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  • Infertility, In Vitro Fertilization (IVF) and Genetic Testing

    Michele Evans, M.D.

  • OutlineInfertilityTreatment optionsIn Vitro FertilizationGenetic TestingPreconceptionPreimplantationPrenatal Controversies

  • Normal FertilityHull, et al: Br Med J 1985:291;1693

  • Overview of Infertility

    Definition: 1 year of well-timed, unprotected intercourse without a pregnancy

    10-15% of population is infertile (subfertile)

  • Causes of Infertility

  • Female Reproductive Organs

  • Physiology

  • Causes of Female InfertilityOvaryTubesUterusCervixHormonesChromosomes

  • Causes of Female Infertility - Ovary AGE

    Problems with ovulation

    Premature ovarian failure

  • Ovary - Female AgeWomen are born with their lifetime egg supply4 million at 20 weeks gestation400,000 at birth100,000 eggs left at time of pubertyFertility initially declines at age 27Significant decline at age 37-38Rare pregnancies after age 44

  • Percentage of Married Women Who are InfertileFrom 3 national U.S. surveysMenken et al, Science 1989;23:1389

    Age (years)Infertile20-247.025-298.930-3414.635-3921.940-4428.7

  • Ovarian Reserve Testing

    Day 3 FSH/E2FSH (mIU/mL)E2 (pg/mL)Normal100

  • Clinical pregnancy per cycleas function of both FSH and agePearlstone et al, Fertil Steril 1992:58:674

  • Prevalence of genetically abnormal oocytes in infertile womenAbnormal (%)

  • Ovary - Ovulation

  • Ovary - OvulationHistoryRegular menses (90%)Premenstrual symptomsPatient self-testingBBT, urinary ovulation kits (LH)Laboratory testsMid-luteal serum progesterone > 10 ng/mLEndometrial biopsy

  • Ovary - Causes of AnovulationHormone imbalanceObesityAnorexiaSignificant stressPatients display:Irregular menstrual cyclesSkipped cyclesMinimal or absent premenstrual symptoms

  • Ovary Premature Ovarian FailureMenopause prior to age 40EstrogenFSHCausesAutoimmuneGeneticIdiopathic 1-2% pregnancy rate

  • Causes of Female Infertility Fallopian Tubes

    Infection (chlamydia)

    Endometriosis

    Tubal ligation (female sterilization)

  • Open Tubes

  • Blocked Tubes

  • Female Infertility - UterusUterusFibroidsPolypsMullerian (congenital) defectsAbsentBicornuate/SeptumAshermans syndrome

  • Female Reproductive Organs

  • Female Infertility

    Uterine muscle tumor

    Benign (>95%)

    25-30% of women

  • Normal Shape of Uterus

  • Fibroid Uterus

  • Female Infertility - UterusUterusTumorsFibroidsPolypsMullerian defects (congenital)Absent uterusBicornuate/septateAshermans syndrome

  • Mullerian Defect

  • Treatment with Hysteroscopy

  • Treatment with Laparoscopy

  • Female Infertility - UterusUterusTumorsFibroidsPolypsMullerian defects (congenital)Absent uterusBicornuate/septateAshermans syndrome

  • Female Infertility - Cervix

    CervixPost-surgicalStenosisMucus changes

  • Female Infertility - HormonesEndocrine abnormality (hormones)ThyroidProlactinPolycystic ovary syndrome (PCOS)Estrogen, insulinHypothalamic hypogonadismStressExercise (ballet dancer)

  • Other Causes of Female Infertility

    OthersChromosome abnormalitiesTurners syndrome (XO)Androgen Insensitivity (XY)Male pseudohermaphroditeFemale phenotypeBlind vaginal canalInguinal hernia (50%)

  • Causes of Male Infertility

    Abnormality in sperm production

    Abnormality in sperm function

    Obstruction in the ductal system

  • Male Reproductive Organs

  • Sperm: Semen AnalysisVolume: > 2 mLConcentration: > 20,000,000 per mLMotility: > 50%Normal morphology: > 40% normalKrueger strict criteria: > 14% normalBest predictor of fertilizing ability

  • Normal Sperm Morphology

  • Abnormal Morphology

  • Abnormal Morphology

  • SpermHow many are needed for fertilization?Natural conception20,000,000Intra-uterine insemination1,000,000In-vitro fertilization (IVF)10,000Intra-cytoplasmic sperm injection (ICSI)1

  • FertilizationBinding to zona pellucidaPenetration of oocyteDecondensation and aster formationPronucleus formation

  • Causes of Male Infertility

    Abnormality in sperm production

    Abnormality in sperm function

    Obstruction in the ductal system

  • Abnormalities of Sperm ProductionGeneticY chromosome microdeletionsDamage to testes anatomicalCryptorchidismVaricoceleInfectionMumps orchitisGonadotoxins

  • Abnormalities of Sperm Function

    Antisperm antibodiesGenital tract inflammationprostatitisVaricoceleFailure of acrosome reactionProblems with sperm binding/penetration

