Recurrent Pregnancy Loss

Sharing Personal Experience (10 years)

Dr. Sharda Jain

Director :-

Sec General : Delhi Gynae Forum

RECURRENT PREGNANCY LOSS

Dr. Sharda Jain Dr. Jyoti Agarwal Dr. Jyoti Bhaskar

How much is the problems of

Abortion / RM

60% of embryos never yield a live birthEdmonds et al,1982

30% of “Implanting embryos” miscarry, often before the woman realizes she is pregnant

Miller et al ,198015-20% of clinically detectable pregnancies

abort

5% women have RM > 2

1 % woman have RM > 3

Should we start investigating the

couple after 2nd abortion ??

Yes

What is the role of RPL Clinic ?

Yes

RECURRENT PREGNANCY LOSS

A PROBLEM OF DILEMMAS

How

To

Manage

RECURRENT

Abortion

Causes - Biggest DILEMMAS

Uterine Causes

Anatomical Causes

AETIOLOGY

Infectious Causes ?

TBGenetic Causes

AUTO IMMUNOLOGIC CAUSES

APLA syndrome Endocrine causes ?

ThrombophiliaAllo-munity

•Environmental Causes • Oxidative stress•Psychological •Unknown aetiology

Summary of Cochrane Review

• Parental Chromosomal rearrangements

• Anatomic defect of the uterine fundus and cervix,•APLA Sydr. (phospholipid antibodies)• Thrombophilia activated protein C resistance, factor V and II gene mutation –

Play definite Role

The majority of cases are due to repeated

fetal chromosome abnormalities occurring

consecutive by chance.

Summary of Cochrane Review

Karyotype POC

• Progesterone deficiency, hypersecretion of LH,

infective agents, and immune rejection are not

currently considered causes of RM.

• Empirical treatment with progesterone , high LH

suppression , or immunotherapies are of no

proven benefit.

• Subclinical/ overt

thyroid disorder or diabetes mellitus are rare

Summary ofCochrane Review

We Run Dedicated

Recurrent Miscarriage Clinic since 2003

Our Experience of 680 Recurrent consecutive Miscarriages – Updated

(30th June 2013)

ANATOMICAL /UTERINE 22.4 %

INFECTIONS – Tuberculosis 39 %

TB + TNF a ↑ 31%

GENETIC 2.8 %

Karyotype (Products of Conceptions) 66 % (219/348)

ENDOCRINE CAUSES - ↑ Glycosylated HB 16%

- S/C Hypothyrodism 26 %

- Thyroids Anti Bodies + 9 %

- PCOD – ↑ LH 14%

- LPD 22%

AUTOIMMUNITY

Apla Syndrome 6%

Thrombophilia 3 %

Alloimmunity TNF a, and / or NK Cells

8 %

Diagnosis and management of recurrent Pregnancy Loss (Since 2003 – June 2013)

In

50%

More

Than

1

cause

My AIM Is

Share Our Experience last 10 years with RM,Clinical tips & management strategy

Three Independent risk factors

• Gestational Age at abortion

• Age of the patient. Both Husband / Wife

• History of previous abortions

Is Gestational Age of any importance?

Gest. Age at abortion guides us of underline cause • 4 - 6 wks Alloimmunity & LPD • 5 - 7 wks - Genetic causes• 8 - 10 wks - Immunological Causes• Mid trimester - Anatomical Causes , APLA

Yes

Advanced parental age

• MATERNAL AGE: increased risk of chromosomal abnormality (Trisomy 13, 18, 21, 47XXY, 47XXX)

• PATERNAL AGE: increased risk of Autosomal dominant, X-linked recessive Ds

Age of the patient.

Oocyte quality and

ovarian reserveDecline

starts after 35 yrs

60% oocytes after 35 yrs are aneuploidic

Remember Women who have had at least

one live born infant :- Good Prognosis

a. with no prior fetal losses - recurrence risk is 12 % for next preg •

b. With atleast 1 prior fetal loss - recurrence risk is 24 % for next preg•

c. With two prior fetal losses - recurrence risk is 26 % for next preg

• d. With three prior fetal losses - recurrence risk is 32 % for next preg

WOMEN WHO HAVE NOT HAD ATLEAST ONE LIVEBORN infant with 2 or more fetal losses –

Recurrence Risk for the next pregnancy is 40 - 45 % .

