Recurrent miscarriage

Question 1

Recommended Ix in recurrent miscarriage

Answer 1

• 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

Question 2

When should testing for Factor V Leiden, prothrobin gene mutation and protein S deficiency be undertaken?

Answer 2

Women with second trimester miscarriage, ideally within a research context
—> at least weeks postpartum and in the absence of hormonal contraception

Question 3

Inherited thrombophilias and recurrent miscarriage

Answer 3

weak association,
Therefore, routine testing for protein C, antithrombin deficiency and methylenetetrahydrofolate reductase mutation is not recommended

Question 4

What is the lifestyle advice that should be offered to women with recurrent miscarriage

Answer 4

• Maintain a BMI between 19 and 25
• Smoking cessation
• Limit ETOH
• Limit caffeine to < 200mg/day

Question 5

How should antiphospholipid syndrome be managed in pregnancy

Answer 5

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**

Question 6

Uterine septum and recurrent miscarriage

Answer 6

Resection should be considered, ideally within audit or research context

Question 7

Euthyroid + TPO positive?

Answer 7

Thyroxine supplementation not routinely recommended

Question 8

Progestogen supplementation

Answer 8

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)

Question 9

Miscarriage definition

Answer 9

Spontaneous loss of pregnancy before fetus reaches viability

Question 10

Sporadic vs recurrent miscarriage

Answer 10

• 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

Question 11

Clinical discretion

Answer 11

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)

Question 12

Consecutive losses or no?

Answer 12

• 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

Question 13

AMA and miscarriage

Answer 13

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%

Question 14

APA and miscarriage

Answer 14

Increased miscarriage rates for men >40y, although far less pronounced c.f. AMA

Question 15

Risk of miscarriage is higher with higher number of previous miscarriages

Answer 15

No previous miscarriages: 11%
1 previous: 17%
2 previous: 28%
3 previous: 40%
4 previous: 47%
5 previous: 64%

Question 16

Previous live birth and recurrent miscarriage

Answer 16

In two studies, previous live birth did not result in a significantly different future prognosis

Question 17

Smoking

Answer 17

Increases the risk of sporadic miscarriage

Question 18

5+ alcoholic drinks/week

Answer 18

Increases risk of spontaneous miscarriage (approx 10 units/week)

Question 19

Caffeine intake and sporadic miscarriage

Answer 19

There is some evidence for an association between increased caffeine intake and sporadic miscarriage

Question 20

BMI and recurrent miscarriage

Answer 20

< 19 and > 25 = increased risk

Question 21

Antiphospholipid syndrome

Answer 21

• 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

Question 22

APS testing

Answer 22

• 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

Question 23

Inherited thrombophilias

Answer 23

• There is a stronger and more consistent association between second trimester miscarriage.

Question 24

FV Leiden

Answer 24

• Associated with first and particularly second trimester recurrent miscarriages

Question 25

Prothrombin gene mutation

Answer 25

Is associated with recurrent miscarriage

Question 26

Protein S deficiency

Answer 26

Has not demonstrated a consistent association with recurrent first trimester miscarriage, but has an association with second trimester

Question 27

Protein C deficiency

Answer 27

Has not shown a consistent association with recurrent miscarriage

Question 28

Methylenetatrahydrofolate reductase (MTHFR) mutation (heterogenous and homozygous)

Answer 28

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

Question 29

Antithrombin deficiency

Answer 29

• Rarer yet most thrombogenic mutation
• However, only a possible association with sporadic miscarriage

Question 30

Parental chromosomal rearrangements

Answer 30

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

Question 31

Fetal chromosomal anomalies

Answer 31

• 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

Question 32

The higher the number of euploid miscarriages, the higher the chance of a subsequent miscarriage,

Answer 32

Presumably owing to the higher chance of a persistent maternal pathology rather than a sporadic aneuploidy.

Question 33

Congenital uterine anomalies - prevalence

Answer 33

Prevalence:
- 5.5% in unselected women
- 8% in infertile women
- 13% in women with recurrent miscarriage
- 25% in women with infertility and recurrent miscarriage

Question 34

Congenital uterine anomalies - most common

Answer 34

Commonest appear to be canalisation defects (i.e. septate variety), followed by unification defects (i.e. bicornuate and unicornuate variety)

Question 35

Congenital uterine anomalies - first trimester miscarriage:

Answer 35

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

Question 36

Congenital uterine anomalies - second trimester miscarriage:

Answer 36

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.

Question 37

Myomas

Answer 37

Overall, no increase risk of miscarriage. However, more data is needed to delineate by submucosal vs intramural vs subserosal

Question 38

Endometrial polyps

Answer 38

No specific data.
=> recommend management similar to that of the general population

Question 39

Intrauterine adhesions

Answer 39

Not enough data for conclusive statement.
Small cohort studies have suggested that women with intrauterine adhesions and ET <5mm have higher sporadic miscarriage rates.

Question 40

Main contributors of second trimester miscarriage

Answer 40

cervical insufficiency, infection and congenital uterine anomalies

Question 41

Cervical insufficiency

Answer 41

• True incidence unknown, since the diagnosis is clinical
• Previous cone biopsy or an ultrasonographically short cervix, appear to significantly predispose to second trimester miscarriage

Question 42

Endocrine

Answer 42

• 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

Question 43

Subclinical hypothyroidism and thyroid antibodies

Answer 43

Associated with increased risk of recurrent or sporadic miscarriage

Question 44

PCOS and miscarriage

Answer 44

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

Question 45

Hyperprolactinaemia and miscarriage

Answer 45

Increased risk.
Treated hyperprolactinaemia = lower risk than untreated.

Question 46

BV and miscarriage

Answer 46

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

Question 47

Male factor and recurrent miscarriage

Answer 47

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.