dr sohani verma

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Dr Sohani Verma Dr Sohani Verma Sr. Consultant Obstetrics & Gynaecology Infertility & ART Specialist Clinical & Academic Coordinator Indraprastha Apollo Hospitals, New Delhi Chairperson North Zone AICC RCOG President Elect Indian Fertility Society

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Dr Sohani Verma

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  • Dr Sohani Verma

    Sr. Consultant Obstetrics & Gynaecology

    Infertility & ART Specialist

    Clinical & Academic Coordinator

    Indraprastha Apollo Hospitals, New Delhi

    Chairperson North Zone AICC RCOG

    President Elect Indian Fertility Society

  • Introduction

    A woman of reproductive age who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner.

    Offer an earlier referral for specialist consultation to discuss the options for attempting conception, further assessment and appropriate treatment where

    - the woman is aged 36 years or over

    - there is a known clinical cause of infertility or a history of predisposing factors for infertility

    NICE Guidelines 2013

  • Multiple relatively minor abnormalities, either with 1 partner or both, account for 30% of all causes

    Main Causes of Infertility

  • Assisted Reproductive Techniques (ART)

    Any treatment that deals with means of conception other than vaginal intercourse is termed as ART.

    NICE guideline 2013

    IUI Intra Uterine Insemination (Husband / Donor)

    IVF + ET In Vitro Fertilization + Embryo transfer

    ICSI Intra Cytoplasmic Sperm Injection

  • IUI

    Injection of washed prepared sperms into

    the uterine cavity through a fine catheter

    during peri-ovulatory phase in a natural

    or stimulated cycle.

    Although pregnancy may not occur as quickly, a policy of initial treatment by IUI will probably save 20% of couples from moving onto IVF After 3-4 cycles of failed IUI treatment, patients should be encouraged to opt for IVF
  • The procedure may help in increasing the chances of pregnancy in following ways

    Allowing sperm-ovum contact close to the date and time of ovulation

    By bringing the sperm very close to the site of fertilization and by passing the cervical factors

    Sperm preparation increases the sperm density and removes all antigens on the surface of sperm and in seminal plasma

    IUI is the simplest and the least expensive method of ART

    IUI alone (natural cycle) does not improve pregnancy chances, hence mild ovarian stimulation is usually recommended.

    IUI

  • Indications for Intra Uterine Insemination (IUI)

    - At least one Fallopian tube must be normal and
    patent
    - Mild male infertility
    - Unexplained infertility
    - Ovulatory dysfunction, PCOS
    - Mild endometriosis
    - Cervical factors
    - Coital problems
    - Immunological factors
    - HIV, HBs Ag infection
    - Donor Sperm

  • Indications for Donor Sperm IUI

    Azoospermia (where ICSI is not an option)

    Severely subnormal semen parameters (ICSI not an option)

    Persistent failure of ICSI

    Rh Isoimmunization

    Hereditary disease in the male partners

  • Indication for ART IUI or IVF

    The indications for IUI are often not dissimilar to those for IVF (or even for ICSI for moderate male factor) and often interchangeable with overlapping.

  • Common Indications for IUI Indications for IVF

    Unexplained infertility- Unexplained infertility

    Endometriosis (mild)- Endometriosis (moderate to severe)

    Male factor infertility (mild) - Male factor infertility (moderate to severe)

    Ovulatory disorders - Ovulatory disorders

    Inability to have vaginal intercourse

    People with conditions that require - Tubal pathology

    specific consideration (such as man HIV - Donor Oocyte

    positive) - Genetic Surrogacy

    - People in same-sex relationship - PGD (Possibility of genetically

    - Donor Sperm transmitted disease) - Fertility preservation in cancer patients

    - Where ICSI is indicated (Azoospermia)

  • Meta-Analysis of IUI in Male Factor

    Pregnancy Rate

    Timed intercourse in natural cycle2.4%

    Timed intercourse in COH cycle 5.0%

    IUI in natural cycle 6.5%

    IUI in COH cycles 12.6%

    Cohlen BJ et al Cochrane database Syst Rev 2003

  • Basic requirements for IUI success

    Patient selection

    Age of female partner < 35 years

    Duration of infertility < 5 years

    Cause of infertility (at least one functional normal

    fallopian tube and no uterine factors)