Management Tips

Which would be of significance to you in the management of subsequent pregnancy.

DILEMMA of our Role

2nd Abortion under our care

• Document Pattern and Trimester of the pregnancy loss and

whether a live embryo or a fetus was present. Clinical / USG

• Carefully document any suspected uterine abnormally at surgical evaculation.

• Send product of conception for HPE , TB & karyotype,

At the time 2nd & 3rd Miscarriage

The TLC approach is important to (see couple together, sympathy, sensitivity)

History and examination for • Causative Factors • Associated Factors

• Obstetric history Confirm true diagnosis of • Pregnancy : biochemical , Ultrasonography • Gestation of former losses

• “RM” - pattern of losses

RM Assessment and Evaluation

Counseling after the 2nd and 3rd Abortion

Family History : of RM , PCOD, Diabetes, Genetic disorder,

Thrombophilia - early onset cardiovascular disease or stroke (<50 yr)

Physical examination : identify signs of endocrine / Gynae Disease

• Oppurtunistic screening (BP , Pap smear, Rubella IgG),

RM Assessment and Evaluation

Counseling after the 2nd and 3rd Abortion

Investigations of RM All Patients

• PELVIC USG• PARENTAL, KARYOTYPE• Miscarried tissues Karyotype

• Early follicular phase ,LH,FSH, testosterone (Day 2-3)• APLA / APS Lupus anticoagulant and ACL• Thrombophilia - Activated protien C resistance - Factor V leiden gene mutation - Prothrombin gene mutation• Glucose tolerance test or glycoselated HB• Thyroid – TSH / Antibodies TPO• TNF a• Serology for rubella• Blood group and rhesus type• Viral Markers optional

TB , Mx Test, Latent TB, MTBC,TB PCR

Selected Investigations of RM

• Uterine Factor

- HSG/Hysteroscopy/laparoscopy

- Three – dimensional pelvic ultrasound ?

• Full Thrombophilia Screening

In additional to those taken in all patients - protein C, protein S, antithrombin III, MTHER, factors XII and VIII

Personal Family History of vascular thrombosis

Autoimmune disease – Jt Pain , Skin rash , allergy

APS – Migraine ,epilepsy, Jt pain, vascular thrombosis

TVSDILEMMAS

• TUBERCULOSIS • Uterine Malformations • Evaluating the uterus/cervix• Evaluating the ovaries /endometrium• Evaluating the corpus luteum• Evaluating the pregnancy.

TVS

• Persistently

THIN Endometrium

Is a common finding

In TB

•Endometrium hardly 2-3 mm.

•Endometrial lining appears broken, bright echogenic.

In TB

•Peri ovarian inflammation and spec’s of calcification on ovarian surface.

In TB

• PID with no pain is most important symptom/ sign.

• It may present as -• Fluid collection in cul-

de-sac• Fluid collection in

endometrial cavity.• Fluid collection inside

the tubes (if adhesions at fimbrial end, fluid shows a definite oblong expansion

In TB

• T-O mass are seen as unilocular or multilocular thick walled mass with diffuse internal echoes.

• Layering effect seen when debri settles down.

• Outer margins poorly delineated if adhesions present

• Restricted mobility (Frozen pelvis)

In TB

Uterine Artery Doppler

The chance for pregnancy is almost zero if the PI is more than 3.019 on the day of hCG administration

Patients who get pregnant have a lower RI (0.53 vs 0.64)

MID LUTEAL DOPPLER ASSESSMENT OF

UTERINE ARTERY BLOOD FLOW IN RPL

• Increased resistance to uterine artery blood flow may be an important contributing factor to some causes of RPL and may represent an independent indication of risk of pregnancy loss.

