Recurrent Miscarriage – Long journey of gyn&obs

Epidemiology

Recurrent miscarriage has been defined as three or more first trimester miscarriages.
However,
clinicians are encouraged to use their clinical discretion to recommend extensive evaluation after
two first trimester miscarriages, if there is a suspicion that the miscarriages are of pathological and
not of sporadic nature.

Affects about 1% of women.
A similar incidence of approximately 1% is also the case for women
experiencing a second trimester miscarriage

Overall, the greatest determinant of the incidence of recurrent miscarriage is age, while the number
of previous miscarriages affects the chance of a live birth across all age groups.

The incidence of recurrent miscarriage would more than double if two miscarriages were used for
the definition, as the pooled risk has been shown to be 1.9% (1.8–2.1%) for two miscarriages and
0.7% (0.5–0.8%) for three miscarriages.

Risk factors

Advancing maternal age
Advancing paternal age, although not as markedly as with maternal age
Number of previous miscarriages
Black ethnic background
Smoking
Excess alcohol consumption
Excess caffeine consumption
BMI < 19 or BMI > 25 kg/m2

The age-related risk of miscarriage is: (MRCOG II 2015; 2017)

12–19 years = 13%;
20–24 years = 11%;
25–29 years = 12%;
30–34 years = 15%;
35–39 years = 25%;
40–44 years = 51%; and
45 or more years = 93%.

no of previos mc	risk of recurrence %
1	11
2-3	28
4	39
5	47
6	63

Recommended investigations

Thrombophilias

Women with recurrent miscarriage should be offered testing for acquired thrombophilia,
particularly for lupus anticoagulant and anticardiolipin antibodies, prior to pregnancy.
Women with second trimester miscarriage may be offered testing for Factor V Leiden, prothrombin
gene mutation and protein S deficiency, ideally within a research context.
Inherited thrombophilias have a weak association with recurrent miscarriage. Routine testing for
protein C, antithrombin deficiency and methylenetetrahydrofolate reductase mutation is not recommended.

Antiphospholipid syndrome (APS) is defined as the association between antiphospholipid (aPL)
antibodies (lupus anticoagulant, anticardiolipin [aCL] antibodies and anti-beta-2-glycoprotein-I
antibodies) and adverse pregnancy outcome or vascular thrombosis.

Adverse pregnancy outcomes include

three or more consecutive miscarriages before 10 weeks of gestation
one or more morphologically normal fetal losses after the tenth week of gestation
one or more preterm births before 34+0 weeks of gestation because of placental disease.

Lupus anticoagulant has the strongest association with recurrent miscarriage (OR 7.79; 95% CI
2.30–26.45).
To diagnose APS it is recommended that the woman should have two positive tests at least 12
weeks apart (and at least 6 weeks post miscarriage).

Cytogenetics (MRCOG II 2021; 2023)

Chromosome anomalies of the pregnancy are the commonest cause of both sporadic miscarriage
and recurrent miscarriage.
Approximately 50% of sporadic miscarriages are a result of fetal
chromosome anomalies. Among those with anomalies, in descending order of frequency were:
trisomy (51.9%); polyploidy (18.8%); monosomy (15.2%); structural anomalies (6.5%); and others
(7.6%)
The incidence of aneuploidy in recurrent miscarriage was found to be approximately 40%,
suggesting that non-genetic factors may play a more important role in recurrent miscarriage.

Miscarriages following assisted reproductive treatment have rates of cytogenetic anomalies similar
to sporadic miscarriages (56.8% versus 53.6%; OR 1.11, 95% CI 0.71–1.73).

Cytogenetic analysis should be offered on pregnancy tissue of the third and subsequent
miscarriage(s) and in any second trimester miscarriage.

Parental peripheral blood karyotyping should be offered for couples in whom testing of pregnancy
tissue reports an unbalanced structural chromosomal abnormality or there is unsuccessful or no
pregnancy tissue available for testing.
A translocation is present in

2.2% of parents after one miscarriage,

4.8% after two miscarriages,
and 5.7% after three miscarriages.

The chances of parents with a balanced structural chromosome abnormality having a healthy child
was found to be 83%, which was similar to the control couples (84%), the former had a higher
chance of a subsequent miscarriage compared with the latter group (49% versus 30%; P < 0.01).

