Management of Recurrent Miscarriage (708)

A full history should be obtained to identify any risk factors and will help guide management of RM: 

• Maternal age: the risk increases with advancing maternal age, with studies suggesting that spontaneous miscarriage occurs in approximately 9% of women aged 20-24years, rising steeply after mid-30s to approximately 75% in those aged 45 years or more.
• Advancing paternal age is also associated with RM, however to a lesser degree
• Parity and obstetric history (primary RM is defined as no previous pregnancies beyond 24+0 weeks; secondary RM is defined as 1 ≥previous pregnancy beyond 24+0 weeks)
• Gestation and type of pregnancy losses
• Fertility investigations
• Menstrual cycle and gynaecological history (including smear history, known uterine malformation, fibroids, polycystic ovarian syndrome (PCOS))
• Body Mass Index (BMI) (a healthy BMI 19-25 is recommended)
• Past medical and family history
• Social history: Smoking, alcohol, caffeine intake, illicit drug use
• Medication: including the use of folic acid/vitamin D
• Toxin exposure: such as occupational exposure to lead, mercury, organic solvents, ionising radiation and teratogenic medications
• Domestic abuse
• History from Male Partners: Assessment of past medical history and lifestyle factors e.g. smoking, alcohol/drug misuse, exercise history and BMI.  Children from previous relationship.

Investigations should be tailored to each individual. The prognosis is based on the number of preceding pregnancy losses and maternal age. Written information should be given regarding the investigations being offered and support services available. Women should be asked to wait for the results before conceiving.

• Genetic testing
  Cytogenetic analysis of products of conception (POC) should be offered on pregnancy tissue of 3^rd first trimester miscarriages (and any subsequent 1^st trimester loss), and in any second trimester miscarriage.
  
  Currently within Scottish Genetic services, funding is only available for analysis of POC from the third or subsequent loss and testing of parental samples is only performed where an abnormality has been found in the POC. This is not in line with RCOG guidance, however, at time of writing (2024), this is a genetic test that is not currently available in Scotland.
  
  Issues to remember when considering pregnancy tissue genetic testing include,

• • The pregnancy losses do not need to be consecutive.
  • POC must NOT be sent in formalin, tissue should be sent dry in a universal container.
  • This test is for explanatory purposes and to detect couples carrying a balanced parental chromosomal rearrangement.
  • Around one third of samples will be reported as having “no suitable material” for genetic analysis. Suitable material is recognisable fetal tissue or chorionic villi.
  • Testing for parental karyotypes is indicated if there is an unbalanced structural chromosomal abnormality identified from analysis of the POC. This will prompt referral to Medical Genetics
  • Testing for parental karyotype may be offered by Medical Genetics if a different genetic abnormality (for example trisomy ) is identified on analysis of POC
  • If pregnancy tissue is not available at the 3^rd or subsequent miscarriage (i.e. pregnancy loss managed at home) then discussion with Medical Genetics may be indicated to determine suitability for testing the parental karyotype, however this cannot currently be offered in GG&C.
  • Miscarriage of a euploid pregnancy is associated with increased risk of further miscarriage.
  • Further information can be found in the GGC guideline Fetal Tissue handling and disposal (up to and including 23+6 weeks gestation 
    
    
• Acquired Thrombophilia - Antiphospholipid syndrome (APS)
  APS is the association between antiphospholipid antibodies (aPL antibodies) and adverse pregnancy outcome or vascular thrombosis.  Adverse pregnancy outcome is defined as 3 or more miscarriages before 10 weeks gestation, 1 or more miscarriage of a morphologically normal fetus after 10 weeks gestation, or 1 or more preterm births before 34 weeks due to placental disease.
  
  Issues to remember when considering acquired thrombophilia testing, include,

  • Lupus anticoagulant (LA) and Anticardiolipin antibodies (ACA IgG and IgM): may be tested no sooner than 6-8 weeks post pregnancy loss.
    
    Tests should be performed when women are not taking any anticoagulant or oestrogen-based medication as these can result in erroneous lupus anticoagulant results.