    Adequate ovarian reserve (based on Serum AMH, antral

    follicle count, Day 2 FSH, LH, E2 levels)

    Semen parameters Post wash TMSC >5 million/ml

    Best pregnancy rates with >10 million/ml

    < 1 or 2 million/ml do not waste time in IUI. Advice IVF / ICSI straight away

  • Basic requirements for IUI success contd

    Choice of ovarian stimulation used

    Number of dominant follicles 1 to 3 follicles

    Use of transvaginal ultrasound follicle monitoring

    Timing of IUI

    Between day 12 to 16 of the cycle usually highest pregnancy rates

    Interval from hCG injection 32-42 Hours usually recommended (range 12-60 hours)

    Single IUI 36 hours after hCG is usually the preferred option.

  • Semen preparation technique Quality and expertize of lab personnel

    Procedure of IUI & type of catheter used

    Luteal support is recommended

    How many IUI cycles- 3-6 cycles usually recommended

    Basic requirements for IUI success contd

  • INTRAUTERINE INSEMINATION ESHRE Guidelines

    There is general agreement in the literature that chances of success are better after mild ovarian stimulation and the maturation of a maximum of two or three follicles.

    However, the cycle must be monitored by ultrasound and hormonal analysis; if there are more than three mature follicles, the attempt should be cancelled.

    While the concurrent use of ovarian stimulation may increase pregnancy rates, it may be at the expense of a high chance of multiple pregnancy.

    The majority of pregnancies occur during the first six cycles. In any case, the number of attempts should not exceed nine cycles.

    When assessing the duration of an IUI programme, the age of the woman must be taken into account, to ensure timely transfer to more complex treatments if indicated.

  • The world's first "test-tube baby", Louise Brown, has spoken of her joy at giving birth to her first child. Baby Cameron was born on 20 December06 in Bristol, where his 28-year-old mother lives with husband Wesley Mullinder.

    Well over two million "test-tube" babies have been born globally since Louise's 1978 birth after IVF

  • IVF and ET

    In Vitro Fertilization (IVF) and Embryo Transfer (ET) are the basic ART for all related technology. These include:

    -Intra Cytoplasmic Sperm Injection (ICSI)

    -Assisted hatching

    -Pre-implantation Genetic Diagnosis (PGD)

    -Cryopreservation

    -Donor oocyte IVF programs

    -Donor embryo (genetic surrogacy)

    -Intracytoplasmic Morphologically selected

    Sperm Injection (IMSI)

    - And many more

  • Pre IVF work-up

    Ovarian stimulation

    Monitoring

    Preparation of sperms

    Oocyte retrieval

    Embryo transfer

    Luteal Support

    Ovulation induction

    In Vitro Fertilization

  • IVF & ET
    Procedure

    Picture
  • In vitro embryo development

    COC at the time of retrieval

    M II oocyte with a PB (Mature)

    2 PN embryo

    4 cell embryo

    8 cell embryo

    Fully grown blastocyst

  • Indication for IVF

    I. IVF as first line infertility treatment

    Tubal pathology (severe, non-repairable)

    Donor Oocyte

    Genetic Surrogacy

    PGD (Possibility of genetically transmitted disease)

    Fertility preservation in cancer patients

    Where ICSI is indicated (Azoospermia)

    II. IVF following failed cycles of IUI

    Usually up to six cycles of IUI with controlled ovarian stimulation are recommended, but there are situations where couples should move to IVF earlier.

  • Indicators for early referral

    I.Female age

    -The biological clock is the major adversary to human reproduction

  • Womans age is the initial predictor of her overall chance of success

    NICE Guideline 2013

    Live birth rates per Embryo transfer by age (HFEA post-October 2007 data)

  • II.Diminished Ovarian Reserve at any age

    -AMH- anti-Mullerian hormone of less than or equal to 5.4pmol/l

    Antral Follicle Count (AFC) Less than or equal to 4

    Day 2/3 FSH >8.9 IU/L

    Endometriosis

    Moderate (more than slightly abnormal) degree of semen quality abnormalities.

