Dr Ying Li is the Head of Fertility Department, Royal Prince Alfred Hospital, Medical Clinical Lead Health Informatics, Women’s Health, Digital Health and Innovation, Sydney Local Health District.

Introduction

Pregnancy loss is unfortunately a common experience, occurring in as many as 30% of pregnancies¹. In 2024, the first Australasian Recurrent Pregnancy Loss (RPL) guidelines were released by the Australasian Certificate of Reproductive Endocrinology and Infertility (CREI) Consensus Expert Panel on Trial Evidence (ACCEPT) group. These guidelines summarise the most current evidence on the definition, causes, investigation, and management of recurrent pregnancy loss^{1, 2}.

Defining Recurrent Pregnancy Loss

Pregnancy loss is defined as the spontaneous loss of a foetus prior to viability. RPL is now defined as two or more losses before 20 weeks of gestation. This aligns with definitions from the American Society of Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE).

Causes, Investigation and management of Recurrent Pregnancy Loss

Many factors and their relationship to RPL have been studied. These include chromosomal errors, anatomical anomalies, thrombophilias, autoimmunity, endocrine disruption, inflammatory issues, endometrial deficits, environmental factors and male factors.

The Role of Aneuploidy in Recurrent Pregnancy Loss

Embryonic aneuploidy (an embryo with an abnormal number of chromosomes) is often implicated as a cause in RPL as it is the most common cause of pregnancy loss in the first trimester. The rate of aneuploidy is directly related to parental age, especially maternal age. Additionally, roughly 4-5% of couples with RPL have a parent with a balanced chromosomal rearrangement, most commonly translocation (a chromosomal abnormality where a segment of one chromosome is transferred to another

chromosome without any genetic material being lost or gained). The rate of embryonic aneuploidy in a parent with a balanced translocation is 70-80% independent of age³.

It is strongly recommended that products of conception (POC) be analysed using molecular methods, either Comparative Genomic Hybridisation (CGH), or Single Nucleotide Polymorphism (SNP) arrays to assess embryonic aneuploidy. It is also recommended that parental karyotypes (a genetic test that examines the number and structure of chromosomes in parents to identify abnormalities such as translocations or inversions) should be part of initial RPL investigations. In parents with chromosomal rearrangements, genetic counselling and pre-implantation genetic testing – structural rearrangement (PGT-SR) should be offered. In parents with normal karyotypes with RPL, preimplantation genetic testing for aneuploidy (PGT-A) may be beneficial and can be discussed with the patients^1,2.

Anatomical Issues and Their Impact

Anatomical issues are either acquired (such as polyps, intrauterine adhesions and leiomyomas) or congenital (müllerian anomalies). There is a higher prevalence of müllerian anomalies in RPL populations ⁴. There are also associations of RPL with submucosal and intramural fibroids⁵ and intrauterine adhesions⁶. There does not appear to be a strong association between endometrial polyps and increased risks of pregnancy loss⁷.

It is recommended that a 3D ultrasound with possible sonohysterogram is an appropriate first-line investigation for anatomical causes of RPL. MRI may also be beneficial. It is noted that combined hysteroscopy and laparoscopy remains the gold standard for investigation of müllerian duct anomalies, but their benefits must be weighed against the invasive nature and potential risks associated with these procedures^1,2.

There is insufficient evidence to confirm that correcting müllerian anomalies leads to reduced pregnancy loss or increased live births. However, well-powered prospective randomised trials that have examined this issue are lacking. Hysteroscopic excision of intrauterine adhesions are recommended as this does seem to increase live birth rates and there is some evidence that resection of submucosal fibroids may lead to improved pregnancy outcomes. This evidence does not seem to extend to intramural fibroids^{1, 2}.

Thrombophilias: Blood Disorders and Pregnancy Loss

The evidence linking thrombophilias to RPL is controversial. There is no strong evidence linking inherited thrombophilias to RPL, while there is better evidence linking acquired thrombophilias to RPL. Acquired thrombophilias especially antiphospholipid syndrome (APS) is strongly linked to RPL⁸.

Women with RPL should be screened for APS as per the updated International Consensus Sydney (ICS) criteria. If APS is diagnosed, heparin and low-dose aspirin should be commenced after a positive pregnancy test. Based on the latest evidence, the screening for inherited thrombophilias in the context of RPL is not recommended as there is no strong evidence of either causality or treatment ^1,2,9.

Autoimmunity

There are significant changes to the immune system with implantation and subsequent pregnancy. It has been hypothesised that various derangements in the immune system’s adaptation to pregnancy is linked to RPL. This includes changes in human leukocyte antigen antibodies function and expression, changes in the type and function of natural killer (NK) cells with more recent interest in uterine killer cell receptors ¹⁰.

