Recurrent pregnancy loss Flashcards
Definition of pregnancy loss and RPL
Pregnancy loss - (12-15% of pregnancies but affected significantly by female age)
spontaneous demise of a pregnancy before the fetus reaches viability (24weeks) (ESHRE and RCOG)
spontaenous demise of a pregnancy before 20 weeks (ACCEPT)
Recurrent miscarriage
Two or more pregnancy losses (ESHRE and Accept) (5% incidence)
Three or more first trimester miscarriages, in keeping with the previous (RCOG guidelines). (1% incidence)
Two first trimester clinical pregnancy losses (i.e. those documented by ultrasonography or histopathological examination) (ASRM)
All guidelines have now moved away from consecutive losses.
Molar and ectopic pregnancies excluded.
ESHRE and ACCEPT ask for urinary or serum bHCG proof - include biochemical losses in definition, ASRM don’t.
Value of a RPL service
Increased psychological impact of RPL on couples.
Increased anxiety in future pregnancy.
Patients value care by a dedicated and supportive individual physician or team.
Limited and weak evidence that this care improves pregnancy outcomes.
RPL outpatient clinic - offers specialist investigations, support and if possible, treatment of couples with RPL.
ESHRE - what the RPL clinic should offer:
Staffing - experienced nurse, gynaecologist/fertility specialist.
First visit - including written information before attending.
Equipment - access to USS and ability to arrange 3D USS/saline sonohysterogram
Provision of information -info leaflet
Appropriate evaluation (testing)
Care tailored to the psychological needs of the couple
Treatment plan
Research
Risk factors for RPL
Advanced maternal age
Advanced paternal age (linked to miscarriage risk but not studied in RPL)
Stress - more prevelant in women with RPL ?does RPL cause stress or stress cause RPL
Environmental exposures - pesticides, heavy metals, lack of micronutrients)
chronic endometritis - Further research is needed including prospective observational studies and randomized controlled trials before screening women for endometritis can be recommended. May be an association - difficult
Health behaviours (modifiable)
Smoking - assoc with RPL less clear, cessation obviously recommended.
BMI - assoc with RPL. Female underweight also inc risk. Gradual weight loss improves fertility and risk of miscarriage, impact on RPL hasn’t been studied.
Caffeine - some but not all studies have demonstrated incr risk of RPL with caffeine intake, seems to be dose dependent.
Alcohol - association with RPL less clear. Cessation whilst TTC recommended.
Exercise - no studies have looked at this in context of RPL
Endometrial changes that might be associated with RPL
Defective decidualization -
Decidualisation denotes differentiation of resident endometrial stromal cells into specialist decidual cells, which transform the endometrial mucosa into a robust, tolerogenic matrix to accommodate invading trophoblast.
Progesterone dependent process.
Leads to emergence of progesterone independent anti inflammatory decidual cells and also progesterone-independent senescent decidual cells.
Senescent decidual cells secrete inflammatory mediators and extracellular matrix proteases - help with endometrial remoddeling for embyro implantation.
Senescent decidual cells are cleared by uNK = essential to prevent chroinc sterile inflammation and break down of the emergin maternal fetail interface in pregnancy.
RPL found to have lack of bone marrow derived decidual progenitor cells and increased frequency of menstrual cycles characterised by excessive senescent decidual cells.
Lower uNK cell activity is associated with a higher miscarriage risk.
Frequency of abnormal cycles correlates with recurrence risk in miscarriage.
Genetic examination of susequent miscarriages
Not routinely recommended by could be performed for explanatory purposes (ESHRE)
Cytogenetic analysis should be offered on pregnancy tissue of the third and subsequent miscarriages and in any second trimester miscarriage (RCOG)
Risk of aneuploid about 45-60% per miscarriage. Aneuploidy rates are lower in RPL miscarriages than rates in sporadic miscarriges.
If genetic testing is done - array-CGH is recommended based on reduced maternal contamination effect compared to karyotype assessment.
array comparative genomic hydrbidisation (CGH) - scans the entire genome and doesn’t require culture. Almost no failure rate.
Karyotype assessment results in culture failure (20%) and maternal cell contamination (22%).
FISH - can be used if culture failure occurs with karyotype - will only assess the chromosomse with probes.
Newer techniques - NGS, SNP array, WGS, Whole exome sequencing (WES) have not been extensively investigated in genetic anaylsis of pregnancy tissue but may become useful in the near future.
Parental genetic analysis
Abnormal parental karyotypes were found in 2-5% of couples referred for genetic testing after RPL.
Reciprocal translocation and inversions have higher rates of pregnancy loss than Robertsonian translocations
Recommendations:
Could be carried out after individual assessment of risk for diagnostic purposes (ESHRE)
When cytogenetic analysis is indicated but testing of the pregnancy tissue is unsuccessful or there is no pregnancy tissue available for testing, parental karyotyping should be offered. (RCOG)
Karyotyping of both partners is indicated in couples with recurrent pregnancy loss (ACCEPT and ASRM)
Thromobophilia screening
Acquired -
RCOG, ASRM, ACCEPT, ESHRE - women should be offered testing for APLS.