Miscarriage rates for parents with

reciprocal translocations,

inversions,

Robertsonian translocations, and other types of chromosomal anomalies have been shown to be 54%, 49%, 34% and 27% respectively.

Uterine anomalies

Women with recurrent miscarriage should be offered assessment for congenital uterine anomalies,
ideally with 3D ultrasound.

A systematic review and international consensus has reported that the most accurate
methodologies for diagnosing congenital uterine anomalies in descending order of overall accuracy are:

3D ultrasound (97.6%, 95% CI 94.3–100),
saline-infusion ultrasound (96.5%, 95% CI 93.4–99.5),

hysterosalpingography (86.9%, 95% CI 79.8–94.0) and

2D ultrasound (86.6%, 95% CI 81.3–91.8).

There were no studies reporting on the use of magnetic resonance imaging (MRI) as a
screening tool, however comparative studies have shown MRI to be at least similar in accuracy
compared with 3D ultrasound when expert examiners are used.

Based on these findings, acceptability and relative low cost, 3D ultrasound is recommended as the
first line for the diagnosis of congenital anomalies, reserving MRI and endoscopic evaluation for
complex anomalies when a diagnosis cannot be reached with 3D ultrasound.

The commonest anomalies across all populations appear to be the canalisation defects (i.e. the
septate variety) followed by the unification defects (i.e. the bicornuate and unicornuate variety).

The risk of sporadic first trimester miscarriage was not significantly increased in women with
arcuate (RR 1.22, 95% CI 0.87–1.72; six studies), didelphys (RR 1.13, 95% CI 0.45–2.86; four
studies) and unicornuate uteri (RR 1.38, 95% CI 0.83–2.28; five studies) versus normal controls.

However, women with septate (RR 2.65, 95% CI 1.39–5.06; six studies) and bicornuate uteri (RR
2.32, 95% CI 1.05–5.13; four studies) had a significantly increased risk of sporadic first trimester
miscarriage versus normal controls.

The risk of sporadic second trimester miscarriage was not significantly increased in women with
didelphys (RR 1.71, 95% CI 0.63–4.59; four studies) and unicornuate uteri (RR 2.27, 95% CI 0.64–
7.96; four studies) versus normal controls.

However, women with arcuate (RR 1.98, 95% CI 1.06–3.69; five studies), septate (RR 2.95, 95% CI
1.51–5.77; five studies) and bicornuate uteri (RR 2.90, 95% CI 1.56–5.41; four studies) had a
significantly increased risk of sporadic second trimester miscarriage versus controls.

In a large meta-analysis of a general obstetric population, including 1394 women with myomas and
20 435 without, no increase in risk of miscarriage was found (11.5% versus 8.0%; RR 1.16, 95% CI
0.80–1.52).

An analysis from prospectively collected data in a recurrent miscarriage population
found a similar incidence of myomas to that reported in the general population (8.2% versus 10.4%).

Endocrine tests

Women with recurrent miscarriage should be offered >>>>thyroid function tests and assessment for
thyroid peroxidase (TPO) antibodies.

Thyroxine supplementation is not routinely recommended for euthyroid women with TPO who have a history of miscarriage.

Women with recurrent miscarriage should not be routinely offered immunological screening (such
as HLA, cytokine and natural killer cell tests), infection screening or sperm DNA testing.

Well-controlled diabetes mellitus and treated thyroid dysfunction are not risk factors for recurrent
miscarriage.
PCOS has been linked to an increased risk of miscarriage but the exact mechanism remains
unclear.

Polycystic ovarian morphology, elevated serum LH levels or elevated serum testosterone
levels do not appear to predict an increased risk of future pregnancy loss among ovulatory women
with a history of recurrent miscarriage who conceive spontaneously.

Recommended interventions

Women with recurrent miscarriage should be advised to

maintain a BMI between 19 and 25 kg/m2,

smoking cessation,

limit alcohol consumption and

limit caffeine to less than 200 mg/day.

