Recurrent Miscarriage
Polycystic Ovarian Syndrome
Reduced Fetal Movement
Recurrent Miscarriage
Funmi Odusoga MBCHb DFRSH MRCOG
Table of content
1. Introduction/Definition
2. Incidence
3. Aetiology
4. Investigations/ management
5. Treatment
6. Essential points for General practitioners
7. Reference
Introduction / Definition
- Recurrent miscarriage is the loss of three or more consecutive pregnancies
- Incidence-Affects 1% of couples trying to conceive
- 1-2% of second trimester pregnancies miscarry before 24weeks of gestation
- It could be primary or secondary
- Primary refers to women who have never carried a pregnancy to viability
- Secondary refers to women who have had a previous life birth
- Prognosis for pregnancy is better with secondary
Incidence
- 15% of pregnant women experience sporadic loss of a clinically recognised pregnancy
- 2% of women experience two consecutive pregnancy losses
- 0.4-1% have three consecutive losses
- Prevalence of miscarriage is higher with increased maternal age and at very early gestational age
- Risk of miscarriage
< 6weeks gestation 22-57%
6-10 weeks 15%
10 weeks 2-3%
Risk factor/ Aetiology
The cause is detected in only 50% of patient
Epidemiological factor
- Previous pregnancy loss-Risk increases after each successive pregnancy loss
(Women with 13:14 translocation have a 25% risk, 22:22 translocation will almost always miscarry)
- Advancing maternal age-Due to decline in the quantity and quality of oocytes.
(The risk of miscarriage is highest amongst couples when the woman is >34 and the man is > 39years of age.)
- Previous birth does not preclude a woman from recurrent miscarriage
- The effect of anaesthetic gas on miscarriage for theatre workers is conflicting.
- Obesity may increase the risk of sporadic and recurrent miscarriages
Aetiology
- Antiphospholipid syndrome –Present in 15% of women with recurrent miscarriages
- It is the most important treatable cause of recurrent miscarriages
- It is the association between Antiphospholipid antibodies i.e. Lupus Anticoagulant ,Anticardiolipin antibodies and Anti-B2 glycoprotein I antibodies and adverse pregnancy outcome or Vascular thrombosis
- Adverse pregnancy outcome includes- (1) 3 or more consecutive miscarriage before 10 weeks of gestation (2) One or more morphological normal fetal loss after 10 weeks gestation (3) One or more preterm birth before 34 weeks gestation due to placental disease
Pathophysiology of Antiphospholipid Syndrome
- Inhibition of trophoblastic function and differentiation
- Activation of complement pathway in the maternal and fetal interface resulting in a local inflammatory response
- Thrombosis of the uteroplacental vasculature in later pregnancy
- NB: Live birth rate is as low as 10% in women with recurrent miscarriage associated with APS if there is no pharmacological intervention during their pregnancy
2. Genetic Factors
- In 2-5% of recurrent miscarriage one partner carries a balanced structural chromosomal anomaly. Most commonly a balanced reciprocal or robertsonian translocation
- Carriers of balanced translocation have an increased risk of both miscarriages and live births with multiple congenital malformation and /or mental disability
3. Embryonic chromosomal abnormalities occurs in 30-57% of patients with RM
4. Congenital Uterine Malformation –
Exact contribution is unclear. Prevalence is 1.8-37.6%. It is commoner in 2nd trimester miscarriages
5. Cervical Weakness –
True incidence is unknown
6. Endocrine Factors –
Well controlled diabetes mellitus and thyroid disorders are nor risk factors. There is increased risk of 1st trimester miscarriage and fetal malformation in patients with raised HBA1C. Polycystic ovarian syndrome is linked to high incidence of miscarriage
7. Immune Factor –
No clear evidence to support hypothesis
8. Infective Agents-
Bacteria vaginosis in the first trimester is linked to 2nd trimester miscarriage and preterm deliveries.