  • Obstructions in Ductal SystemVasectomy

    Congenital bilateral absence of the vas deferens

    Epididymis/ejaculatory ductsCongenital or acquired

  • Male Infertility - LifestyleTobaccoMarijuanaAlcoholCocaineSteroids (can be permanent)HeatExercise

  • Infertility: Initial EvaluationEggsOvulationEgg qualitySpermPresenceQualityGamete transport/ImplantationHysterosalpingogram

  • Infertility: Initial EvaluationEggsOvulation - serum ProgesteroneEgg quality - AGE, day 3 FSH/EstradiolSpermPresence - semen analysisQuality - strict morphology assessmentGamete transport/ImplantationHysterosalpingogram - routine

  • Unexplained Infertility

    Work-up is negative

    15-20 % of couples

  • TreatmentsObservation (improve timing)Clomiphene citrate + intrauterine insemination (IUI)FSH + IUIIVFEgg donation

  • Intrauterine Insemination (IUI)

  • Clomiphene Citrate (Clomid)

    Anti-estrogen

    FSH

    egg production

    $

    Estrogen Antagonist

  • PhysiologyClomid

  • ART: Treatment OptionsClomiphene citrate + IUIProspective randomized trialPatients with unexplained infertility

    Deaton et al, Fertil Steril 1990;54:1083

    ObservationCC + IUICycles150148Pregnancies514Fecundity0.0330.095

  • FSH +IUIDaily injections

    Goal is to make multiple follicles (eggs)

    $$

  • Physiology

  • Infertility Treatment OptionsIUI, FSH or FSH + IUIPatients with unexplained infertility

    Serhall et al, Fertil Steril 1988;49:602

    TreatmentCyclesPregnancyPregnancy per cycleIUI3012.7%FSH4936.1%FSH+IUI34926.4%

  • In Vitro Fertilization - History1978 First test tube baby was born in England

    1981 IVF in U.S.

    Started with GIFT and ZIFT

    2004 - >98% IVF with transfer of embryo to uterus

  • In Vitro Fertilization (IVF)

  • Who Needs IVF?Failed other treatmentsTubal damageSignificant male factorAbsent uterusCarriers of genetic diseasesCancer patients?

  • Ovarian Hyperstimulation

  • Egg Retrieval

  • Good Egg

  • Bad Egg

  • Fertilization

    2 Pronuclei (2PN)

    1 day after egg retrieval

  • Day 3 Embryo

  • Day 3 Embryo

  • Day 3 Embryo

  • Day 3 Embryo

  • Blastocyst Day 5

  • Hatching Blastocyst

  • Embryo Transfer

  • Embryo Transfer

  • Special IVF ProceduresAssisted hatchingIntracytoplasmic sperm injection (ICSI)Preimplantation genetic diagnosis (PGD)FreezingEgg donationSurrogacy

  • Assisted Hatching

  • Empty Zona

  • ICSI

  • ICSI

  • ICSI

  • How Many Embryos are Transferred?

    Related to age and embryo quality40 = up to 5

    For patients with 2 or more failed IVF cycles, or a poor prognosis, can add more based on clinical judgement

  • IVF Success Rates - 2000

    U.S. Fertility Centers (SART/CDC)Female age40 7.8%

  • IVF Statistics - 2000

    65.1% singletons (16,533)

    30.8% twins (7,817)

    3.9% triplets (1,000)

    0.2% higher order multiples (44)

  • Singleton Pregnancy

  • Twin Pregnancy

  • Triplet Pregnancy

  • IVF and Multiple PregnancyMaternal complicationsFetal complicationsCostSelective reductionSingle embryo transfer vs. success rates

  • IVF Statistics - 2000383 U.S. programs offer IVF

    99,989 cycles of ART treatment

    7,581 donor oocyte cycles

    25,394 deliveries (birth of 35,345 neonates)

  • Current status of ART in the USASART registry, 1998Pregnancy and live birth ratesfor ART cyclesusing fresh,non-donor eggs,by age of woman

  • Cost of IVFIVF cycle + medications = $10,000-15,000Assisted hatching = $500ICSI = $1,500Freezing = $650Storage = $360 Egg Donor = $5,000Surrogate = $10,000-15,000

  • Egg Donation

  • Egg donationIVF for two

    DonorStandard controlled ovarian hyperstimulationEgg retrieval

    RecipientEmbryo transfer

  • Egg Donation

    Known/anonymous donor

  • Current status of ART in the USASART registry, 1998Live birth rates per transferfor fresh embryos from own anddonor eggs, by age of recipient

  • Cumulative pregnancy ratesafter oocyte donationHuman Reprod 1997;12:835

  • Egg Donation Grade A: The Market for a Yale Womans Eggs When a Yale undergraduate explored becoming an egg donor for a wealthy couple willing to pay top dollar to the right candidate, she didn't realize how unsettling the process of candidacy would prove to be by Jessica Cohen

  • Egg DonationOctober 23, 1999 Selling Fashion Models' Eggs Online Raises Ethics Issues By CAREY GOLDBERG

    CAMBRIDGE, Mass. -- To the horror and disgust of mainstream infertility groups, a longtime fashio