Lucan · Conditions

Recurrent miscarriage

Australian guidance: RANZCOG C-Gyn 38

1. Definition and epidemiology

RANZCOG C-Gyn 38 defines recurrent miscarriage as the loss of two or more intrauterine pregnancies of up to 20 weeks gestation, whether or not the losses were consecutive. This definition is broader than the RCOG threshold of three or more first-trimester losses. Between 1% and 4% of couples experience recurrent pregnancy losses, with longitudinal data from Denmark showing a lifetime risk of three consecutive losses of approximately 0.87%. For most women no causative factor can be identified despite thorough investigation.

2. Pathophysiology

Recurrent miscarriage is a heterogeneous condition with multiple overlapping aetiological pathways. Chromosomal aneuploidy accounts for the majority of individual pregnancy losses, but its relative contribution actually decreases with increasing number of losses, suggesting non-chromosomal mechanisms become proportionally more important in recurrent cases (Robbins Ch 22). Antiphospholipid syndrome (APS) causes placental thrombosis and inadequate trophoblastic invasion via pathological activation of complement at the decidua, promoting a pro-inflammatory state that disrupts the maternal-foetal interface. Uterine structural factors (septate uterus, intrauterine adhesions, submucosal fibroids, endometrial polyps) impair implantation and early placentation through inadequate endometrial receptivity or distorted cavity geometry. Thyroid dysfunction, particularly overt hypothyroidism, alters the hormonal milieu required for successful implantation and early placental development. Immunological disturbances including elevated antinuclear antibodies (ANA) and natural killer (NK) cell dysregulation have been observed, though the causal mechanisms remain incompletely characterised. Inherited thrombophilias such as factor V Leiden mutation and prothrombin gene mutation are associated with an increased prevalence in affected women, though evidence that treating them improves live birth rates is lacking. In a significant proportion of couples, no cause is found after full evaluation (Robbins Ch 22).

3. Clinical presentation and diagnostic criteria

Women present with a history of two or more confirmed intrauterine pregnancy losses, typically confirmed by ultrasound or histopathology at less than 20 weeks gestation. The clinical encounter should address the timing and gestational age of each loss, whether losses were embryonic (before 10 weeks) or foetal (10 to 20 weeks), any prior live births, obstetric history including previous caesarean section, menstrual regularity, symptoms of thyroid dysfunction, and a family or personal history of thromboembolism or autoimmune conditions. Both maternal and paternal age should be noted as they influence chromosomal and sperm DNA fragmentation risk respectively. The diagnostic threshold of two or more losses adopted by RANZCOG is based on evidence that risk factor prevalence (particularly APS and balanced translocations) is similar whether the threshold is two or three losses, and that delaying investigation to a third loss may cause unnecessary harm.

4. Investigations and AU-specific cutoffs

RANZCOG C-Gyn 38 Table 1 provides a structured screening framework:

Routinely recommended (strong evidence): - Antiphospholipid antibody panel: lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG and IgM. Positive results require confirmation on two occasions at least 12 weeks apart to meet Sapporo criteria for APS. - Thyroid panel: thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies (TPOAb), and thyroid function tests. Levothyroxine is indicated for overt hypothyroidism (raised TSH, low T4); insufficient evidence to treat subclinical hypothyroidism (TSH greater than 2.5 mIU/L, normal T4) per current evidence. - Pelvic 3D ultrasound: first-line imaging for uterine structural anomalies including uterine septum, fibroids, and polyps. The prevalence of congenital uterine anomalies in recurrent miscarriage is estimated at 7 to 28%.

Consider on a case-by-case basis: - Anti-beta-2-glycoprotein-I antibodies (anti-B2GPI): alongside other antiphospholipid markers. - Parental peripheral blood karyotyping: particularly if a foetal chromosomal structural anomaly has been identified. - Sperm DNA fragmentation: limited treatment evidence; lifestyle modification is the primary intervention. - Antinuclear antibodies (ANA): diagnostic purposes only; no evidence-based treatment currently available.

Not routinely recommended: inherited thrombophilia screen (factor V Leiden, prothrombin gene mutation, protein S and C, antithrombin deficiency), polycystic ovary syndrome markers (fasting insulin, fasting glucose), prolactin, ovarian reserve testing, androgen testing, vitamin D, luteinising hormone, and homocysteine.

5. Management

Management is directed by the identified aetiology.

Antiphospholipid syndrome: Women with confirmed APS and a history of recurrent miscarriage should be offered low-dose aspirin 75 to 150 mg daily (commenced prior to or at positive pregnancy test) combined with low-molecular-weight heparin (LMWH) at prophylactic dose per local protocols, continued until at least 34 weeks gestation. Treatment should be ceased before birth. Unfractionated heparin (UFH) may further increase live birth rates compared to LMWH but requires hospital administration and frequent monitoring; the practical barriers favour LMWH in most Australian settings (GRADE: Moderate).