9. Inherited Thrombophilia Defects –
Implicated as a possible cause in recurrent miscarriages and late pregnancy complications. The presumed mechanism is thrombosis of the uteroplacental circulation
Investigations / Management
- Ideally see couple in a dedicated recurrent miscarriage clinic
- Provide information leaflet
- Antiphospholipid antibodies should be done in all women with recurrent miscarriage and all women with one or more 2nd trimester miscarriage
- Diagnosis of Antiphospholipid syndrome is made based on 2 positive tests at least 12weeks apart for either lupus anticoagulant or anticardiolipin antibodies of IgG and/or IgM class present in a medium or high titre over 40g/l or ml/l or above 99th percentile
- Karyotyping-Do cytogenetic analysis on product of conception of third and subsequent consecutive miscarriages
- -Do parental peripheral blood karyotyping of both partners where testing of products of conception reports an unbalanced structural chromosomal abnormality
NB: (The risk of miscarriage as a result of fetal aneuploidy decreases with an increasing no of pregnancy losses. If the karyotype of the miscarried pregnancy is abnormal, there is better prognosis for the next pregnancy)
- Pelvic USS to assess uterine anatomy should be done in women with first trimester recurrent miscarriages and all women with one or more 2nd trimester miscarriages
- Uterine anomaly may require further investigations such as laparoscopy, hysteroscopy and 3D pelvic USS to confirm diagnosis
- Screen for inherited thrombophilia including factor V leiden, factor II (Prothrombin) gene mutation and Protein S
Treatment
- Refer to specialist clinic
- Antiphospholipid syndrome- When pregnant offer low dose aspirin plus heparin to prevent further miscarriage (Meta-analysis suggests it reduces miscarriage by 54%)
- Even when Aspirin and heparin are administered, this pregnancies are high risk of repeated miscarriage, pre-eclampsia, fetal growth restrictions and preterm birth. This pregnancies require close antenatal surveillance
- Corticosteroids and immunoglobulins do not improve live birth rates in recurrent miscarriages
- Refer abnormal parental karyotype to clinical geneticist for genetic counselling
- Reproductive options in couples with chromosomal rearrangements
- Further natural pregnancy with or without prenatal diagnosis test (50%-70% chance of a healthy live birth)
- Preimplantation genetic diagnosis +I.V.F=30% live birth
- Gamete donation
- Adoption
- Preimplantation genetic testing +IVF does not improve live birth rates in women with unexplained recurrent miscarriages
- Insufficient evidence to assess effect of uterine septum resection in women with RM and uterine septum
- Offer serial cervical sonography in women with history of 2nd trimester miscarriages and suspected cervical weakness. Offer cerclage if cervical length of 25mm or less is detected by TV scan before 24weeks
- Insufficient evidence to evaluate the effect of progesterone supplementation in patients with RM
Promise trial
1568 women assessed for eligibility
836 conceived naturally within 1year
404 on progesterone /432 on placebo
Follow up rate was 98.8%
Life birth rate 65.8% in the progesterone group and 63.3% in placebo group
Relative rate,1.04 95% CI 0.94-1.15
No significant differences in rate of adverse event.
- Insufficient evidence to evaluate the effect of HCG supplementation in women with RM
- Suppression of high luteinising hormone among ovulatory women with RM and PCOS does not improve life birth rates
- Insufficient evidence to evaluate effect of metformin to prevent miscarriage in women with PCOS
- Immunotherapy does not improve live birth rates in patient with unexplained recurrent miscarriage. It is expensive and poses potential serious side effects e.g. transfusion reaction, hepatitis, anaphylactic shock
- Heparin may improve live birth rates in women with 2nd trimester miscarriage associated with inherited thrombophilia
- 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.
Essential Points For Gps
- Antiphospholipid antibodies should be done in all women with recurrent miscarriage and all women with one or more 2nd trimester miscarriage
- Diagnosis is made based on 2 positive tests at least 12weeks apart for either lupus anticoagulant or anticardiolipin antibodies of IgG and/or IgM class present in a medium or high titre over 40g/l or ml/l or above 99th percentile
- Antiphospholipid syndrome- When pregnant offer low dose aspirin plus heparin to prevent further miscarriage (Meta-analysis suggests it reduces miscarriage by 54%)
- Even when Aspirin and heparin are administered, this pregnancies are high risk of repeated miscarriage, pre-eclampsia, fetal growth restrictions and preterm birth. This pregnancies require close antenatal surveillance