  • LA: reported as negative or positive

  • ACA: reported as negative (<20g/l) or positive (>20g/l)

  • All positive results should be repeated ≥12 weeks later for confirmation of the result.

  • 2 positive results at least 12 weeks apart are required to make the diagnosis of antiphospholipid syndrome.

  • A positive followed by a negative result is considered to be negative.

• Inherited thrombophilia (factor V Leiden, prothrombin gene mutation, protein S deficiency)
  There is a weak association between inherited thrombophilia and recurrent miscarriage, therefore this is not recommended routinely.  However, testing for the presence of an inherited thrombophilia should be carried out after second trimester miscarriage.
  
  There is currently limited evidence that treatment changes reproductive outcomes.
  
  Additionally, testing should be considered to assess a women’s venous thromboembolism (VTE) risk prior to pregnancy in women with,
  
  
  • Family history of both thrombophilia and VTE
  • A first degree relative with a history of VTE which was either unprovoked  or provoked by a minor risk factor (hormone related, minor trauma or long distance travel)
  • Personal history of either an unprovoked or provoked (by a minor risk factor) VTE.
    
    
• Endocrine testing
  Well controlled diabetes and thyroid function are not associated with an increased risk of first trimester miscarriage.
  
  Thyroid function tests and TPO antibodies may be considered as meta-analyses have reported an association between TPO antibodies, thyroid dysfunction and recurrent miscarriage.  The presence of TPO antibodies in euthyroid women should prompt thyroid function testing in pregnancy.
  
  Other endocrine assessments are not indicated unless there are clinical signs of pathology such as diabetes or hyperprolactinaemia.
  
  
• Vitamin D
  There is an association between low levels of vitamin D and RM.  Routine testing is recommended.
  
  
• Assessment for congenital uterine abnormality
  • Transvaginal ultrasound scan (TVS) out with pregnancy should be undertaken to assess uterine anatomy.
  • TVS has a high sensitivity and specificity to distinguish between a septate uterus and a bicorporeal uterus with a normal cervix (formerly known as a bicornuate uterus).
  • TVS may also detect the presence of adenomyosis which may be associated with pregnancy loss (not just RM).
  • MRI pelvis or hysteroscopy may be considered if there is any abnormality detected or further assessment is indicated.
  • If Mullerian malformations are diagnosed, further investigation of the kidneys and urinary tract should be offered.

• Parental karyotype – as described previously, test if an unbalanced translocation is identified on genetics testing of POC or if advised by Medical Genetics
• Prolactin - only test if signs/symptoms of hyperprolactinaemia (e.g. oligo/amenorrhoea)
• Antinuclear antibodies (ANAs)
• Inherited thrombophilia: as described above.
• Natural Killer (NK) cells or Human Leukocyte antigen (HLA)
• Glucose, insulin, HBA1C assessment of Polycystic ovarian syndrome (PCOS)
• LH/FSH/testosterone unless indicated
• Assessment of ovarian reserve (AMH)
• Semen analysis

Early pregnancy ultrasound scans and engagement with an early pregnancy specialist midwife or clinician gives support and reassurance in subsequent pregnancies. Women should be aware of the referral process to the EPAU from 6 weeks if asymptomatic or earlier depending on clinical symptoms or history. Patients can self-refer to EPAU by phone or a referral can be made via Trakare by a clinician. 

Pregnancy loss counselling and support services are available via the Miscarriage Association (tel: 01924 200 799). In addition, referral to Clinical Psychology within GGC (tel: 0141 211 4532 (24532)) can be made via BadgerNet (found under MNPI) or via the GP.

For more advanced pregnancy losses, referral to the Child Bereavement Service (tel: 0141 370 4747) within the Royal Hospital for Children in Glasgow may be offered.

Advice and support should be offered on smoking cessation, regular exercise, weight management and limiting alcohol intake. Caffeine intake should be limited to less than 200 mg/day (e.g. approx. 1-2 cups of tea or instant coffee/day, energy drinks should be avoided).  In women with BMI≥ 30kg/m²  5mg folic acid daily can be offered pre-conceptually.

Genetic counselling should be offered where there is an abnormal fetal +/- parental karyotype.

