Table 1

Proposed evaluation of women with recurrent miscarriage*

Medical history
Ask about gestational age of miscarriagePre-embryonic and embryonic are the most common type of recurrent miscarriage. The aetiology may differ from cases of losses occurring later.
Assess obstetric historyPoor obstetric outcomes, such as early and late miscarriage, pre-eclampsia, stillbirth and prematurity, are major predictors of subsequent pregnancy risk complications.
Assess history of uterine malformations and cervical incompetencePrevious obstetric complications such as miscarriage, preterm labour or breech presentation may suggest uterine malformation or cervical incompetence.
Assess whether the mother has had a fetus or child with an inherited anomalyCongenital abnormalities raise the possibility of a parental chromosomal abnormality.
Evaluate findings related to APSFeatures include thrombosis, fetal death, pre-eclampsia and other poor obstetric outcomes, livedo reticularis, thrombocytopenia and autoimmune diseases.
Ask whether the patient has a history of thyroid abnormalities, diabetes or polycystic ovary syndromeConsider overt clinical and subclinical forms of hypothyroidism. Do not contemplate cases of subclinical thyroid hyperfunction. Be aware in cases of recurrent miscarriage and TSH ranging from 2.5 to 4.5 IU.
Assess personal or family history of thromboembolic diseasesVenous thromboembolic history, mainly in young people and in uncommon locations, may be related to inherited thrombophilias and/or APS.
Physical examination
Perform pelvic and uterine examinationStandard manual pelvic examination cannot rule out cervical abnormalities.
Look for signs of thyroid diseases, diabetes, obesity and hyperandrogenaemiaComplete physical examination.
Look for signs related to systemic autoimmune diseasesSome skin signs that accompany normal gestation (eg, malar blushing, facial pigmentation, alopecia, hand erythema, telangiectasia or carpal tunnel syndrome) may be difficult to differentiate from those related to systemic or rheumatic diseases.
Usually recommended test: pros and cons
Sonohysterography and hysterosalpingographyMRI and hysteroscopy are more informative but more expensive and invasive, respectively. Both screening tests are increasingly being used. Transvaginal ultrasound is useful in cases of short or incompetent cervix.
Chromosomal analyses of the coupleParental karyotyping is expensive and does not always provide valuable information. Furthermore, treatment options are limited and do not surpass results of spontaneous conception. Parental karyotyping would be performed in couples with recurrent miscarriage where testing of products of conception shows unbalanced structural chromosomal abnormalities.
Sperm morphologyAlthough frequently recommended, sperm morphology analyses do not appear to be predictive of further miscarriages.
Sperm DNA studiesData regarding the relationship between miscarriages and DNA sperm fragmentation in IVF cycles are contradictory. Routine testing for sperm ploidy (FISH or DNA fragmentation) is not recommended.
Chromosomal analyses of products of conceptionConceptus karyotyping test is a matter of debate. Aneuploid conceptus indicates a favourable outcome of further pregnancy. Mosaicisms may be difficult to evaluate. Abnormalities in conceptus karyotyping would support chromosomal testing in the couple.
Preimplantation genetic screening in IVFThis screening genetic test, using FISH, does not improve the live birth rate and should probably not be recommended.
aPL panel according to Sydney recommendationsLupus anticoagulant test is reported as positive or negative. aCLs are expressed in GPL and MPL units according to a standardised test. Anti-β2GPI antibodies are measured in arbitrary, non-standardised units (AU). Clinical criteria apart, APS is diagnosed when tests at least 12 weeks apart are repeatedly positive. Other aPLs such as antiprothrombin/antiphosphatidylserine or anti-domain I anti-β2GPI antibodies and IgA isotype are not yet considered classification laboratory criteria.
Inherited thrombophilic disordersUncertain value in pre-embryonic and embryonic losses, mainly referring to factor V Leiden. Test should be performed out of pregnancy, especially for protein S levels.
Not recommended laboratory tests
Progesterone levels in previous luteal phase, ‘atypical’ aPLs, anti-Müllerian hormone, anti-paternal cytotoxic antibodies, HLA class I/II screening, cytokine numbering and ratios, NK cells and NK KIRs.Overall, these tests are not systematically recommended. These parameters may be tested only for clinical research reasons in monographic units.
  • *Modified from Alijotas-Reig and Garrido-Gimenez67 and Branch et al.10

  • aCL, anticardiolipin antibody; aPL, antiphospholipid antibody; APS, antiphospholipid syndrome; β2GPI, β2-glycoprotein I; FISH, fluorescent in situ hybridisation; HLA, human leucocyte antigen; IVF, in vitro fertilisation; KIR, killer cell immunoglobulin-like receptor; NK cells, natural killer cells; TSH, thyroid-stimulating hormone.