However, the evidence linking autoimmunity to RPL is conflicting and weak. There are also issues with establishing normal ranges for certain immune system investigations that can change in pregnancy and change within the menstrual cycle. There is some evidence that the presence of high antinuclear antibody test (ANA) titres (levels of antinuclear antibodies in the blood, which may indicate autoimmune activity) may increase the risk of RPL but there is uncertainty regarding the pattern of ANA and the efficacy of treatment ¹¹.

Investigation for autoimmunity in the context of RPL should be limited to coeliac antibodies in symptomatic patients or those with a strong family history. Immunotherapy in the for RPL is controversial with limited, conflicting evidence of benefit. There are some studies suggesting improvement in live birth in women with RPL of four or more pregnancy losses with no known cause. However, these studies are hampered by small numbers and are limited to certain ethnicities¹². Other immunotherapies do not seem to demonstrate clear benefits and have potential adverse effects. An individualised approach to immunotherapy is recommended ².

Endocrine Disruption

Some maternal endocrine disorders have been linked to RPL. These include thyroid disorders, uncontrolled PCOS and glucose intolerance.

Overt hypo- or hyperthyroidism is linked with pregnancy loss and must be treated prior to conception by an endocrinologist. There is some evidence that euthyroid patients with positive thyroid antibodies may have an increased risk of RPL. The management is controversial but either monitoring of thyroid function or treatment with thyroxine can be considered. Subclinical hypothyroidism may be linked to pregnancy loss. There is consensus amongst available guidelines that TSH levels of 4.0 or over should trigger consideration of thyroxine management. It is also recommended, given thyroid function normal ranges are heavily linked to population levels, clinicians are familiar with normal ranges of thyroid function for their specific population ¹³.

Uncontrolled PCOS has been linked to higher rates of pregnancy loss, though confounding factors such as obesity and insulin resistance make this link difficult to prove¹⁴. It is recommended that controlling insulin resistance and healthy weight loss aiming for a healthy BMI is offered to patients with RPL^{1, 2}.

The link of hyperprolactinaemia to RPL is weak but normalising any true elevations in prolactin may be beneficial in RPL¹.

Progesterone supplementation has been hypothesised to enhance endometrial receptivity and thus improve pregnancy loss rates. The studies in the context of RPL is controversial. There may be some evidence that supplementation may improve pregnancy loss in those with three or more previous losses or threatened miscarriage ¹⁴.

Inflammation

Chronic endometritis is more common in the RPL population however the evidence for causation is weak. Those with RPL can consider having an endometrial biopsy to exclude chronic endometritis. There is limited evidence that antibiotic therapy may improve live birth rate in the RPL population ^{2, 15}.

Endometriosis and adenomyosis causes chronic inflammation which can affect embryo quality, receptivity and early pregnancy outcomes. There is some weak evidence linking endometriosis to RPL but the link to adenomyosis is tenuous. There is also minimal evidence that resection of endometriosis in the context of RPL is linked to improved live birth rates ².

Lifestyle and environment

Environmental stressors linked to RPL include endocrine disruptors such as. BPA and phthalates, smoking, and potentially increased exposure to alcohol and heavy metals. Evidence linking caffeine and psychological stress to RPL is inconclusive. However, reducing these exposures may be beneficial. There is also weak evidence to suggest care for patients in a supportive environment may be linked to improved pregnancy outcomes ^{2, 16}.

Male factors

Several male factors have been linked to RPL. These include obesity, environmental exposures, excessive alcohol, smoking and occupational exposures. These can result in poor sperm quality such as elevated DNA fragmentation in sperm^{2, 17}.

Recommendations for men include minimising toxin exposure (cessation of smoking and alcohol and environmental or occupational chemicals), normalisation of weight, regular moderate exercise and healthy diet should be recommended to all males who have partners experiencing RPL².

Those with high DNA fragmentation in sperm can consider antioxidant therapy. Consultation with a urologist can be considered in those with varicocoeles. If conservative therapy is unsuccessful, advanced sperm selection methods in the context of assisted reproduction technologies (ART) can be considered^{18, 19}.

Unexplained

About 50–75% of cases or RPL remained unexplained. Treatment of these couples is challenging and an individualised approach should be taken^1,2.

Summary

• RPL is defined as two or more pregnancy losses before 20 weeks.
• Referral to specialised services should be considered.
• Embryonic aneuploidy is a major cause of pregnancy loss. Examination of POC for aneuploidy and screening of parental karyotypes should be performed.
• Managing endocrine conditions may improve pregnancy loss rates.
• Progesterone supplementation may be beneficial.
• Lifestyle modification should be encouraged for the couple experiencing RPL. This includes cessation of smoking and alcohol, and healthy normalisation of BMI.
• Unexplained RPL is common and is a challenging condition to manage.