Natalia Lazarin et al fertil steril june 2007

TVS doppler of uterine arteries during midluteal phase of untreated cycles

• Which are the defects max asso. with RSA

• Best diagnostic tool

ANATOMIC FACTOR

DILEMMA

Incidence of term pregnancy before and after treatment

Sepate Uterus

2.05% N = 14

15% >80% after surgery

Bicornuate Uterus

2.7% N = 18

60% 80 (with TLC)

Didelphic Uterus

N = 2

Infertility

10%

Surgery not indicated

Our Experience

Septate Uterus

• Most COMMON anomaly 55%• May be complete/ incomplete

•25 % early abortions•5 - 7% late abortions & Premature labors

SEPTAL DEFECT in our experience

• Diagnosed on USG/HSG/HYSTEROSCOPY

• Correctable with Hysteroscopic Metroplasty

Personal Experience - We had 14 cases Term pregnancy 7/14

Bicornuate Uterus

• 10% of anomalies• Incomplete fusion of Uterine horns at level of fundus• Two separate but communicating endometrial cavities• Abortion rate 30%• Preterm labour 20%• Strassman Metroplasty ???

Successful Pregnancy

are well known

Unicornuate Uterus

• 20% of anomalies• Agenesis or hypoplasia of one Mullerian duct• May be alone or accompanied by Rudimentary horn

With presence / absence of cavity Communicating / Non communicating

• Associated Renal anomalies occur in

40% patients Ipsilateral to hypoplastic horn

Successful Pregnancy

are well known

Uterus Didelphys

• Least common anomaly -5-7%• Abortion rate 43%,Premature birth rate 38%

Resection of Vaginal septum if there is difficulty in intercourse / vaginal delivery Strassmann Operation not indicated. Once pregnancy is there with IUI - there is no difficulty . Personal experience of two cases.

Arcuate UterusNo Role

T shaped UterusNever seen

• Diethylstilbestrol treatment for Premature labour started 1940 Banned 1970

Uterine Causes (22.4%)

Congenital Anomalies

septum = 2.05 %

Bicornuate Uterus = 2.7 %

Acquired Abnormalities

Synaechie = 3.5% + more

Myomas submucus = 4 %

Endometrial Polyp = 14.5%??

Cervical incompetence = 6%

Experience

Cervical Incompetence

6 %

When do you think it is advisable to give a cerclage?

• Cervical length<2.5cms

• Internal os width>1.5cm

• Available closed cervical length >1/2

Timing of cerclage:Any time between 12 wks to 28 wks

FIBROIDS & RSA

• Do FIBROIDS cause

Recurrent pregnancy loss?

Sub mucus fibroids may be asso. With RPL should be removed hysteroscopicallyIntramural and subserous do not require removal.

Intra Uterine Synechia

3.5% (24)Number is much More

Uterine Abnormalities Treatment SUMMARY

• Uterine septum: GnRH analogue and hysteroscopy septal resection and temporary intrauterine device.

• Intrauterine adhesions : hysteroscopic division and temporary intrauterine device: postoperative course of cyclic estrogen and progesterone therapy.

• Fibroids: GnRH analogue and myomectomy

Microbiologic Agents<1%

Organisms implicated in causing Recurrent Abortion include:

Chlymadia Mycoplasma Ureaplasma

HerpesCytomegalovirusToxoplasma

TORCH is a uselessInvestigation

DILEMMA

Clarifying Tubercular Endometritis in RM

Tubercular Endometritisin RM

Are we justified in starting ATT on the basis of a positive molecular (PCR) test, Histochemistry positive test (MTBC) with

no other obvious clinical features

?