    V. Tubal Compromise

    NICE Guideline 2013

  • Unprecedented successful development of ART which has revolutionized the management of severe male infertility (Van Steirte-ghen 1992)The procedure involves the direct injection of a single sperm into the egg cytoplasm

    ICSI

  • Indications for ICSI

    Severe alterations of semen characteristics

    History of fertilization failure in conventional IVF
    attempts

    Testicular or epidydimal sperm

    Other relative indications

  • Success rates following IVF / ICSI

    24.7 percent clinical pregnancies of all women who undergo IVF treatment (HFEA 2011).

    50% of all embryos cultured in vitro reach blastocysts stage by day 6.

    About 15% of transferred embryos will develop into a baby

  • Basics requirements for IVF/ICSI success

    Pre IVF work up of the infertile couple

    Clinical history

    Examination

    Investigations

    Counseling

    Why necessary?

    To identify the cause of infertility and thereby prognosis

    To identify and correct associated adverse factors before treating

    primary disorder

    To decide most appropriate treatment protocol
    - Type of drug
    - starting dosage
    - expected response and problems

    To assess reproductive ageing and plan early access / resort to ART treatments

  • 2. To get adequate number of good quality oocytes

    Predictors of COHS response Normal responders
    Hyper responders
    Hypo- responders
    - Age, AMH, AFC

    - Response to earlier COHS

    - Basal FSH, LH, E2

    - BMI, Smoking, Alcohol
    - Previous Ovarian Surgery

    B. Selection of COHS protocol
    - Agonist versus Antagonist protocols
    - Mild stimulation protocols



    Basic requirements for IVF/ICSI success contd

  • C. Ultrasound monitoring with power and colour

    Doppler

    D. Biochemical Monitoring

    Ovulation induction
    - hCG - urinary / recombinant
    - GnRh agonist

    Technique of Oocyte retrieval

    Embryology lab quality and expertize

    IVF or ICSI

    Selecting best embryo (s) for transfer

    Number of embryos transferred

    Embryo transfer technique

    Luteal Support

    Basic requirements for IVF/ICSI success contd

  • Luteal Support

  • Luteal Support

    The transformation of mature follicle into corpus Luteum (CL) after the release of ovum is triggered by an optimal LH surge.

    The function of CL is dependent upon continued LH stimulation in luteal phase.

    CL is an essential source of pro-fertility hormones ie Progesterone (P), Estrogen (E) and other vasoactive and growth factors.

  • Luteal Support

    It is well established that the ovarian stimulation regimens used in assisted reproduction cycles alter the luteal phase.

    Edwards et al 1980, Kolibianakis et al 2003

    Ovarian stimulation causes

    an inadequate development of the endometrium

    an asynchrony between the endometrium and the transferred embryo and

    adverse effects on endometrial receptivity

    Macklon & Fraser 2000, Devroey et al 2004

  • Luteal Support contd

    The luteal phase defect in IVF is present whether GnRH agonist or antagonist is used (Friedlers et al 2006).

    The possible mechanism responsible may be

    Continuation of pituitary down regulation effect

    Duration of luteal phase is shortened

    Formation of multiple CL leading to inhibition of pulsatile LH release

    Loss of granulosa cells during oocyte retrieval

  • Luteal Phase Support

    Endometrial support complements production by CL

    Progesterone preparation

    Estrogen preparation

    Agents which support CL

    hCG

    GnRH-analogue

    LH

    Newer agents which promote angiogenesis and

    vascular supply

  • Progesterone preparations available

    Micronized

    Oral / vaginal - 200-400 mg BD

    Vaginal Gel (8%) - 90 mg daily

    Vaginal Pessary - 100-400 mg daily

    Intramuscular (oil based) - 100-400 mg daily

    (iii) Subcutaneous (aqueous preparation) - 25 mg daily

    (iv) Synthetic Dydrogesterone - 10 mg BD or TDS

  • Estrogen as an adjuvant to LPS

    Estradiol valerate. Hemihydrate

    Oral (intravaginal)

    2-6 mg/day

    Micronized Estradiol

    Oral or intravaginal

    2-6 mg/day

    Transdermal Estradiol

    Patches (2 per week)

    50-100 ugm/day

  • Luteal Phase Support for assisted reproduction cycles (Cochrane Review 2011)

    Tesarik J et al 2006 published their result on 600 women randomly assigned to receive a single injection of GnRH agonist (0.1 mg of triptorelin) or placebo on Day 6 after ICSI. The results showed improvement of implantation and live birth rates.