Thyroid dysfunction: Levothyroxine is strongly recommended for women with overt hypothyroidism prior to and during pregnancy. For subclinical hypothyroidism (TSH greater than 2.5 mIU/L) the evidence is insufficient to recommend levothyroxine routinely; TSH should be rechecked at 7 to 9 weeks gestation. Women with TSH less than or equal to 2.5 mIU/L and positive TPOAb should not be offered levothyroxine (GRADE: Moderate for overt; Very Low for subclinical).

Progesterone in recurrent miscarriage with early bleeding: Micronised progesterone 400 mg vaginally twice daily from the time of early pregnancy bleeding, continued to 16 weeks gestation, is recommended for women with two or more previous miscarriages who experience early pregnancy bleeding. This intervention is not recommended in the absence of first-trimester bleeding (GRADE: Moderate).

Uterine anatomical factors: Septum resection is not routinely recommended as evidence is insufficient to show improved live birth rates. When considered, decisions should be made on a case-by-case basis. Hysteroscopic adhesiolysis, polypectomy, and myomectomy for submucosal fibroids carry a similarly limited evidence base and are offered case-by-case (GRADE: Very Low).

Unexplained recurrent miscarriage: Supportive care in a dedicated recurrent miscarriage clinic setting, including regular early pregnancy scans and psychological support, is associated with improved outcomes. IVF with preimplantation genetic testing for aneuploidy (PGT-A) does not improve live birth rates in those without a known genetic condition and is not routinely recommended. Intravenous immunoglobulin (IVIg) is not recommended outside a narrow cohort (four or more losses with suspected immune-mediated mechanism); evidence is insufficient for routine use (GRADE: Moderate).

Genetic factors: Couples with a balanced chromosomal translocation should be offered genetic counselling and may consider natural conception or IVF with preimplantation genetic testing for structural rearrangements (PGT-SR) on a case-by-case basis (GRADE: Very Low).

6. Pharmacology and AU PBS notes

Low-dose aspirin (75 to 150 mg daily): Available as generic aspirin 100 mg tablets across AU pharmacies; not PBS-subsidised for this indication but inexpensive over the counter. Commence prior to or at confirmation of pregnancy in APS; cease before birth given risk of postpartum haemorrhage with doses up to 150 mg (OR 1.20).

Low-molecular-weight heparin: Enoxaparin (Clexane) is the most widely used LMWH in Australia. Prophylactic dosing per local institutional protocol; self-administered subcutaneous injection. PBS-subsidised for established venous thromboembolism but off-label for APS-related recurrent miscarriage; confirm local funding pathway. Continue to at least 34 weeks gestation. UFH is an alternative with potentially higher live birth rates but requires IV or SC injection in a hospital setting plus frequent laboratory monitoring; generally reserved for women with contraindications to LMWH.

Micronised progesterone (Utrogestan 200 mg capsules): Used vaginally 400 mg twice daily from first-trimester bleeding to 16 weeks in women with two or more prior losses. PBS Streamlined Authority code is not established for this indication; prescribe as Authority Required with clinical documentation of recurrent miscarriage with bleeding.

Levothyroxine (Eutroxsig, Oroxine): PBS-subsidised for hypothyroidism; titrate to pregnancy-specific TSH reference ranges per RANZCOG C-Obs 46 guidance. Prescribing and monitoring outside scope of midwifery; requires GP, obstetrician, or endocrinologist.

7. Complications and monitoring

Psychological morbidity is substantial; anxiety and grief responses should be assessed at each encounter and referral to psychological support services offered proactively. Women with APS on LMWH require platelet count monitoring for heparin-induced thrombocytopenia (more common with UFH) and bone mineral density consideration with prolonged use.

Monitoring in subsequent pregnancies after recurrent miscarriage: early pregnancy unit review from 6 weeks gestation with serial transvaginal ultrasound is recommended. TSH should be checked at 7 to 9 weeks in women with subclinical hypothyroidism or positive thyroid autoantibodies regardless of whether levothyroxine has been commenced. Serial beta-hCG is appropriate if early pregnancy viability is uncertain. Women with APS require ongoing obstetric surveillance for intrauterine growth restriction, preeclampsia, and preterm birth beyond the first trimester. Live birth rates in unexplained recurrent miscarriage with supportive care alone are reported as favourable, with many studies showing rates of 65 to 75%, providing important reassurance during counselling.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.