In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.
Levels of evidence (Ia-IV) and grading of recommendations (A-C) are defined at the end of the "Major Recommendations" field.
Investigations and Treatments
Genetic Factors
C - All couples with a history of recurrent miscarriage should have peripheral blood karyotyping performed. The finding of an abnormal parental karyotype should prompt referral to a clinical geneticist.
C - In all couples with a history of recurrent miscarriage cytogenetic analysis of the products of conception should be performed if the next pregnancy fails.
Cytogenetic testing is an expensive tool and may be reserved for patients who have undergone treatment in the index pregnancy or have been participants in a research trial; for them, karyotyping the products of conception provides useful information for counselling and future management.
Cervical Weakness
B - Cervical cerclage is associated with potential hazards related to the surgery and the risk of stimulating uterine contractions and hence should only be considered in women who are likely to benefit.
Transvaginal ultrasound assessment of the cervix during pregnancy may be useful in predicting preterm birth in some cases of suspected cervical weakness. [Evidence level Ib]
Endocrine Factors
A - There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage.
Exogenous progesterone supplementation should only be used in the context of randomised controlled trials. [Evidence level Ia]
A - There is insufficient evidence to evaluate the effect of human chorionic gonadotrophin (hCG) in pregnancy to prevent miscarriage.
HCG supplementation in early pregnancy should only be used in the context of randomised controlled trials. [Evidence level Ib]
A - Prepregnancy suppression of high luteinising hormone (LH) concentration among ovulatory women with recurrent miscarriage and polycystic ovaries who hypersecrete LH does not improve the live birth rate.
B - Polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.
A - There is insufficient evidence to assess the effect of hyperprolactinaemia as a risk factor for recurrent miscarriage.
Immune Factors
Antithyroid Antibodies
B - Routine screening for thyroid antibodies in women with recurrent miscarriage is not recommended.
Antiphospholipid Syndrome (APS)
C - To diagnose APS it is mandatory that the patient should have two positive tests at least six weeks apart for either lupus anticoagulant or anticardiolipin (aCL) antibodies of immunoglobulin G (IgG) and/or IgM class present in medium or high titre.
A - Currently there is no reliable evidence to show that steroids improve the live birth rate of women with recurrent miscarriage associated with antiphospholipid antibodies (aPL) when compared with other treatment modalities; their use may provoke significant maternal and fetal morbidity.
A - In women with a history of recurrent miscarriage and aPL, future live birth rate is significantly improved when a combination therapy of aspirin plus heparin is prescribed.
B - Pregnancies associated with aPL treated with aspirin and heparin remain at high risk of complications during all three trimesters.
Although aspirin plus heparin treatment substantially improves the live birth rate of women with recurrent miscarriage associated with aPL, these pregnancies remain at high risk of complications during the three trimesters including repeated miscarriage, pre-eclampsia, fetal growth restriction, and preterm birth, necessitating careful antenatal surveillance. [Evidence level III]
Alloimmune Factors
A - Immunotherapy, including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes, and intravenous immunoglobulin (IVIG), in women with previous unexplained recurrent miscarriage does not improve the live birth rate.
The use of immunotherapy should no longer be offered to women with unexplained recurrent miscarriage and routine tests for human leukocyte antigen (HLA) type and anti-paternal cytotoxic antibody should be abandoned. [Evidence level Ia]
The USA Food and Drug Administration has recently issued a statement to clinicians that administration of such cells or cellular products in humans can only be performed by a licensed clinical researcher holding a currently approved Investigational New Drug application.
Infective Agents
C - TORCH (toxoplasmosis, other [congenital syphilis and viruses], rubella, cytomegalovirus, and herpes simplex virus) screening is unhelpful in the investigation of recurrent miscarriage.
A - Screening for and treatment of bacterial vaginosis in early pregnancy among high-risk women with a previous history of second-trimester miscarriage or spontaneous preterm labour may reduce the risk of recurrent late loss and preterm birth.
Inherited Thrombophilic Defects
In the absence of a randomised trial, the poor pregnancy outcome associated with factor V Leiden (FVL) mutation, coupled with the maternal risks during pregnancy, may justify routine screening for FVL and offering thromboprophylaxis for those with FVL mutation and evidence of placental thrombosis.
Unexplained Recurrent Miscarriage
C - Women with unexplained recurrent miscarriage have an excellent prognosis for future pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit.
Data suggest that the use of empirical treatment in women with unexplained recurrent miscarriage is unnecessary and should be resisted. Further, clinical evaluation of future treatments for recurrent miscarriage should only be performed in the context of randomised trials that are suitably matched and corrected to exclude fetal chromosomal aberrations. [Evidence level IV]
Definitions:
Grading of Recommendations
Grade A - Requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence levels Ia, Ib)
Grade B - Requires the availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendations (evidence levels IIa, IIb, III)
Grade C - Requires evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates an absence of directly applicable clinical studies of good quality (evidence level IV)
Levels of Evidence
Ia: Evidence obtained from meta-analysis of randomised controlled trials
Ib: Evidence obtained from at least one randomised controlled trial
IIa: Evidence obtained from at least one well-designed controlled study without randomisation
IIb: Evidence obtained from at least one other type of well-designed quasi-experimental study
III: Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies, and case studies
IV: Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
