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Recurrent Pregnancy Loss in the First Trimester
Dr Sujoy DasguptaMBBS (Gold Medalist, Hons)
MS (Obst & Gynae- Gold Medalist)DNB (Obst & Gynae), FIAOG
Fellow- Reproductive Endocrinology & Infertility (ACOG)Assistant Professor: SRIMSH, Durgapur
Consultant: Techno India Group of Hospitals, KolkataRSV Hospital, KolkataBehala Balananda Brahmachary Hospital, Kolkata
Secretary, Perinatology Committee: BOGS- 2016-17Managing Committee Member: BOGS- 2016-17Executive Committee Member, Medical College Ex-Students’ Association (MCESA)- 2016-1715 Publications: National & International Journals
Pregnancy and Miscarriage
Incidence of Pregnancy Loss
• Once heart beat is seen- chance of miscarriage- <5%• Once 12 weeks have passed- chance of miscarriage- 4%
Morley L, Shillito J, Tang T. TOG 2013;15:99–105.Everett C. BMJ 1997; 351(7099): 32-34 Regan L, et al. BMJ 1989; 299(6698): 541-545.
Clinical pregnancy loss
Pre-clinical loss
30%
10%
30%
30%
Live Birth
Miscarriage (<22 weeks)
After Implantation (Before Missed Period)- Biochemical Loss
Before Implantation (After Fertilization)
Recurrent Pregnancy Loss (RPL)• ≥3 consecutive miscarriages before the age
of fetal viability**Weight <500 gram, GA- ≤22 weeks (WHO), ≤24 weeks (RCOG)
1. Primary RPL- No previous successful pregnancy
2. Secondary RPL- Previous ≥1 successful pregnancy
2 or 3- Number Game?
After 2 loss-• Loss of subsequent loss similar• Chance of detecting cause is significant• Especially- if subfertility or >35 years• Avoid 3rd potential psychological trauma • Women starting reproductive career late• Patient → Impatient• Pressure on gynaecologists
1st Trimester
RPL
Genetic3-5%ParentalFetal
Anatomical12-16%Mullerian AnomalyFibroid/ PolypAshermanAdenomyosis
Endocrine17-20%LPDPCOSPOFThyroid, DM, PRL
Immune20-50%Cell-mediatedAlloimmuneAutoimmune
Inherited Thrombophilia10-20%FVLProthrombin G20210APr S deficiency
APS15%PrimarySecondary
Infection ?
Life-styleObesity, StressSmoking, CaffeineDrugsEnvironmental
Inherent defects in embryo/ endometrium
1st Trimester
RPL
Genetic3-5%ParentalFetal
Anatomical12-16%Mullerian AnomalyFibroid/ PolypAshermanAdenomyosis
Endocrine17-20%LPDPCOSPOFThyroid, DM, PRL
Immune20-50%Cell-mediatedAlloimmuneAutoimmune
Inherited Thrombophilia10-20%FVLProthrombin G20210APr C/ Pr S/ AT III deficiency
APS15%PrimarySecondary
Infection ?
Life-styleObesity, StressSmoking, CaffeineDrugsEnvironmental
Inherent defects in embryo/ endometrium
UNEXPLAINED50-70%
Case Scenario
Mrs AD, 27 years, P0+0presented at 7 wk+- amenorrhoea with bleeding
P/VUPT +veNo investigations done yetClinically- POC felt through osTVS- Retained POC seenΔ- Incomplete MiscarriageDecision for D/E taken
Couple wants explanation
1. Counseling• Majority are sporadic
miscarriage• Very few would recur2. Offering Tests- Not
justified
Explain Facts And FiguresBackground Risk 10-20%
By chance 0.34 %
Rec Miscarriage 1 %
No cause found 50 %
Successful preg 75%
Subsequent PregnancyAfter one Miscarriage Pregnancy loss Live birth One 20% 80%Two 25% 75%Three 30% 70%Four 40% 60%Six 50% 50%
Gap between conception?
