[CG] Recurrent pregnancy loss

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Recurrent Pregnancy Loss (RPL) is defined as the loss of 3 or more pregnancies from conception to 24 weeks and excludes molar or ectopic pregnancies. It is associated with significant grief and stress. Care should be delivered sensitively and enable the psychosocial needs of the couple to be met. 

Women with ≥3 pregnancy losses should be referred to a clinician with a special interest in RPL. Referral after 2 early pregnancy losses may be considered in women ≥38 years old or when there are other risk factors identified by the Early Pregnancy Unit (EPU), such as assisted conception. This clinic should be held in an appropriate setting and with adequate facilities.

Women with RPL often present to clinic with an abundance of information from a variety of sources and therefore a thorough explanation and re-education of investigation and treatments available may be required. It is important to allow sufficient time to obtain a detailed history but also to explain that in most cases there may not be a cause for RPL found (unexplained RPL). When a cause is found, treatment options may be limited or poorly understood and not offered routinely. It must also be emphasised that stress is not a cause, rather a result, of RPL as many patients will be concerned that stress has led to their pregnancy loss. 

History

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

  • Maternal age: the risk increases rapidly over the age of 40
  • Parity (primary RPL is defined as no previous pregnancies beyond 24 weeks; secondary RPL is defined as 1 ≥previous pregnancy beyond 24 weeks)
  • Gestation and type of pregnancy losses
  • Fertility investigations to date
  • Menstrual cycle and gynaecological history (including smear history, known uterine malformation/fibroids, PCOS)
  • BMI (extremes of BMI <18 and >30kg/m2)
  • Past medical (inc diabetes, renal malformations) and family history
  • Social history: Smoking, alcohol, drugs
  • 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

Investigations

This should be tailored to each individual. The prognosis is based on the number of preceding pregnancy losses and the maternal age. Written information should be given to the patient on what investigations are being performed and support services available. When investigations are being carried out, women should be advised to wait for the results before trying for another pregnancy. 

  • Genetic testing:
  • Pregnancy tissue may be sent for cytogenetic testing at the 3rd and subsequent pregnancy loss where pregnancy tissue (products of conception, POC) is available
    • The pregnancy losses do not need to be consecutive
    • This test is for explanatory purposes, although a cause may only be found in approximately 50% of cases. It is used to detect couples at risk of carrying a balanced parental chromosomal rearrangement
    • POC should include fetal tissue and specimens will not be processed if amnion tissue alone is sent to the lab
    • Testing for parental karyotype is only indicated if there is an unbalanced structural chromosomal abnormality identified from analysis of the POC. This should prompt referral to Medical Genetics
    • If pregnancy tissue is not available at the 3rd or subsequent miscarriage (ie. pregnancy loss managed at home) then discussion with Medical Genetics may be indicated to determine suitability for testing the parental karyotype
  • Lupus anticoagulant (LA) and Anticardiolipin antibodies (ACA): may be tested for 6-8 weeks post pregnancy loss, usually when the patient attends for follow up counselling.
  • In certain circumstances, tests can be done >1 week post pregnancy loss however it is recommended that these are performed when the patient attends for follow up counselling at 6-8 weeks (ie. when the pathology results are also available) to avoid additional hospital appointments
  • Tests are preferably performed off any anticoagulant or oestrogen-based medication (these two latter medications can result in erroneous lupus anticoagulant results, usually false positives)
    • LA: reported as negative or positive
    • ACA: reported as negative (<20g/l) or positive (>20g/l)
      All positive results should be repeated  later for confirmation of the result
  • Assessment of uterine anatomy: Refer to gynaecology for a transvaginal ultrasound scan (TVS) unless clearly visualised and documented as normal at previous early pregnancy scan
  • 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)
    • 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
  • Investigation of Male Partners:
  • Assessment of past medical history and lifestyle factors should be carried out and include smoking, alcohol/drug misuse, exercise history and BMI

Testing for the following is not routinely recommended:

  • Parental karyotype: Only test if an unbalanced translocation identified on genetics screening of POC or if advised by Medical Genetics
  • Thyroid function tests (TFT’s) and Thyroxine Peroxidise Antibodies (TPOABs): Only test if clinically indicated
    • Abnormal if: TSH <0.05mU/L or >3.4mU/L or fT4 <10pmol/L or >18pmol/L  Whilst hyperthyroidism is associated with pregnancy complications, it is not clearly associated with recurrent pregnancy loss 
  • Prolactin: only test if signs/symptoms of hyperprolactinaemia (eg. oligo/amenorrhoea)
  • Antinuclear antibodies (ANA’s): may be considered in those with autoimmune conditions and may be offered for explanatory purposes
  • Heritable thrombophilias: testing should only be considered to assess a women’s venous thromboembolism (VTE) risk prior to pregnancy in women with a:
    • 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.
  • NK cells or HLA
  • Glucose/insulin/assessment of PCOS
  • LH/FSH/testosterone unless indicated
  • Assessment of ovarian reserve (AMH)
  • Semen analysis from the partner unless indicated

Treatment and Interventions to Improve Live Birth Rate (LBR) in RPL

Early pregnancy ultrasound scans and talking to an early pregnancy specialist midwife or clinician can provide a great amount of support and reassurance for patients in subsequent pregnancies. Women should be aware of the referral process to the EPU (via trakcare or by phone) from 6 weeks if asymptomatic or earlier depending on clinical symptoms or history. Patients can self refer to EPU 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 ‘emotional wellbeing’) or via the GP. Currently appointments are held within the Princess Royal Maternity and Queen Elizabeth University Hospital maternity buildings but are available for all patients within GG+C. 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. 

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

Anti-thrombotic prophylaxis for the treatment of hereditary thrombophilias is not recommended to reduce the risk of RPL or in those with unexplained RPL (although it may however 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 limited evidence to support the use of pre-conceptual Aspirin 75-100mg/day plus heparin from the start of pregnancy in those with APL syndrome and a background of RPL.
    • Low molecular weight heparin (LMWH) is preferred over unfractioned heparin due to its’ lower side effect profile however there is very limited evidence to support the use of LMWH in reducing RPL
    • The risks and benefits of treatment should therefore be discussed with the patient when attending the EPU
    • A VTE risk assessment should routinely be performed in early pregnancy and women with APL syndrome may therefore require LMWH anyway if they meet criteria for treatment
    • For those with a positive initial test for APS syndrome that conceive before a second confirmatory test is performed, the risks and benefits of aspirin+/-LMWH in pregnancy should be discussed. The second test should be performed >6weeks after pregnancy for confirmation of the result.

Hypothyroidism:

  • Levothyroxine should only be offered to women with proven hypothyroidism
  • Subclinical hypothyroisim  and thyroid autoimmunity
  • Treatment with levothyroxine should only be offered if there is true hypothyroidism (i.e. the T4 level are low). TFTs should only be checked if there is a clinical indication for this

Progesterone:

  • Progestogen supplementation in the first trimester of pregnancy may reduce the rate of early pregnancy loss in those with unexplained recurrent miscarriage
  • A recent systematic review and meta-analysis showed that the rate of pregnancy loss was lower when synthetic progestogen supplementation was used in the first trimester. The preferred dose or route of progestogen therapy was inconclusive and further trials are needed to establish this

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 RPL

Recurrent second trimester losses:

  • Recurrent pregnancy loss in the second trimester is associated with cervical weakness and therefore serial cervical length scans +/-cervical cerclage is recommended

Treatment with the following is not routinely recommended:

  • Hcg/metformin
  • IV immunoglobulin or glucocorticoid for immunological or unexplained RPL
  • Heparin or aspirin for unexplained RPL
  • Intralipid

Last reviewed: 26 November 2019

Next review: 30 November 2024

Author(s): Dr Joy Simpson

Approved By: R Jamieson