All recommend LA and ACLA but RCOG doesn’t support b2 glycoprotein 1 testing, ESHRE says can consider it. ASRM and ACCEPT recommend.
Hereditary -
RCOG - women with second trimester m/c may be offered testing for Factor V Leiden, prothromin gene mutation, protein S deficiency (made aware that there is limited evidence that treatment changes reproductive outcomes).
ESHRE - recommend against screening, unless in the context or research or in women with additional risk factors for thrombophilia.
ASRM - not currently recommended - may be clinically justified when a patient has a personal history of VTE, or a first degree relative has a known or high risk hereditary thrombophilia.
Inherited thrombophilias
Factor V Leidien and acquired activated protein c resistence (APC) are associated with an increased risk of RPL but there is no effective treatment.
Protein C and S deficiency, Prothrombin variant, antithrombin deficiency have weak association with RPL and no treatment options.
Cochrane review 2014 showed no benefit in treating inherited thrombophilias with aspirin and/or LMWH.
APLS diagnosis and treatment
Diagnosis:
Positive LA, ACLA or B2 glycoprotein 1 in two samples 12 weeks apart.
Plus one of the clinical scenarios:
Previous thrombosis (venous or arterial)
Obstetric morbidity:
3 consecutive first trimester miscarriages (<10 weeks)
1 or more unexplained deaths of morphologically normal fetus at or beyond 10 weeks
1 or more preterm birth(<34 weeks) of a morphologically normal neonate due to eclampsia, PET or recognised features of placental insufficiency.
Treatment
Cochrane review (2020) - APLS and greater than 2 pregnancy losses, aspirin + heparin. may improve LBR outcomes compared to aspirin alone (low certainty evidence from one large RCT)
Aspirin - 75-100mg /day (some units use 150mg due to reduce PET risk with higher dose)
Heparin - now use LMWH - 20-40mg/day
Start from positive pregnancy test - close follow up in early pregnancy serial hCG and early scan.
Continue to at least 6 weeks pp.
If not diagnosed based on history with APLS. But positive antibodies then would recommend aspirin during pregnancy (Catherine-Nelson-Pearcy)
Immune screening
anti-HLA antibodies - not recommended
NK cell testing - insufficient evidence to recommend NK cell testing of peripheral blood or endometrial tissues with RPL.
ANA testing - could be considered for explanatory purposes (linked with RPL in a meta-analysis but no treatment options)
Cytokines and cytokine polymorphisms should not be tested
HLA determination in women with RPL is not recommended in clinical practice. Only HLA class II determination could be considered in Scandinavian women with secondary RPL after the birth of a boy for explanatory and prognostic purposes.
Anti_Hy - measurement not recommended in clincial practive.
“Since the risk increment conferred by carrying these HLA alleles is substantial in women with secondary RPL after a birth of a boy, clinicians could consider offering HLA-DRB1 typing to these patients for clarification of the pathogenesis and assessment of prognosis. However, so far the testing will provide no change in treatment offers.”
Thyroid dysfunction - physiology of impact on reproduction
Thyroid hormones are essential for fetal development.
A review on the thyroid function and reproduction concluded that thyroid hormone disorders and increased Thyroid peroxidase (TPO) antibodies (TPOAb) are associated with disturbed folliculogenesis, spermatogenesis, fertilization and embryogenesis, supporting an important role for thyroid hormone disorders and thyroid autoimmunity in subfertility and pregnancy loss.
Thyroid dysfunction and RPL
Thyroid screening (TSH) is recommended in women with RPL. (ESHRE, RCOG, ASRM )
Abnormal TSH levels should be followed up by T4 testing.
ASRM only recommend TSH not TPO antibodies unless abnormal.
There is a meta-analysis showing a link between TPO antibodies and RPL. Even with euthyroidism.
PCOS and RPL
Assessment of PCOS, fasting insulin and fasting glucose is not recommended in women with RPL to improve next pregnancy prognosis. (++– Strong).
PCOS - association with RPL - metformin may prevent sporadic PL but no evidence for RPL.
Insulin resistance had been associated wtih RPL OR 3.6.
Prolactin testing and RPL
Not recommended unless there are clinical symptoms of hyperprolactinaemia. (oligomenorrhoea/amenorrhoea)
Ovarian reserve testing in RPL
Not routinely recommended (++– strong)
Meta-analysis 15 studies - found that more women with RPL seemed to have DOR as compared to controls (AMH: OR = 2.77; 95%CI 1.41-5.46; AFC: OR = 2.45; 95%CI 1.16-5.19). The reviewers further concluded that more studies are needed to make any
conclusions on the prognostic value in the management of women with RPL. However, their results were not adjusted for the effect of age in the original studies.
Luteal phase insufficiency and RPL
ESHRE recommendations for uterine anomalies diganosis
Male factor and RPL
Higher sperm DNA fragmentation in couples with RPL
Higher rate of total sperm aneuploidy in RPL couples
Altered methylation of sperm imprinted genes is associated with SDF and pregnancy loss rates.
When you superimpose smoking, drinking and occupational exposure to environmental hazards the risk of RPL further increases.
Not well established which assays to use and what the references ranges are.
Lifestyle modification of the male partner could improve clinical outcomes