• Traditional concept- 6 weeks wait to recover physically/ psychologically
• 20% women may suffer from profound depression
• No differences in outcomes between- Early conception and delayed conception
• As soon as they feel physically and mentally fit
Before planning next pregnancy
• Preconception counseling- Medical History and Examination
• Lifestyle changes- Obesity, Smoking• Folic Acid• Rubella Status- Vaccination if non-immune
(Negative IgG)• Blood Group• Hb Electrophoresis
Any other drugs to consider?
• Progesterone• Low dose aspirin (LDA)• Empirical Ovulation
Induction with CC
Not Evidence Based
Mrs AD missed her period within 3 months
• Folic Acid• Early TVS/ ẞ-HCG
monitoring- Should be offerred
TVS of Mrs AD
• Intrauterine GS 3.5 cm
• no fetal parts• no heart beat
POC Karyotyping after 2nd loss
RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
•Chromosomal anomaly of the embryo- Commonest cause of single sporadic miscarriage•Provides opportunity to offer genetic counseling•Prognosis for future pregnancy is BETTER if the karyotype of POC abnormal•Chance of aneuploid miscarriage DECREASES as the number of miscarriage increases•Avoid contamination
Would you offer investigations?
• Lupus Anticoagulant (LAC)- Positive
• Anti-Cardiolipin Antibody (ACL)
IgG/ IgM- Moderate to High Titre (>40
IU/L)
• Anti-ẞ2-glycoprotein IgG/ IgM Moderate to High Titre
• Considerable laboratory variations and lack of standardization
• LAC- dRVVT (with platelet neutralization)- better than aPTT
• ACL and ẞ2-glycoprotein- ELISA
• In 2 occasions ≥12 weeks apart
Anti-Phospholipid Antibody (APLA)
Anatomical Defects• All women with RPL should be assessed for uterine
anomaly (congenital/ acquired)• Septate Uterus- RPL in 1st TM• Bicornuate/ Arcuate Uterus- RPL in 2nd TMRCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent
First trimester and Second-trimester Miscarriage
Initial Screening• 2D USG• HSG/ SSG
Further Testing• 3D USG• Hystero/Laparoscopy• MRI- ?
Parental choromosomal analysis
• Not Routine• Only if karyotyping of POC reveals
unbalanced structural abnormalities• If POC karyotype not known- ?
Other TestsThrombophilia screening
Only for 2nd trimester Miscarriage
Association with 1st trimester RPL is weak
Thyroid and Diabetes Screening
Not helpful for asymptomatic women
Ovarian Reserve Testing
D3 FSH, AFC, AMH Not helpful
Tests for LPD D21 Progesterone, Endometrial Biopsy
Not helpful
Tests for PCOS FSH:LH, USS Not helpful for who conceived naturally
TORCH
• Not implicated in RPL• SHOULD BE
ABANDONED RCOG Green Top Guidelines No 17. April
2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
Fetus withPaternalantigens
T helper 1cell response
Miscarriage ofThe Fetus
T helper 2cell response
Protection of The Fetus
Immunological Study
Any tests required?• Peripheral blood NK
cells• Uterine NK cells-
culture• HLA typing of
parents• Mixed lymphocyte
cultures• Cytokine estimation No role
Autoantibodies• Anti-TPO in euthyroid• ANA, anti-ds-DNA
without clinical features of SLE
Not indicated
Don’t advise any test if you do not know what to do with the result !!!
If Definite Cause of RPL is Found
• Targeted Therapy• Explain- the role of
chance factors
Genetic Factors• Couples with balanced translocations • Genetic Counseling by clinical geneticist
Healthy Live Birth rate
•Natural Conception ± PND 50-70%
•IVF + PGD 20-30% (Proven Fertility)
•3rd Party Reproduction
•Adoption
APLA Syndrome
• LDA (75 mg/day) after +ve UPT
• LMWH- after confirmation of fetal cardiac activity
• IVIG/ Corticosteroid- No role in primary APS
Prophylactic Dose
No intervention AntithromboticsLive Birth rate 10% 80%Improvement 54%
Anatomical Factors
• RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
• Role of Fibroid resection- ?
