large ones
• endometrial polyps

The proposed mechanism is interference with the blood supply to the implantation site, or with placentation.

Dr. Singh's management framework, drawn from the guidelines, grades the treatments differently. In it, myomectomy (surgical removal of fibroids) is recommended for multiple submucosal fibroids, which bulge into the cavity, or fibroids with a significant intramural component, lying within the muscle wall. For polyps the evidence is inconclusive: it is not established that they cause loss. Even so, the guidelines consider it reasonable to offer hysteroscopic polypectomy to a woman with recurrent loss and an endometrial polyp. Mild to moderate intrauterine adhesions can be treated hysteroscopically, through a camera passed via the cervix; see the cost of hysteroscopy procedures.

Cervical incompetence: signs and cerclage

In the second trimester, cervical incompetence, a cervix that opens too early without contractions, becomes a leading consideration. It is diagnosed largely on history, and the history is characteristic:

• recurrent spontaneous rupture of the membranes in the second trimester
• completely normal ultrasound findings in the baby
• bulging of the membranes through the cervix
• painless cervical dilatation

Management is cervical surveillance and, where indicated, cerclage, a stitch placed around the cervix. Surveillance begins at 14 to 16 weeks, with serial ultrasound measurement of cervical length. Cerclage is considered if the cervical length falls below 25 mm before 24 weeks.

Endocrine causes: thyroid, PCOS, diabetes and prolactin

The endocrine causes with a specific treatment in Dr. Singh's framework are thyroid disease, polycystic ovarian syndrome, uncontrolled diabetes and hyperprolactinaemia; luteal phase defect is no longer evaluated.

Luteal phase defect has been dropped. It was once routinely evaluated and treated with progesterone, but the guidelines no longer recommend evaluating it. Progesterone may still be considered for an individual woman.

Polycystic ovarian syndrome (PCOS) causes not only infertility but also recurrent loss, through poor oocyte quality. Treatment rests on diet and exercise, which carry particular weight in PCOS, and on metformin when PCOS or insulin resistance is present. In answering a question from the audience in the masterclass Live Discussion, Dr. Singh set out the timing: metformin should be started at least two to three months before conception and is safe in early pregnancy; it is continued where diabetes or gestational diabetes is present, but not for PCOS alone, because it has not been shown to prevent miscarriage. ESHRE does not recommend metformin specifically to prevent pregnancy loss. It must be monitored with a glucose tolerance test, regular HbA1c and blood sugar checks.

Uncontrolled diabetes causes recurrent loss and, separately, birth defects in the baby. Good glycaemic control is the treatment.

Thyroid disease, if untreated, contributes to loss. Dr. Singh's target is strict: the dose of levothyroxine is adjusted to keep the woman's TSH below 2.5. Where thyroid function is normal and only TPO antibodies are positive, most studies advise against treatment. She tests TPO antibodies regardless, as a marker of autoimmune predisposition rather than as a treatment trigger.

Hyperprolactinaemia, a raised level of the hormone prolactin, is relevant when there is galactorrhoea (milk from the breast), anovulation or infertility, or anovulatory or prolonged cycles. Bromocriptine is used only when hyperprolactinaemia is confirmed.

Across all endocrine causes, lifestyle correction comes first: obesity must be addressed, and folic acid and pregnancy-safe multivitamins should be started early.

Infections and recurrent miscarriage: is TORCH testing needed?

The TORCH group (toxoplasmosis, rubella, cytomegalovirus and others) is generally not regarded as a cause of recurrent loss, and infection overall is a less common explanation. Most are viral infections that leave immunity behind, so they do not strike pregnancy after pregnancy. They can damage a single pregnancy, and they should be suspected when that pregnancy shows fetal growth restriction, ventriculomegaly (enlarged fluid spaces in the brain) or calcification on ultrasound. The outcome in such a pregnancy is usually poor, but the infection does not explain repeated losses.

Serology is read accordingly. A positive IgG with a negative IgM generally indicates immunity, not active infection.

