Recurrent pregnancy loss and second trimester miscarriage Flashcards
Definition of recurrent miscarriage.
3 or more consecutive pregnancy losses before 20 weeks gestation.
What is the prevalence of recurrent 1st trimester miscarriage?
What is the prevalence of second trimester miscarriage?
Recurrent miscarriage = 1%
1-2% second trimester pregnancies miscarry before 24 weeks.
What is the risk of miscarriage after 3 consecutive miscarriages?
40%
What are the known causes of recurrent miscarriage? And second trimester miscarriage?
- Up to 50% cases no cause found
- APS (found in 15% RPL cases, MOST important treatable cause)
- Aneuploidy (30-57% foetuses will have chromosomal abnormality - most sporadic; 2-5% couples - 1 will have balanced reciprocal translocation or robertsonian translocation)
- Inherited thrombophilia
- Uterine malformation (Strongest association with septate uterus, greater effect on 2nd trimester miscarriage)
- Grave’s disease and TRAbs
- TPO Abs in hypothyroidism
- Poorly controlled diabetes
- PCOS (esp. if high FAI or insulin resistance)
- Lifestyle issues (smoking, alcohol, drugs, obesity)
- Advancing age (maternal and paternal)
2nd trimester additional causes:
- Cervical incompetence
What are the investigations for recurrent miscarriage?
- APS screen - lupus anticoagulant, anticardiolipin abs, anti-B2 glycoprotein-1 abs - (Dx needs 2 positive test >12 weeks apart - IgG and/or IgM, with medium/high titres - levels >99th percentile)
- Heritable thrombophilia screen - prothrombin mutation, factor V leiden, protein S deficiency
- Cytogenetics of PoC
- ONLY If aneuploidy in PoC, maternal and paternal blood for karyotype
- USS or hysterosalpingogram for uterine abnormality
- if detected requires 3D USS or hysteroscopy +/- laparoscopy for assessment and treatment
What are risk factors for RPL?
- AMA (>35 = 25% risk miscarriage, >40 = 50%, >45 = 90%)
- Previous miscarriages
- Advanced paternal age
- Smoking
- Caffeine
- Alcohol moderate consumption or more
- Obesity
- Maternal medical conditions: APS, inheritedthrombophilia, DM, thyroid disease, PCOS
How does APS cause pregnancy loss?
1) Prevents normal trophoblast invasion and differentiation
2) Activation of complement pathway in fetomaternal unit causes localised inflammation
3) thrombosis of vasculature and infarction of placenta (mostly in more advanced pregnancy)
What is the pregnancy prognosis in women with recurrent miscarriage and APS without treatment? And with LDA/heparin treatment?
Without Rx - Live birth rate as low as 10%.
LDA and heparin - >50% improvement in outcomes
Still remain high risk for: miscarriage, stillbirth, IUGR, PET, preterm birth, VTE
What is the general approach to RPL or second trimester loss management?
- Managed ideally within specialised RPL clinic
- Both partners present
- Thorough HX
- Investigations as appropriate
- Careful explanation of causation
- Management of identifiable causes and optimisation of medical conditions
- Address lifestyle modifications (weight loss, caffeine/alcohol/smoking cessation)
- Planning for future pregnancies (e.g. LDA and Heparin in APS)
- Providing written information to take away
- Ongoing support and serial scanning in subsequent pregnancies
Counsel a woman with confirmed diagnosis of APS about the evidence around aspirin and heparin for improving pregnancy outcomes.
LDA and heparin are only proven effective intervention for improving APS pregnancy outcomes
Addition of heparin to LDA reduces pregnancy loss by over 50% as compared to LDA alone
LMWH and unfractionated heparin are equally effective at reducing pregnancy loss
There are are no documented adverse fetal effects from taking LDA or heparin, and heparin dose not cross placenta.
BUT Heparin can cause: bleeding, HIT, osteoporosis.
The benefits of LMWH over UFH are its once daily dosing, doesn’t require monitoring of PT, lower risk of HIT and heparin induced osteoporosis.
Counsel a couple with a confirmed abnormal maternal/paternal karyotype about their options for having children.
Counselling best done by an experienced genetic counsellor - advise will arrange referral
Options:
- Not having children
- Adoption
- Donor gametes and IVF
- IVF and PIGD
- Spontaneous conception nd invasive antenatal testing
- Spontaneous conception and testing after birth
NB. Regarding PIGD - couples should be advised may have to pay privately for rounds of PIGD/IVF. Rates of love birth after PIGD lower than if continue to conceive naturally (30% vs 50-70%)
What management options are available for couple with unexplained recurrent pregnancy loss?
Encourage spontaneous conception - good outcomes in majority cases - chance live birth rate around 75%.
Ongoing support and serial scanning through RPL clinics has been shown to improve outcomes, though mechanism is unclear.
No evidence to give aspirin.
No place for IVF +/- PIGD - outcomes are better for spontaneous pregnancy (75% vs 30%)
What is the evidence and guidance for cervical cerclage to prevent second trimester loss and preterm birth?
Reduces second trimester miscarriage and preterm birth rates in women who:
- Have 3 or more 2nd trimester loss or PTB
- Have previous 2nd trimester loss or PTB AND cervical length <25mm
There is no significant evidence that cerclage reduces second trimester loss or preterm birth, except in a sub-group analysis of women with 3 or more second trimester loss or preterm birth. It also carries risk of complications. (cochrane review)
For women with risk factors not having history indicated cerclage, serial TVS cervical length should be employed 16-24 weeks.
US indicated cerclage should be placed if length <25mm, as subgroup analyses shows benefit of cerclage for women with a history of preterm birth and short cervical length.
(Meta-analysis on USS indicated cerclage 2005)
How does progesterone support pregnancy?
What is the evidence for prophylactic progesterone pessaries in recurrent miscarriage?
Progesterones effects:
- increases during luteal phase of menstrual cycle promoting thickening of endoemterium in preparation for implantation
- Promotes capillary formation and reduces vascular tone to promote low pressure high flow environment at uteroplacental unit
- Promotes uterine quiesence
- Reduces smooth muscle tone, thus reducing myometrial activity
- down regulating pro-inflammatory Th1 cytokines and up-regulating anti-inflammatory Th2 cytokines.
There is no conclusive evidence supporting progesterone use in recurrent miscarriage. Not recommended by RANZCOG.
The PROMISE trial, a large multi centre RCT (2016) did not demonstrate any significant reduction in recurrent miscarriage, or any secondary adverse pregnancy outcomes.
PRISM trial (2019) subgroup analysis found an increase in LBR for women with threatened miscarriage AND 3 or more previous miscarriages.
What is the association between PCOS and recurrent miscarriage?
Does metformin treatment help reduce risk of RPL in these women?
It appears to be the insulin resistance, high circulating insulin and hyperandrogenism that increases risk of RPL.
A high free androgen index is correlated with increased risk of miscarriage.
There is no strong evidence showing the benefit of metformin, though small unblinded trials have shown some benefit for reducing RPL.
