Recurrent miscarriage Flashcards
Recommended Ix in recurrent miscarriage
- Lupus anticoagulant and anticardiolipin antibodies (for acquired thrombophilia)
—> test at least 6 weeks post miscarriage, and need 2 x positive tests at least 12 months apart - Cytogenic analysis of pregnancy tissue of the 3rd and subsequent miscarriage(s), and in any second trimester miscarriage
—> parental peripheral blood karyotyping for couples in whom an unbalanced structural chromosomal abnormality is detected in pregnancy tissue, or there is unsuccessful or no pregnancy tissue available for testing - USS for congenital uterine abnormalities
- TFTs and TPO antibodies
When should testing for Factor V Leiden, prothrobin gene mutation and protein S deficiency be undertaken?
Women with second trimester miscarriage, ideally within a research context
—> at least weeks postpartum and in the absence of hormonal contraception
Inherited thrombophilias and recurrent miscarriage
weak association,
Therefore, routine testing for protein C, antithrombin deficiency and methylenetetrahydrofolate reductase mutation is not recommended
What is the lifestyle advice that should be offered to women with recurrent miscarriage
- Maintain a BMI between 19 and 25
- Smoking cessation
- Limit ETOH
- Limit caffeine to < 200mg/day
How should antiphospholipid syndrome be managed in pregnancy
Aspirin and heparin should be offered from a positive test until 34 weeks of gestation
** Aspirin and/or heparin should not be given to women with unexplained recurrent miscarriage**
Uterine septum and recurrent miscarriage
Resection should be considered, ideally within audit or research context
Euthyroid + TPO positive?
Thyroxine supplementation not routinely recommended
Progestogen supplementation
Should be considered in women with recurrent miscarriage who present with bleeding in early pregnancy (e.g. 400mg micronised vaginal progesterone BD at the time of bleeding until 16 weeks gestation)
Miscarriage definition
Spontaneous loss of pregnancy before fetus reaches viability
Sporadic vs recurrent miscarriage
- Sporadic miscarriage is often the result of random fetal chromosomal anomalies.
- –>Incidence increases with age
- Recurrent miscarriage = 3 or more miscarriages
—> affects approx 1% of women - Second trimester miscarriage also affects approx 1% of women
—> the incidence of random fetal chromosomal anomalies are significantly lower
Clinical discretion
Clinicians are encouraged to recommend extensive eval after 2 first trimester miscarriages, if there is a suspicion that the miscarriages are of pathological and not sporadic nature (e.g. if a woman has had a pregnancy loss with a normal NIPT or karyotype)
Consecutive losses or no?
- Owing to the fact that the incidence of certain diagnoses does not appear to differ between women with consecutive vs non-consecutive losses, the definition is NOT restricted to women suffering with consecutive losses only.
- It is also not restricted to miscarriages suffered with the same partner, as certain maternal pathologies would be unaffected by the partner
AMA and miscarriage
AMA is associated with decline in both the number and quality of the remaining oocytes, resulting in higher rates of aneuploidy in the fertilized embryos.
Risk of miscarriage:
- 12-19y: 13%
- 20-24y: 11%
- 25-29y: 12%
- 30-34y: 15%,
- 35-39y: 25%
- 40-44y: 51%
- 45y or over: 93%
APA and miscarriage
Increased miscarriage rates for men >40y, although far less pronounced c.f. AMA
Risk of miscarriage is higher with higher number of previous miscarriages
No previous miscarriages: 11%
1 previous: 17%
2 previous: 28%
3 previous: 40%
4 previous: 47%
5 previous: 64%
Previous live birth and recurrent miscarriage
In two studies, previous live birth did not result in a significantly different future prognosis
Smoking
Increases the risk of sporadic miscarriage
5+ alcoholic drinks/week
Increases risk of spontaneous miscarriage (approx 10 units/week)
Caffeine intake and sporadic miscarriage
There is some evidence for an association between increased caffeine intake and sporadic miscarriage
BMI and recurrent miscarriage
< 19 and > 25 = increased risk
Antiphospholipid syndrome
- Acquire thrombophilia
- Defined as the association between antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2-glycoprotein-I antibodies) and adverse pregnancy outcomes or vascular thrombosis.
- Adverse pregnancy outcomes include:
—> Three or more consecutive miscarriages before 10 weeks gestation
—> 1 or more morphologically normal fetal losses after the 10th week gestation
—> one or more preterm births before 34+0 weeks of gestation because of placental disease
APS testing
- Lupus anticoagulant has the strongest association with recurrent miscarriage (OR 7.79)
- IgG and IgM anticardiolipin antibodies were found to have the second strongest association (OR 3.57 and 5.61)
- Anti-beta-2-glycoprotein-I antibodies showed a trend towards a positive association but this did not reach statistical significance
Inherited thrombophilias
- There is a stronger and more consistent association between second trimester miscarriage.