For women diagnosed with antiphospholipid syndrome,

aspirin and heparin should be offered from a positive test until at least 34 weeks of gestation, following discussion of potential benefits versus risks.–significantly reduces miscarriage rate by 54%

Aspirin and/or LMWH does not increase the live birth rate in women with unexplained recurrent
miscarriage, may be associated with adverse effects and should therefore not be used.

There is a lack of evidence to support routine treatment for women with Factor V Leiden, protein S deficiency and prothrombin gene mutation to reduce the incidence of recurrent miscarriage or second
trimester loss.

Reproductive options in couples with chromosomal rearrangements includes proceeding to a
further natural pregnancy, undergoing assisted reproductive treatment with preimplantation
genetic testing for structural rearrangements (PGT-SR), formerly known as pre-implantation genetic
diagnosis (PGD), or gamete donation.

Resection of a uterine septum should be considered for women with recurrent first or second
trimester miscarriage, ideally within an appropriate audit or research context.

Progestogen supplementation should be considered in women with recurrent miscarriage who
present with bleeding in early pregnancy (for example 400 mg micronised vaginal progesterone
twice daily at the time of bleeding until 16 weeks of gestation).

Routine progesterone supplementation should be used with caution in asymptomatic women with
unexplained recurrent miscarriage.

However, there is a lack of consistently demonstrable benefit when used routinely in women with unexplained recurrent miscarriage, and there remains uncertainty about the optimal specific drug, route, timing and dose.
The PROMISE trial, the largest multicentre RCT to date, which was adequately powered and with a very low risk of bias, showed that routine progesterone supplementation did not improve the outcome.

Thyroxine supplementation may be considered for women with moderate SCH (TSH more than 4
mIU/l) but is not routinely recommended for women with mild SCH (TSH more than 2.5 mIU/l)
irrespective of TPO status.

Regular TSH measurement from 7–9 weeks of gestation is recommended in cases with TPO and/or SCH.

TSH LEVEL DURING PREGNACY

T1- 0.1- 2.5 mU/ml

T2 – 0.2- 3mU/ml

T3 – 0.3 -3 mU/ml

Women with unexplained recurrent miscarriage should be offered supportive care, ideally in the
setting of a dedicated recurrent miscarriage clinic.

Immunotherapy (e.g. paternal cell immunisation, third-party donor leucocytes, trophoblast
membranes and intravenous immunoglobulin [IVIg]) is not recommended for women with recurrent
miscarriage.

Medical management of miscarriage – NICE (MRCOG II 2016)

Do not offer mifepristone as a treatment for missed or incomplete miscarriage.

Offer vaginal misoprostol for the medical treatment of missed or incomplete miscarriage.
Oral administration is an acceptable alternative if this is the woman’s preference
For women with a missed miscarriage, use a single dose of 800 micrograms of misoprostol.

Advise the woman that if bleeding has not started 24 hours after treatment, she should contact her
healthcare professional to determine ongoing individualised care.

For women with an incomplete miscarriage,
use a single dose of 600 micrograms of misoprostol.
(800 micrograms can be used as an alternative to allow alignment of treatment protocols for both
missed and incomplete miscarriage)
Offer all women receiving medical management of miscarriage pain relief and anti-emetics as
needed
Inform women undergoing medical management of miscarriage about what to expect throughout
the process, including the length and extent of bleeding and the potential side effects of treatment
including pain, diarrhoea and vomiting.

Advise women to take a urine pregnancy test 3 weeks after medical management of miscarriage
unless they experience worsening symptoms, in which case advise them to return to the healthcare
professional responsible for providing their medical management.

Advise women with a positive urine pregnancy test after 3 weeks to return for a review by a
healthcare professional to ensure that there is no molar or ectopic pregnancy.

Systematic review evidence (MRCOG II 2016).
Compared with vaginal misoprostol of 800 ug or sublingual misoprostol of 600 ug, lower-dose
regimens (200 ug or 400 ug) by any route of administration tend to be significantly less effective in
producing abortion within about 24 hours
The most effective treatment was sublingual misoprostol of 600 ug and the least effective was oral
misoprostol of 400 ug.
Vaginal misoprostol of 400 ug was reported with fewer side effects and sublingual misoprostol of
600 ug was reported with more side effects.
Sublingual misoprostol of 600 ug or vaginal misoprostol of 800 ug may be a good choice for the first
dose.