Yes

Tubercular Endometritis

We Run Dedicated Rec. Miscarriage Clinic

since 2003

Our Obsession with TB started in 2005

Our Experience of 680 Recurrent consecutive Miscarriages – Updated

(30th June 2013)

2005 IVF Failure -13

7 Cases positive for MBTC (EB)4 Cases Conceived on their own

3 required Lit TherapyAll had Threatened Abortion

Eye opener experience of LIFECARE

INFECTIONS –

Tuberculosis

TB + TNF a ↑

39 %

31%

Diagnosis and management of RM (Since 2003 – June 2013) & 680 Cases

Diagnosis :- TB Gold Test , MTBC, TB PCR

Treatment and Results Tubercular Endometritis in RM is very satisfying

37 % - 3 months16 % - IUI

32% - IVF

• Almost all chromosomally abnormal conception spontaneously abort. 70% of abortuses are chromosomally abnormal.

• Over 90% of conception having normal karyotype continue

Miscarriage may be viewed as nature’s quality control process.

Genetic Causes & RM

KARYOTYPE OF PARTNERS

• MANDATORY

• About 5% of the couples with RM are carriers of balanced translocations.

• They themselves are healthy but during gametogenesis there is malsegregation of chromosomes ,resulting in either monosomy or trisomy.

The chances of RM with one partner with balanced translocation is 30%

Difficult to convince patients – Cost

DILEMMA

KARYOTYPE OF POC

Aneuploidies of conceptus are a well recognised cause of sporadic abortion.

Trisomies affecting chromosomes 13, 16, 18, 21, 22 constitute the largest group. Strong association with advanced maternal age.

Monosomy X is the single most common chromosomal abnormality in sporadic abortions. No age association.

KARYOTYPE OF POC

• May be advised• Not always successful to culture• FISH can be done• Often reveals aneuploidy which is not a cause of

RPL• Does have a role in directing the management.• Women who abort chromosomally normal

pregnancies should be investigated for causes other than genetic.

• If abortus does show unbalanced translocation then could point to parents being balanced carriers

Genetic in Male • Both abnormal sperm morphology and ↑DNA

fragmentation increase recurrent pregnancy loss.

• Carrell and colleagues found higher rates of sperm DNA fragmentation in couples with recurrent early pregnancy loss following spontaneous conception.

(Arch Androl 2003;49:49-55)

Autoimmune Causes15%

Immune system has ability to discriminate between self and non-self.

The failure of self tolerance is called “autoimmunity”.

SLE associated with increased abortion.Antiphospholipid antibodies– associated in pregnancy loss in healthy women.

DILEMMA

APS / APLAANTIPHOSPHOLIPID ANTIBODY SYNDROME

• CHARACTERISED BY CIRCULATING ANTIBODIES AGAINST MEMBRANE PHOSPHOLIPID (LA. ACA….)

• LUPUS ANTICOAGULANT IS most important • Thrombosis / Placental infarction

9-10 wks

2nd Trim. More frequent

THROMBOPHILIA-Associated with RMHow common?

• About 50% to 60% of patients with recurrent miscarriages harbor a coagulation defect.

• Identification of the defect, followed by appropriate therapy, will lead to normal-term delivery in 98%.

Roger L.Bick, Dec. 2004 Medscape

ACQUIRED AND CONGENITAL THROMOBOPHILIAS

• 66% of RPL cases have atleast one thrombophilic defect compared to 28% controls.

• Two defects found in 21% of patients Sarig G etal fertil steril 2002

These datas suggest that hypercoagulable states might be an

important Factor for RPL

Apla Syndrome, Thrombophilia - Complications

Abortion IUFD PIHAPLA Syndrome ++ ++ ++

Factor V Leiden mut. ++ ++ ++APC Resistance + ++ ++Hyperhomocysteinemia. + + +

Antithrombin III def. ++ ++ +Protein C deficiency + ++ +Protien S deficiency + ++ +

Other APL’s anti bodies

• Whether other APL’s such as antiphosphatidylserine and antiphosphatidylethanolamine,should be looked for and whether anticoagulation treatment should be given.

