Recurrent Miscarriage and Adverse
Pregnancy Outcome.
Classification: Clinical Guideline
Author: Vanessa Lawton, Clinical Director, Davina
Kahakachchi
Authors Division: Neurosciences and Surgery
Unique ID: GSCOG02(15)
Issue number: 2
Expiry Date: May 2018
Contents
1.
2.
3.
4.
5.
6.
7.
8.
8.1
9.
9.1
9.2
9.3
9.4
9.5
9.6
9.7
10.
11.
12.
13.
Section
Page No
Who should read this document
Key practice points
Background
Definitions
Scope
Follow-up after miscarriage
Causes of miscarriage
Assessment & Investigation
Initial Investigation
Treatment
General Measures
Unexplained miscarriage
Anti-phospholipid syndrome
Other thrombophilias
Suspected cervical weakness
Congenital Abnormalities of the Uterus
Chromosomal disorders
Standards
Explanation of Terms & Definitions
References & supporting documents
Roles & responsibilities
Document control information (Published as separate document)
Document Control
Policy Implementation Plan
Monitoring and Review
Endorsement
Equality analysis
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1. Who should read this document?
Medical staff working in gynaecology
Early Pregnancy Unit nursing staff
Nursing staff caring for women experiencing miscarriage.
2. Key Practice Points

Women should be investigated after 3 consecutive first trimester
miscarriages or after a single adverse pregnancy outcome.

Investigations are tailored to identification of thrombophilias, structural
abnormalities or the uterus and parental chromosomal disorders.

All women should receive lifestyle advice to reduce their risk of
miscarriage.

The outcome of pregnancy should be optimised through facilitating
optimisation of pre-existing conditions and pre-conceptual counselling.

Aspirin and heparin should only be prescribed for specific indications.

Management of unexplained miscarriage should be supportive.

Women should not be advised that they require cervical cerclage after
two or fewer mid-trimester losses. Ultrasound cervical surveillance
should be recommended for this group.

Couples with parental chromosomal abnormalities should be referred to
a geneticist.
3. Background
This clinical guideline was developed to provide consensus on the
management of women who have suffered from recurrent miscarriage or
related adverse pregnancy outcomes. It is based on the recommendations of
the RCOG Guideline no 17, Recurrent Miscarriage: Investigations and
Treatment of Couples, authored by Regan, Marcos and Rai (2011)1 but also
documents clinical consensus developed around areas of uncertainty. That
process has included the views of obstetric consultants working in
neighbouring Trusts who will be responsible for the care of pregnant women
from 9 weeks gestation onwards. This consensus is designed to promote
seamless care between services and avoid conflict between women and
clinicians as care is transferred in the first trimester of pregnancy.
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4. Definitions
Recurrent miscarriage is defined as three consecutive first trimester
miscarriages and affects 1% of couples attempting to conceive. Adverse
pregnancy outcome is defined below in section 5.
5. Scope
This guideline describes the investigation and management of women with
recurrent miscarriage as defined above and other adverse pregnancy
outcomes. Although women experiencing second trimester miscarriage are
rarely managed in the gynaecology unit at Salford Royal they may
subsequently be referred for investigation.
In addition to investigation after three consecutive first trimester
miscarriages, couples should also receive appropriate investigation after the
following adverse pregnancy outcomes:



second trimester miscarriage
any morphologically normal loss over 10 weeks
one or more pre-term births before 34 weeks with placenta disease
(IUGR, pre-eclampsia)
6. Follow up after Miscarriage
Couple should be treated sensitively and sympathetically as even a single
miscarriage may be devastating for them. Follow up may be offered to any
women after a miscarriage if requested but women should be advised that
investigation will not be undertaken unless the above criteria are met.
Couples should be encouraged to attend for follow up together.
7. Causes of Miscarriage
The following are known causes or risk factors for recurrent miscarriage:





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



increased maternal age (esp. over 35 years)
increased paternal age (esp. over 40 years)
high maternal alcohol consumption
obesity
anti-phospholipid syndrome
parental chromosomal re-arrangements especially balanced
translocations.
congenital uterine malformations
cervical weakness (second trimester miscarriage)
poorly controlled diabetes mellitus
Polycystic ovarian syndrome (PCOS)
inherited thrombophilias
bacterial vaginosis (second trimester miscarriage)
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Possible additional risk factors are:
 high caffeine consumption
 maternal smoking
8. Assessment and Investigation
Follow up after recurrent miscarriage is an opportunity to identify modifiable
risk factors for maternal and fetal wellbeing throughout future pregnancies, not
just the first trimester. Assessment should be directed at the identification of
all such features.
An appropriate clinical assessment should include:
 history of miscarriages
 a full obstetric history
 relevant past medical history especially identification of chronic
conditions and venous thrombo-embolism
 medication
 smoking and alcohol intake
 recreational drug use
 BMI
8.1 Initial Investigation
The following investigations should be performed for all women with recurrent
first trimester miscarriages:



