Definition and prevalence
• First-trimester recurrent miscarriage (RM) – loss of 3 or more consecutive pregnancies.
• 1–2% of second-trimester pregnancies miscarry before 24 weeks of gestation.
• Approximately 15% of all clinical pregnancies end in pregnancy loss, with 3 or more losses
affecting 1–2% of women of reproductive age and 2 or more losses affecting around 5% of
women.
Risk factors
• Cause of recurrent pregnancy loss (RPL) remains unknown in the majority of women.
• Maternal and paternal age – risk of miscarriage is highest among couples where the woman
is > 35 years of age and the man > 40 years of age.
* Maternal age – advancing maternal age is associated with a decline in both the number
and quality of the remaining oocytes.
* The age-related risk of miscarriage – see graph.
• Advanced paternal age is also a risk factor for miscarriage.
• BMI – obesity increases the risk of both sporadic and RPL.
History
• Obstetric history – risk increases after each successive pregnancy loss, reaching approximately
40% after 3 consecutive pregnancy losses.
• Details of previous loses – gestational age, scan confirmation of fetal pole, painless or painful
loss especially in second trimester loss.
• Past history – diabetes or thyroid disorders, congenital or acquired thrombophilias.
• Heavy alcohol consumption is toxic to the embryo and the fetus. Even moderate consumption
of ≥ 5 units per week may increase the risk of sporadic miscarriage.
• Occupational history – working with or using video display terminals does not increase the risk
of miscarriage. The evidence on the effect of anaesthetic gases for theatre workers is conflicting.
• Maternal smoking and caffeine – associated with an increased risk of spontaneous miscarriage in
a dose-dependent manner. However, current evidence is insufficient to confirm this association.
Antiphospholipid antibodies (LAC/ACA)
• Screen women with first-trimester RPL and women with one or more second-trimester miscarriage before
pregnancy.
• Two positive tests at least 6 weeks apart for either LAC or ACA of IgG and/or IgM class in medium or high
titre are necessary for diagnosis.
Uterine anomalies
• Offer pelvic USS for women with first-trimester RPL and women with one or more second-trimester
miscarriages.
• 2D USS and/or HSG can be used as an initial screening test.
• Combined hysteroscopy and laparoscopy and possibly 3D USS should be used for definitive diagnosis.
• Value of MRI scanning remains undetermined.
Cervical weakness
• Women with a history of second-trimester miscarriage and suspected cervical weakness who have not undergone
a history-indicated cerclage may be offered serial cervical sonographic surveillance.
Genetic factors
• Perform cytogenetic analysis of the products of conception on third and
subsequent miscarriage.
• Perform parental peripheral blood karyotyping of both partners in couples with
RPL where testing of products of conception reports an unbalanced structural
chromosomal abnormality.
• Current data suggest that routine karyotyping of couples with RPL cannot
be justified owing to the cost. Selective parental karyotyping may be more
appropriate when an unbalanced chromosome abnormality is identified in the
products of conception.
Inherited thrombophilic defects
• Screen women with second-trimester miscarriage for inherited thrombophilias
including factor V Leiden, factor II (prothrombin) gene mutation, and protein S.
Antiphospholipid syndrome (APS)
• APA are present in 15% of women with RPL.
• APS – antiphospholipid antibodies (APA) + adverse
pregnancy outcome or vascular thrombosis.
• APA – lupus anticoagulant (LAC), anticardiolipin
antibodies (ACA), and anti-B2 glycoprotein-I antibodies.
• Adverse pregnancy outcomes:
* ≥ 3 consecutive miscarriages < 10 weeks of gestation.
* ≥ 1 morphologically normal fetal loss > 10 weeks.
* ≥ 1 PTB < 34 weeks owing to placental disease.
• Mechanisms – inhibition of trophoblastic function and
differentiation, activation of complement pathways at the
maternal–fetal interface resulting in a local inflammatory
response and in later pregnancy, thrombosis of the
uteroplacental vasculature.
• LBR with no medical intervention is as low as 10%.
Genetic
• Parental structural chromosomal anomaly –
2–5% of couples. Most commonly a balanced
reciprocal or Robertsonian translocation.
* Carriers are phenotypically normal, but their
pregnancies are at increased risk of miscarriage
and may result in a live birth with multiple
congenital anomalies.
* Risk of miscarriage is influenced by the
size and genetic content of the rearranged
chromosomal segments.
• Embryonic chromosomal abnormalities – account
for 30–57% of further miscarriages. Risk
increases with advancing maternal age.
Endocrine factors
• Diabetes and thyroid disorders – women with uncontrolled diabetes in
the first trimester are at risk of miscarriage. Well-controlled diabetes
mellitus and treated thyroid dysfunction are not risk factors for RPL.
• Anti-thyroid antibodies – women with RPL are no more likely than
women without RPL to have circulating thyroid antibodies.
• PCOS – possible increased risk of miscarriage but the exact mechanism
remains unclear. The increased risk is attributed to insulin resistance,
hyperinsulinaemia, and hyperandrogenaemia. The prevalence of insulin
resistance is increased in women with RPL compared with fertile
controls.
* Polycystic ovarian morphology, elevated LH levels, or elevated
serum testosterone levels do not predict an increased risk of future
pregnancy loss.
* Elevated free androgen index appears to be a prognostic factor for a
subsequent miscarriage in women with RPL.
Immune factors
• No evidence to support the hypothesis of human
leucocyte antigen (HLA) incompatibility between
couples.
• Natural killer (NK) cells – peripheral blood NK
cells are phenotypically and functionally different
from uterine NK cells. No evidence that altered
peripheral blood NK cells are related to RPL.
Anatomical factors
• Congenital uterine malformations – risk of RPL
is unclear and the association is debatable.
Prevalence of uterine anomalies in RPL – 2–38%.
Prevalence is higher in women with secondtrimester
miscarriages compared with women
who suffer first-trimester miscarriages.
• Cervical weakness – recognized cause of secondtrimester
miscarriage. The true incidence
is unknown, as the diagnosis is essentially
clinical, based on a history of second-trimester
miscarriage preceded by spontaneous rupture of
membranes or painless cervical dilatation.
Infective agents
• Any severe infection that leads to bacteraemia or viraemia can cause sporadic
miscarriage.
• TORCH – for an infective agent to be implicated in the aetiology of RPL, it must
be capable of persisting in the genital tract and avoiding detection, or must
cause insufficient symptoms to disturb the woman. Toxoplasmosis, rubella,
cytomegalovirus, herpes, and Listeria infections do not fulfil these criteria.
• Bacterial vaginosis:
* BV in the first trimester has been reported as a risk factor for second-trimester
miscarriage and PTD, but the evidence for an association with first-trimester
miscarriage is inconsistent.
* Treatment of BV with oral clindamycin early in the second trimester
significantly reduces the incidence of second-trimester miscarriage and PTD.
* No published data to assess the role of antibiotic therapy in women with a
previous second-trimester miscarriage.
Inherited thrombophilic defects
• Activated protein C resistance (factor V Leiden mutation), deficiencies of protein C/S and antithrombin III,
hyperhomocysteinaemia, and prothrombin gene mutation.
• Possible cause of RPL and late pregnancy complications owing to thrombosis of the uteroplacental
circulation.
• Association between inherited thrombophilias and fetal loss varies according to type of thrombophilia.
• Association between thrombophilia and late pregnancy loss has been consistently stronger than for early pregnancy loss.