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Complete over view of the causes diagnosis management of Recurrent Pregnancy Loss it is a personal experience of treating recurrent miscarriages with excellent result
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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