Results from one study suggested that APL’s other than LAC and ACA are associated with RPL and will benefit from anticoagulant therapy Franklin RD human reprod 2002

APLA Therapeutic Options

AntiaggregantsAspirin

AnticoagulantsHeparin / LMWH

ImmunosuppressionCorticosteroidsIVIG

Other tt options Plasmapheresis Azothiaprin

THERAPY

• LOW DOSE ASPIRIN AND HEPARIN / LOW MOLICULAR WEIGHT HEPARIN ARE THE FIRST LINE THERAPY

• PREDNISONE OR IMMUNOGLBULINS CAN BE ADDED IN REFRACTORY CASES

• PREDNISONE THERAPY IS ASSOCIATED WITH INCREASED INCIDENCE OF PRETERM DELIVERIES

• DUE TO OSTEOPENIC EFFECTS OF PREDNISONE AND HEPARIN ,CALCIUM SUPPLEMENTATION IS MUST

Alloimmune Causes – Why Is The Baby Not Rejected?

• Unique Phenomenon• Shuts off Rejection immunity of Uterus +• Growth / Development of fetus

1 In a normal pregnancy the father’s DNA in the baby tells the mother ‘s body to set up a protective reaction around the developing embryo.

• If the father’s DNA is too closely matched to the mother, there is a good chance that the embryo created by them is unable to differentiate itself from the mother’s body.

This results in a lack of blocking antibody to pregnancy, and the pregnancy fails.

2 TNF a (TH type – I)

                

Role of Absent Anti Paternal Lymphocytotoxic

Antibodies (Blocking AB)

NK cell measurement and NK cytotoxicity are two measurements for assessing cellular immune response.

In most cases, Natural Killer Cells are good for the body because they prevent cancer. However in excess they kill the embryo and interfere with the endocrine system that produces hormones essential for pregnancy.

Lit therapy ↓ TNF a / NK cell cytotoxicity.

Natural Killer (NK) Cells & NK Cytotoxicity , TNF a

“Alloimmunity”

SYSTEMATIC COCHRANE REVIEW EMPHASIS THAT NONE OF THESE IMMUNOTHERAPIES,IV IMMUNOGLOBULINS, HAVE NO SIGNIFICANT ROLE TO PLAY

?

ENDOCRINE Causes

↑ Glycosylated HB 16%

S/C Hypothyrodism 26 %

Thyroid Anti Bodies + 9 %

PCOD – ↑ LH 14%

LPD 22%

Hypothyroidism / Antibodies

No definite evidence that hypothyroidism causes sporadic or recurrent abortion.

Antithyroid antibodies(thyroglobulin and thyroid peroxidase) are raised in euthyroid recurrent aborters.

Antibody Abortion(%)Absent 8.4Present 17.0

Stagnaro-Green,JAMA,

Diabetes MellitusDiabetes Mellitus• Diabetic women with good metabolic

control are probably no more likely to miscarry than non-diabetic women.

• Diabetic women with raised glycosylated Hb concentrations in first trimester are at increased risk.

• Diabetic patients should be euglycaemic before attempting a pregnancy

Kalter et al Am.J.O.G.,

PCOD – Raised LH

Abortion observed inpatients with raised LHlevels (D5/6 levels > than10 IU/L)

DILEMMA

LH levels Abortion(%) N 12 Raised 65 Regan et al

DOES DOWN REGULATION OF LH LEVELS HELP IN

DECREASING THE ABORTION RATES ?

PCOD – Raised LH

HARDY et al compared embryo quality in PCOS &others undergoing IVF and found

no difference

PCOD – Raised LH

LH may exert deleterious effect by increasing

androgens,suppressing granulosa cells

Or by decreasing endometrial receptivity by

disordered prostaglandin synthesis Franks

PCOD – Raised LH

Results of Prospective Randomised

Study – St Mary’s Hospital ,

London By (Clifford.k)

No benefit from suppressing LH levels.

Luteal Phase Defect

Incidence varies from 10-60%.Evaluated by mid-luteal progesterone and late luteal endometrial biopsy

META-ANALYSIS of Six RCT of use of progesterone during pregnancy –Use of Progesterone or HCG does not reduce miscarriage.

Daya, Br.J.O.G.,Goldstein Br.J.O G.

DILEMMA

PROGESTERONE HELPS !!!When should the supplementation start ?