FV Leiden
- Associated with first and particularly second trimester recurrent miscarriages
Prothrombin gene mutation
Is associated with recurrent miscarriage
Protein S deficiency
Has not demonstrated a consistent association with recurrent first trimester miscarriage, but has an association with second trimester
Protein C deficiency
Has not shown a consistent association with recurrent miscarriage
Methylenetatrahydrofolate reductase (MTHFR) mutation (heterogenous and homozygous)
has been found to have a significant association with recurrent miscarriage in one meta-analysis from China. However other meta-analyses did not find an association and advise against testing for this mutation
Antithrombin deficiency
- Rarer yet most thrombogenic mutation
- However, only a possible association with sporadic miscarriage
Parental chromosomal rearrangements
Association between type of parental chromosomal rearrangement and risk of subsequent miscarriage appear dependent on type of rearrangement.
A translocation is present in 5.7% of parents after 3 miscarriages
Fetal chromosomal anomalies
- commonest cause of both sporadic and recurrent miscarriage
—> approx 50% of sporadic miscarriages = a result of fetal chromosome anomalies (most commonly trisomy)
—> incidence of aneuploidy in recurrent miscarriage was approx 40%, suggesting that non-gentic factors play a more important role
The higher the number of euploid miscarriages, the higher the chance of a subsequent miscarriage,
Presumably owing to the higher chance of a persistent maternal pathology rather than a sporadic aneuploidy.
Congenital uterine anomalies - prevalence
Prevalence:
- 5.5% in unselected women
- 8% in infertile women
- 13% in women with recurrent miscarriage
- 25% in women with infertility and recurrent miscarriage
Congenital uterine anomalies - most common
Commonest appear to be canalisation defects (i.e. septate variety), followed by unification defects (i.e. bicornuate and unicornuate variety)
Congenital uterine anomalies - first trimester miscarriage:
Risk not significantly increased in women with arcuate, didelphys and unicornuate uteri vs normal controls
However, women with septate and bicornuate uteri had a significantly increased risk of sporadic first trimester miscarriage vs normal controls
Congenital uterine anomalies - second trimester miscarriage:
Risk not significantly increased in women with didelphys and unicornuate uteri vs normal controls.
However, women with septate and bicornuate uteri had a significantly increased risk of sporadic second trimester MC vs controls.
Myomas
Overall, no increase risk of miscarriage. However, more data is needed to delineate by submucosal vs intramural vs subserosal
Endometrial polyps
No specific data.
=> recommend management similar to that of the general population
Intrauterine adhesions
Not enough data for conclusive statement.
Small cohort studies have suggested that women with intrauterine adhesions and ET <5mm have higher sporadic miscarriage rates.
Main contributors of second trimester miscarriage
cervical insufficiency, infection and congenital uterine anomalies
Cervical insufficiency
- True incidence unknown, since the diagnosis is clinical
- Previous cone biopsy or an ultrasonographically short cervix, appear to significantly predispose to second trimester miscarriage
Endocrine
- Increased risk with poorly controlled diabetes with high HbA1c -> risk of miscarriage and fetal malformation
- Increased risk in untreated thyroid dysfunction
–> neither is a risk factor when well controlled
Subclinical hypothyroidism and thyroid antibodies
Associated with increased risk of recurrent or sporadic miscarriage
PCOS and miscarriage
Associated with increased risk, but mechanism unclear
?due to insulin resistance, hyperinsulinaemia and hyperandrogenaemia
—> elevated free androgen index appears to be a prognostic factor for a subsequent miscarriage in women with recurrent miscarriage
Hyperprolactinaemia and miscarriage
Increased risk.
Treated hyperprolactinaemia = lower risk than untreated.
BV and miscarriage
Meta-analysis showed statistically significant increase in second trimester miscarriages. But evidence for first trimester miscarriage is inconsistent and there is lack of data in recurrent miscarriage
Male factor and recurrent miscarriage
consistent association between abnormal sperm DNA parameters such as sperm DN fragmentation, nuclear chromatin decondensation, and sperm aneuploidy
—> limited studies are available evaluating interventions that may affect these parameters such as lifestyle modifications, treatment of infections, control of diabetes, treatment of varicocele, sperm selection, etc.