Endocrine Factors• Correction of thyroid and glycaemic abnormalities
• PCOS-1. Suppression of high LH- does not improve live birth- Grade
A2. Metformin- Insufficient evidence- Grade C3. Laparoscopic Ovarian Drilling- ?
If no cause is found
Discuss
Empathy
Empirical Therapy
Endocrine
Antithrombotic
Immunological
Miscellaneous
IVF + PGD
Endocrine TherapyIf no endocrine
abnormalities detected
• L-thyroxine• Insulin sensitizers• Dopamine agonists• Not helpful
Treatment of presumed LPD
• Progesterone• hCG• Oestrogen
Progesterone- Which Molecule?Natural Micronized Progesterone
Dydrogesterone
Selectivity to P4 receptor
More selective
Route Oral, vaginal, IM OralBioavailability BetterMetabolism May increase risk of
obstetric cholestasisLess metabolic load on liver
Progeterone- Which Route?Oral Vaginal IM•Easiest way •Higher uterine
concentration•Optimum blood level
•Can be taken anywhere
•Needs privacy •Extremely painful
•Better acceptable and tolerable to women
•10% may have vaginal dryness/ irritability
•Abscess formation
Route of administration- Does NOT affect the outcome•Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD003511•Van der Linden et al. Cochrane Database of Systematic Reviews 2015
Is progesterone effective in RPL?Wahabi HA, et al. 2011
The evidence suggesting benefit of progestins for women with recurrent miscarriage and with threatened miscarriage, remains preliminary
Haas DM, Ramsey PS. 2013
For an unselected population, no evidence of benefit of progestin for prevention of miscarriageSub-group analysis - women with recurrent miscarriage shows the odds of miscarriage are significantly decreased by progestin treatment
Carp H. 2015 Although all the predictive and confounding factors could not be controlled for, significant reduction of 29% in the odds for miscarriage was found when dydrogesterone is compared to standard care
Clinical Guidelines
RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
Insufficient evidence to recommend progesterone supplementation in recurrent miscarriage
Royal Australian and New Zealand College of Obstetricians and Gynecologists 2013
Progesterone may reduce the risks but cannot be recommended based on current evidence
FOGSI Position Statement 2015 No evidence of harm and some evidence of benefit, although not coming from huge multicentric trialDecision should be based on clinician's discretion until strong evidence is available to recommend routine use
PROMISE TrialFirst Trimester PROgesterone Therapy in Women with a History of Unexplained Recurrent
MIScarriage
Coomarasamy A., et al. N Eng J Med 2015;373:2141-8
PROMISE Trial- Conclusion
• Progesterone therapy in the 1st trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages
Ongoing trial• A randomized double-blind controlled trial of the use of dydrogesterone in women
with threatened miscarriage in the first trimester: a randomized controlled trial
Principal Investigator
Diana Man Ka Chan
Location of study
2 public hospitals in Hong Kong: Queen Mary Hospital and Kwong Wah Hospital
Randomized to 1. dydrogesterone 40 mg PO, followed by 30 mg PO2. placebo until 12completed weeks of gestation or 1 week after the
bleeding has stopped, whichever is longer
Participants A total of 400 patients presenting with 1st-trimester threatened miscarriage
Primary Outcome
percentage of miscarriage before 20 weeks of gestation
Is progesterone Safe?• No significant differences in the rates of
preterm birth, neonatal death, or fetal genital anomalies- between progestogen therapy vs placebo/control.
• No studies reported adverse maternal effects.
Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD003511.
FOGSI Position Statement 2015
•No statistically significant difference in congenital
abnormalities seen in clinical studies between newborns
of mothers who received progesterone & those who did
not
•Progesterone should be used with caution in patients with
cardiovascular diseases & in patients with impaired
liver function & cholestasis
http://www.fogsi.org/fogsi-gcpr/. Accessed on 12th Jan 2016
hCG and OestrogenhCG
• Insufficient evidence• RCOG Green Top Guidelines No 17. April 2011. The
Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
• Higher risk of OHSS• Van der Linden et al. Cochrane Database of
Systematic Reviews 2015
• Smaller placebo controlled study cited hCG benefit confined to a small subgroup of patients with recurrent miscarriage & oligomenorrhoea.