Anti-thrombotic prophylaxis is not recommended, to reduce the risk of RM, for either hereditary thrombophilia or in those with unexplained RM (although it may be required to reduce the risk of VTE if risk factors exist).

• Antiphospholipid (APL) Syndrome:

This is defined as pregnancy loss or vascular thrombosis in addition to positive LA or ACA (on two occasions, at least 12 weeks apart)

There is some evidence to support the use of Aspirin plus low molecular weight heparin (LMWH) from positive pregnancy test until at least 34 weeks gestation in those with APL syndrome and a background of RM.  If LMWH has not been commenced in early pregnancy, VTE risk assessment should be undertaken, as prophylactic LMWH may still be required for VTE prevention.

Patients with APL may already be on Aspirin out with pregnancy due to the risk of other APLS complications such as stroke. 

For those with a positive initial test for APS syndrome who  conceive before a second confirmatory test is performed, the risks and benefits of aspirin+/-LMWH in pregnancy should be discussed and treatment offered.  The second test should be performed >6weeks after pregnancy for confirmation of the result.

Women with APS treated with Aspirin and LMWH are at risk of complications in all 3 trimesters and warrant obstetric led care.

• Hypothyroidism:

Levothyroxine should be offered to women with proven hypothyroidism and pregnancy specific levels should be used to monitor levels during pregnancy.

Subclinical hypothyroidism 

Treatment with levothyroxine should only be offered if there is true hypothyroidism (i.e. the T4 level is low). Thyroxine supplementation may be considered in those with RM and subclinical hypothyroidism (TSH >4.0ml IU/l with normal T4 levels) to ensure TSH 2.5ml IU/l but the risks must be balanced against the benefits of treatment

Thyroid antibodies

Treatment with thyroxine in women who have thyroid auto antibodies (TPO) but whom remain euthyroid does not improve the pregnancy outcome and should not be offered. These women should have TFT checked during pregnancy.

• Vitamin D:

Women with low vitamin D, should be advised to use supplementation 10micrograms (1000 IU) daily.  This can be an over the counter preparation.

• Progesterone:

Progestogen supplementation in the first trimester of pregnancy may reduce the rate of early pregnancy loss in those with unexplained recurrent miscarriage when there is early pregnancy bleeding in the current pregnancy (Progesterone in Spontaneous Miscarriage, PRISM trial, 2019).

Self-administered progesterone pessaries can be offered in this case.

• • 1^st line : Cyclogest 400mg, administered vaginally twice a day.
  • 2^nd line Utrogestan 400mg, administered vaginally twice a day.

Progesterone is not thought to improve the pregnancy outcome in those with RM without early pregnancy bleeding (Progesterone in Recurrent Miscarriage, PROMISE, 2015). Women with unexplained RM may choose to take Cyclogest from earlier in the pregnancy in the absence of bleeding but should be informed that this is not evidence based.

• Hysteroscopic resection of a uterine septum or removal of submucosal fibroid or polyps:

This may be discussed and offered in certain circumstances although there is limited evidence that it reduces the rate of RM

• Recurrent second trimester losses:

Recurrent pregnancy loss in the second trimester is associated with cervical weakness and therefore and individualised plan for obstetric led care with serial cervical length scans +/-cervical cerclage is recommended.

• Treatment with the following is not routinely recommended:

• • Hcg
  • Metformin
  • Heparin or aspirin for unexplained RPL
  • Intralipid
  • IV immunoglobulin
  • Endometrial scratch
  • Pre-implantation genetic screening in conjunction with IVF/ICSI due to the lack of evidence that this improves reproductive outcomes.

• GGC
  • Progesterone use in early pregnancy Guideline
    
    
• RCOG
  • Early Miscarriage
  • Recurrent and Late Miscarriage
    
    
• Miscarriage Association
  • Recurrent Miscarriage (2023)
  • Antiphospholipid Syndrome and Pregnancy Loss (2023)
    
    

• European Society of Human Reproduction and Embryology (ESHRE)
  • Information for Couples with Recurrent Pregnancy Loss (2023)