    Van der Linder et al investigated progesterone versus prog + GnRHagonist

    Six studies (1646 women)

    There were significant results showing a benefit from addition to GnRH agonist to progesterone for the outcomes of live birth, clinical pregnancy and ongoing pregnancy.

    GnRH agonist as an adjuvent to LPS

  • Luteal Phase Support for ART Cycles

    Authors' conclusions

    Cochrane review 2011 showed a significant effect in favour of progesterone for luteal phase support, favouring synthetic progesterone over micronized progesterone. Overall, the addition of other substances such as estrogen or hCG did not seem to improve outcomes.

    They found no evidence favouring a specific route or duration of administration of progesterone.

    It was found that hCG, or hCG plus progesterone, was associated with a higher risk of OHSS.

    The use of hCG should therefore be avoided.

    There were significant results showing a benefit from addition of GnRH agonist to progesterone for the outcomes of live birth, clinical pregnancy and on-going pregnancy.

    For now, progesterone seems to be the best option as luteal phase support, with better pregnancy results when synthetic progesterone is used.

    Cochrane Review 2011

  • Nutritional Supplements and ART outcome

    No definite conclusive evidence

    Anti-oxidants Vit C, E, selenium, zinc, taurine, carotene, lycopene

    Vitamins Folate, Vit B 12

    Myoinositol and D-chiro-inositol (vit B complex)

    L Arginine

    DHEA

  • Dehydroepiandrosterone (DHEA) supplementation

    Cason and associates (2000) were first to suggest therapeutic benefits from the supplementation of DHEA in women with diminished ovarian reserve and suggested it may improve oocyte yields via IGF-1.

    It was left to a 43 year old infertility patient in US (advised donor oocytes) to discover their paper and self administer DHEA while undergoing subsequent IVF cycles.

    The patient underwent nine consecutive IVF cycles and increased oocytes and embryo yields from cycle to cycle, starting with one egg and embryo, respectively, and ending up with 17 oocytes and 16 embryos in her ninth cycle.

    (Gleicher et al 2009)

  • While all other pharmacological agents affect follicle maturation only during the final stage gonadotropin sensitive last 2 weeks, DHEA in contrast appears to affect folliculogenesis at much earlier stages of in-vivo follicle maturation (Gleicher N etal 2011)

    DHEA has been shown to increase the number of primary, preantral and antral follicles.

    DHEA supplementation is reported to improve ovarian response, IVF parameters and pregnancy chances. Younger patients with POA appears to have a slight pregnancy advantage.

    Dehydroepiandrosterone (DHEA) supplementation

  • Cumulative pregnancy rates in women with DOR with and without DHEA supplementation. POA patients appear to have a slight pregnancy advantage, Barad et al 2007

  • Age-stratified miscarriage rates in DHEA supplemented DOR patient in comparison to national U.S. IVF pregnancies. Gleicher et al 2009

    DHEA supplementation is also shown to significantly (50-80%) reduce the miscarriage risks in patients with poor ovarian reserve (Gleicher etal 2007)

  • Treatment protocols, side effects and complications

    Micronized DHEA at a dosage of 25mg TID

    Effects occur relatively quickly (6-8 weeks) but peak only after 5-6 months of supplementation.

    Side effects are small and rare and primarily relate to androgen effects oily skin, acne vulgaris and hair loss.

    Even long-term therapy of DHEA in suggested dosages have been demonstrated safe (Panjari M etal 2009).

    However, before declaring DHEA as a wonder drug, larger RCTs are urgently needed to confirm the benefits.

  • Sohani Verma

    Cervical

    3%

    Uterine

    11%

    Tubal

    23%

    Hormonal

    29%

    Male

    34%