• RPL progesterone supplementation should be started day after ovulation to cause effective secretory changes for implantation and effective immunomodulation to prevent embryonic rejection.

Uterine Specificity In Vaginal administration Ensures efficacy Where it matters

OXIDATIVE STRESS AND ROLE OF ANTIOXIDANTS in RM

What is Their Effectiveness What is Their Effectiveness on Pregnancy outcomeon Pregnancy outcome

??

??

• Multiple micronutrients offered

• Folic acid, calcium,iron beneficial• Vit E,C, carotenoids, carotene,L-Arginine

• Magnesium, zinc, need further elucidation• Lycopene, Lyco-O-Mato,Green Tea extracts,

etc

?

Psychological

• RM is associated with significant psychological morbidity.

• Role of psychological stress is unclear

Tender Loving Care

• Even after three miscarriages the chance of success without treatment is approximately 60% except for women with antiphospholipid syndrome and thrombophilia in which success rates are lower

Diagnosis and management of recurrent Pregnancy Loss (Since 2003 – June 2013)

ETIOLOGY DIAGNOSTICEVALUATION

TREATMENT

Genetic 2.8% Karyotype of partnersPOC ?

genetic counseling / donorgametes

ANATOMIC 22.4% USG/ HSG/ MRIEndoscopy

Surgical CorrectionSeptate S/M firoids & adhesions

Infections TB 39%TB Gold ,MTBC,, TB PCR

ATT

AUTOIMMUNE Apla Syndrome 6%Thrombophilia 3%

LA, ACL Aspirin / Heparin

ALLOIMMUNE 8% TNF a , NKCell Paternal leukocyte therapy

Endocrine PCOD, ,LPD,Hypothyroid. 14%

Diabetes Mellitus

Progesterone 21 / EB,↑ LH, TSH, Glyco. Hb

Hormonal Therapy

TLC

Management OptionsIn Next Pregnancy

Approach

Do Not advocate “Unproven” treatment

Recommends

• TLC Approach

• Liberal use of vaginal progesterone

• Serial Scan to reassure

• Counseling , Acupuncture, Diet

• Offer Low Dose Aspirin And Heparin to women with APS• Offers low – dose heparin to women with thrombophilia

• Patients with diabetes mellitus : good matabolic control

• Patient with hypothyrodism – TSH < 2.5

• Paternal Lit therapy ? ↑ TNF a, TB ? • Low mol. Wt heparin ?? Idiopathic , TB , ↑ TNF a, , APLA

Second Trimester

• Primary cervical carclage with suspected cervical incompetence

• Serial cervical Ultrasonography with insertion of cervical suture with evidence of shortening / funneling

• Serial vaginal swab for Bacterial vaginosis

Diet Advice & LAMART’S Classes

RM is associated - Low birth wt

- ↓ Liquor

- Early IUGR

- IUD

Injection medroxy prog. Acetate if required

Low Mol. wt Heparin if required

Arnine Sachet / 4 L fluid if required

Third Trimester

Level 3 NURSERY

Importance of Abortion / RM Key Message Lifecare34

60% of embryos never yield a live birthEdmonds et al,1982

30% of “Implanting embryos” miscarry, often before the woman realizes she is pregnant

Miller et al ,198015-20% of clinically detectable pregnancies

abort

5% women have RM > 2

1 % woman have RM > 3

In INDIA Genital TB is major cause (2/5), Uterine – 1/5 Paternal Karyotype , Thrombophilia & TNF a

need to be Evaluated More & More

LOGICAL TO OFFER ART?

• IVF WITH EMBRYO BIOPSY• DONOR OOCYTES IN OLDER AGE GROUPS• DONOR OOCYTES FOR RECURRENT

HYDATIDIFORM MOLE• DONOR SPERM IN PT WITH Y CHROMOSOME

DELETIONS• DONOR EMBRYOS IN MOTHERS WITH BALANCED

TRANSLOCATION• SURROGACY UTERINE FACTOR

Day 1

Day 5

Day 4Day 3

Day 2

Thank You