• Quenby S, Farquharson RG. Human chorionic gonadotropin supplementation in recurring pregnancy loss: a controlled trial. Fertil Steril 1994;62:708–10.
Oestrogen• Does not appear to be
associated with improvement in outcomes
• Van der Linden et al. Cochrane Database of Systematic Reviews 2015
AntithromboticsTrial Publication Arms ResultsSPIN Trial (UK) Clark et al. Blood
2010;115:4162-67•LMWH•LDA + surveillance•Surveillance alone
No significant differences
ALIFE Trial (UK)
Kaandorp et al. N Engl J Med 2010;362:1586-96
•LMWH + LDA•LDA alone•Placebo
Non-signifiant improvement with antithrombotics
HABENOX Trial (Finland)
Visser et al. Thromb Haemostat 2011;105:205-301
•LMWH + Placebo•LMWH + LDA•LDA alone
No significant differenceEnded prematurely due to slow recruitment
HepASA Trial (Canada)
Laski et al. J Rheumatol 2009;36:279-87
•LMWH + LDA•LDA Alone
No non-therapeutic armNo significant difference
Immune Therapy
• Immunotherapy is expensive and has potentially serious adverse effects
• Anti-TNF agents - lymphoma, granulomatous disease such as TB, demyelinating disease, CCF and syndromes similar to SLE.
• RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
Miscellaneous• Vitamin B12 + Folate + Pyridoxine- to
reduce homocysteine level
• Antioxidants
• Empirical antibiotics
• Probiotics
• Nitric Oxide donors – as vasodilator
Reported in small studies but no RCT available
Life Style Changes• Weight Control
• Smoking Cessation
• Avoidance of recreational drugs
Can be helpful
Bed Rest• Until further evidence is
available the policy of bed rest cannot be recommended for women at high risk of miscarriage
• Aleman A, Althabe F, Belizán JM, Bergel E. Bed rest during pregnancy for preventing miscarriage. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003576
Role of IVF
• RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
51
Stress Management
• Changes Th2 response in endometrium to Th1 response
• Affects HPO axis• Adrenaline release reduces placental blood
flow
Tender Loving Care (TLC)
• RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
75% will have live-birth, with supportive care alone•Brigham SA,Conlon C, Farquharson RG.A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage.Hum Reprod 1999;14:2868–71.
Unexplained RPL
• Scientific evidence• 2 independent risks of
further miscarriages- increased age and number of miscarriages
• Nothing much can be done• Do not give false
reassurance• Discuss about uncertainty of
empirical medical treatments
• Patient’s wishes• Counsel her and explain
the chances• Reassure that she is in safe
hands• Give psychological
support• Respect her decisions,
even if these are against medical evidences
Right to Information
3rd Pregnancy of Mrs AD
• Unexplained RPL• Agreed for empirical
treatment- LDA, progesterone, LMWH
• Fetal Cardiac Activity seen
But !!!
• At 9 weeks• Brownish vaginal
discharge• Δ- Missed
Miscarriage
To sail through uncertainty
Statistics
0%100%
Mrs AD conceived for 4th time
Cerclage
• No role in repeated 1st trimester miscarriage• Not indicated in uterine anomalies or cervical
surgeries (multiple D/C)
• RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First trimester and Second-trimester Miscarriage
Final Story of Mrs AD
Take Home Messages
• The pathophysiology of 1st trimester RPL is little understood
• Only tests required- APLA screening, pelvic USS and selective karyotyping
• Treatment should be offerred for these abnormalities only
• Unexplained RPL is an enigma for gynaecologists• Gain the confidence of the patients• Tender Loving Care is all that is needed
Thank You