Repeated Pregnancy Loss in First Trimester

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.


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


51

Stress Management

• Changes Th2 response in endometrium to Th1 response

• Affects HPO axis• Adrenaline release reduces placental blood

flow

Tender Loving Care (TLC)


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)


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

Health & Medicine

Repeated Pregnancy Loss in First Trimester