Lupus anticoagulant and anti-cardiolipin antibodies
Karyotyping of products of conception from third or subsequent
miscarriages for unbalanced translocation if possible (medical or
surgical management required)
USS for uterine abnormality
Women with a history of miscarriage after 10 weeks and/or adverse
pregnancy outcome should also be offered testing for
 Factor V Leiden (FVL),
 Protein S deficiency,
 Pro-thrombin gene mutation,
 Activated Protein C Resistance (APCR) and
 Anti-thrombin III deficiency.
Testing for rubella immunity should be considered unless done in the recent
past.
The following investigations should not be performed:
 Tests for cervical weakness using dilators or hysteroscopic techniques
 Parental karyotyping, unless karyotyping of products of conception has
shown a unbalanced structural chromosomal abnormality
 Natural Killer cells levels in peripheral blood or in endometrium
 Thyroid antibodies
 Tests for polycystic ovarian syndrome unless the woman has other
symptoms (oligo- or amenorrhoea, acne, hirsutism)
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

Cytokine tests
Tests for infective agents
9. Treatment
9.1 General Measures
All couples should be advised of the increased risk of miscarriage with
increasing maternal and paternal age.
Women who are overweight or obese should be advised that reducing their
weight will reduce their chance of first trimester miscarriage as well as that of
gestational diabetes, hypertension in pregnancy, dystocia and stillbirth.
Women with a heavy alcohol intake should be advised to reduce this ideally
to less than 5 units per week to reduce their risk of miscarriage.
Women and their partners who smoke should be advised that stopping
smoking may reduce their risk of miscarriage and will also reduce the risk of
intra-uterine growth restriction, premature birth and stillbirth in later pregnancy
Women may wish to limit their caffeine intake which may reduce their risk of
miscarriage.
Advice should be given that women attempting to conceive should take a
daily supplement of 400mcg of folic acid orally ideally 3 months before
trying to conceive until 12 weeks of pregnancy to reduce the risk of fetal
abnormality. 5mg folic acid may be prescribed.
Assessment of women who have experienced recurrent miscarriage may also
present opportunities to identify women with chronic medical disorders who
would benefit from optimisation of their condition, review of medication or
pre-conceptual counselling. The woman’s GP should be advised that
review is necessary either in primary or secondary care.
Supportive care may be provided to all women who have experienced
recurrent miscarriage whether explained or not (see section 9.2).
Consideration may be given to referral to a tertiary unit (e.g. Liverpool
Women’s Hospital) should management fail so that women may benefit from
recruitment to clinical trials.
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9.2. Unexplained Miscarriage
Women with unexplained recurrent miscarriage should mainly be offered
supportive care as the prognosis is good. Women investigated for
recurrent miscarriage may self-refer to EPU for early ultrasound following a
positive pregnancy test. Re-assurance scans may be performed fortnightly
until 10 weeks gestation. If pain and/ or bleeding occurs the EPU guidelines
should be followed.
The best current evidence has demonstrated no benefit for low dose aspirin
or heparin in improving the live birth rate so should not be used. The RCOG
gives clear advice against their use for this group.1
However, low dose aspirin 75mg OD may be commenced in women who
meet the criteria for prophylactic treatment of hypertensive disorders in
pregnancy.2 These are:

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hypertensive disease during a previous pregnancy
chronic kidney disease
SLE & anti-phospholipid syndrome
type 1 or type 2 diabetes
chronic hypertension
Women with two or more of the following risk factors should also be offered
aspirin:
 primiparous women
 women aged 40 years or more
 pregnancy interval greater than 10 years
 BMI of >=35 kg/m2
 family history of pre-eclampsia
 multiple pregnancy
The following treatments should not be used:
 HCG supplementation
 Corticosteroids
 Metformin
 Progesterone supplementation
An association has been established between high levels of uterine natural
killers (uNK) cells found on endometrial biopsy and recurrent miscarriage in a
minority of women. It has been established that pre-conceptual treatment with
prednisolone reduces levels of uNK cells in the endometrium. A small
feasibility randomised placebo controlled trial has been published of
prednisolone in women with high levels of uNK cells on endometrial biopsy.
There was no significant difference in outcome between the two groups in this
under-powered study.3 There is insufficient evidence to support the use of
corticosteroids outside of a trial at the present time.
Evidence for the use of progesterone supplementation in the prevention of
unexplained recurrent miscarriage have been published in 2015.6 The study of
826 women with previously unexplained recurrent miscarriage showed that
those who received progesterone treatment in early pregnancy were no less
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likely to miscarry than those who received a placebo. This was true
whatever their age, ethnicity, medical history and pregnancy history.
Two positives arose from the trial, however
 Nearly two-thirds of the women in the trial had a live birth, whether they
had progesterone or the placebo. So even without treatment, the
chances of a healthy pregnancy after unexplained recurrent
miscarriage are better than some might expect.
 There were no harmful effects of progesterone between treatment arm
and placebo arm. Hence progesterone is safe to use for other reasons
such as fertility.
9.3. Anti-Phospholipid Syndrome
The criteria for diagnosing anti-phospholipid syndrome are:
 two positive tests for either lupus anticoagulant or anti-cardiolipin
antibodies measured at least 3 months apart
And one of the following clinical features
 venous thrombo-embolism
 three or more consecutive miscarriages before 10 weeks of gestation
 one or more morphologically normal fetal losses after the 10th week of
gestation
 one or more preterm births before the 34th week of gestation owing to
placental disease
Anti-phospholipid syndrome should be treated with low dose aspirin and low
molecular weight heparin. Women should be advised to commence 75mg
aspirin OD as soon as they have a positive pregnancy test.
Low molecular weight heparin, in the form of tinzaparin, should be
commenced as soon as practical following a positive pregnancy test. Women
may self-refer or be referred by their GP to the SRFT Early Pregnancy Unit to
initiate this treatment. The doses for tinzaparin are based on maternal weight
as shown in table 1.4
Maternal Weight (kg) Tinzaparin
<50
3500
50-90
4500
91-130
7000*
131-170
9000*
>170
75u/kg/day*
Table 1. Prophylactic tinzaparin doses.1
*consider two divided doses
In the absence of renal failure, monitoring of platelet and anti-Xa levels are
unnecessary.4
Corticosteroids, intra-venous immunoglobulin and other immunotherapies are
ineffective and associated with significant maternal and fetal morbidity so
should not be used in APLS.1
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9.4. Other Thrombophilias
Prophylactic low molecular weight heparin should be offered to women
testing positive for inherited thrombophilias as this reduces the rate of late
miscarriage and may reduce the risk of placental dysfunction in later
pregnancy.1
9.5. Suspected Cervical Weakness
Local obstetric units comply with RCOG guidelines inserting a history
indicated cerclage only after 3 second trimester losses and/or premature
deliveries. Women with fewer losses and suspected cervical weakness are
managed by ultrasound monitoring of cervical length.5 Women with fewer
than 3 losses should NOT be advised that they require a trans-vaginal
cervical cerclage insertion during pregnancy but should expect to be offered
ultrasound cervical surveillance. This is essential to avoid conflict between
women and their obstetricians. Trans-vaginal insertion of cervical cerclage will
not be provided by the gynaecology team at SRFT.
Women for whom trans-vaginal cerclage has failed may be offered referral to
a unit offering trans-abdominal cerclage.
9.6. Congenital Abnormalities of the Uterus
Suspected uterine abnormalities detected by ultrasound may be further
assessed by laparoscopy and/or hysteroscopy. Hysteroscopic resection of
uterine septa may be performed by suitably trained surgeons having
counselled women that the evidence of benefit is based on case series rather
than controlled trials.
9.7. Chromosomal Disorders
The couple should be referred to a clinical geneticist if a parental karyotype
abnormality is identified. Pre-implantation diagnosis, gamete donation and
adoption may be options for the couple.
10. Standards
1. All women should receive lifestyle advice to reduce their risk of
miscarriage.
2. All women should be offered supportive care including serial scans.
3. Heparin and aspirin should be prescribed for specific indications only.
4. Corticosteroids,
HCG,
immunotherapies
and
progesterones/
progestogens should not be used for recurrent miscarriages.
5. Cervical cerclage must not be recommended after one or two midtrimester losses.
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6. Referral to a clinical geneticist must be offered if a parental
chromosomal abnormality is identified.
11. Explanation of Terms & Definitions
RCOG: Royal College of Obstetricians and Gynaecologists
IUGR: Intra-uterine growth retardation
BMI: Body mass index
EPU: Early pregnancy unit
SLE: Systemic lupus erythematosus
RCT: Randomised controlled trials
HCG: Human chorionic gonadotrophin
Other terms are defined within the document.
12. References and Supporting Documents
1. Regan L, Backos M, Rai R. The Investigation and Treatment of Couples
with Recurrent First Trimester Miscarriage (Green-top Guideline 17). RCOG,
London 2011.
2. CG107. Hypertension in Pregnancy. NICE 2010
3. Tang AW, Alfirevic Z, Turner MA et al. A feasibility trial of screening women
with idiopathic recurrent miscarriage for high uterine natural killer cell density
and randomizing to prednisolone or placebo when pregnant. Human Reprod
2013; 28 (7): 1743-52.
4. Greer IA, Thompson AJ. Thrombosis and Embolism during Pregnancy and
the Puerperium, Reducing the Risk (Green-top Guideline 37a). RCOG London
2009.
5. Shennan AH, To MS. Cervical Cerclage (Green-top Guideline 60). RCOG
London 2011.
6. Coomarasamy A et al. A Randomized Trial of Progesterone in Women with
Recurrent Miscarriages. N Eng J Med 2015 Nov 26;373(22):2141-8. DOI:
10.1056/NEJMoa1504927.
13. Roles and Responsibilities
All clinicians caring for women with recurrent miscarriage are expected to
comply with the guideline. The standards should be complied with at all times.
Non-compliance with guidance would be expected to occur infrequently and
for clinical exceptions only. The clinical records should include documentation
of clear reasons for the exception.
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