Two other infective processes do appear in the evaluation. Bacterial vaginosis belongs on the second-trimester list, and chronic endometritis, persistent inflammation of the lining of the uterus, can be investigated by endometrial biopsy and a standard vaginal swab where the history suggests it, and then treated.

Immune causes: NK cells, TNF-alpha and IVIG

The guidelines advise that immune factors should be neither tested for nor treated, but Dr. Singh tests and treats selectively. The immune factors are a much-debated area. Some studies support an immune mechanism of embryo rejection; others find the data insufficient, and the guidelines take that second view.

The underlying concept is this. The embryo is partly foreign to the mother, and pregnancy modulates the maternal immune system towards tolerance of it. Uterine natural killer (NK) cells are normally abundant in early pregnancy, where they help remodel the blood vessels that supply the placenta. In some women, the theory holds, that tolerance fails and a hyperimmune state develops, marked by raised TNF-alpha (an inflammatory signalling protein) and NK cells, which leads to loss of the pregnancy.

Some studies have linked HLA sharing between partners, meaning similar tissue types, to weaker protective antibody formation. HLA testing of couples was once common; it is now done far less often.

Dr. Singh still measures TNF-alpha, CD19 B cells and NK cells (CD16 and CD56) case by case. These markers can be measured in endometrium or blood. For practical reasons she uses blood, although blood NK cells differ from uterine NK cells and do not reliably reflect them. Her indications are:

• a clue to autoimmune disease
• an autoimmune history
• multiple losses with an otherwise normal workup

Treatment follows the same split between guideline and practice. The guidelines do not support IVIG (intravenous immunoglobulin) or intralipid therapy. Dr. Singh does consider them for women with an autoimmune predisposition, especially when nothing else has been found, and in her experience they have helped many women. Glucocorticoids she no longer uses: they have no proven benefit in recurrent loss, and first-trimester use has been linked to a possible small increase in cleft lip and palate.

Sperm DNA fragmentation and recurrent miscarriage

A sperm DNA fragmentation index above 30% generally indicates a high level of damage; values below that may be acceptable. Sperm DNA fragmentation is a newer concept in recurrent loss. ASRM and ESHRE give it conditional acceptance: they do not dismiss it as useless. The theory is that excessive DNA damage in sperm impairs embryo quality, hinders blastocyst development and increases the risk of miscarriage.

The cause is usually multifactorial and is generally attributed to oxidative stress. Contributors include:

• varicocele
• infections
• smoking
• obesity
• advancing age

A man with a high index may need a urological evaluation. Age deserves particular weight. Asked about couples in which the male partner is over 50, Dr. Singh's answer was that there is a high chance of poorer sperm quality at that age and a raised fragmentation index. Without testing, the extent is unknown, but there is a high chance that some sperm carry poor-quality DNA, which can cause recurrent loss or implantation failure.

The interventions are where evidence runs out. The guidelines consider sperm selection procedures of doubtful utility, and whether antioxidants help men with a raised fragmentation index is not known. Dr. Singh orders the test selectively, mainly where infertility coexists with recurrent loss and the rest of the workup is normal.

Which recurrent pregnancy loss treatments work?

Taken together, the non-genetic causes sort into three tiers.

Causes with a specific treatment in Dr. Singh's framework:

• APS, with aspirin and heparin
• thyroid disease, with levothyroxine to a TSH below 2.5
• hyperprolactinaemia, with bromocriptine
• diabetes and PCOS, with metabolic control and metformin
• submucosal fibroids, with myomectomy
• cervical incompetence, with surveillance and cerclage

Plausible but unproven: polyps, inherited thrombophilias, sperm DNA damage.

Contested: the immune factors, where Dr. Singh's selective use of IVIG and intralipid reflects clinical experience rather than guideline endorsement.

Several of these treatments, from cerclage to hysteroscopic surgery, fall within obstetrics and gynaecology. The order in which they are tested is set out in the complete guide to recurrent pregnancy loss.