Perspectives in Assisted Conception Mr. Tarek El-Toukhy, MD MRCOG Consultant in Reproductive Medicine Guy ’ s and St. Thomas ’ Hospital

Why is fertility treatment important? because childlessness matters

Subfertility common problem: 1 in 6 couples failure to conceive after 1 year regular unprotected intercourse remember couples want a baby not investigations manage as a couple

Subfertility co-operative approach between community and hospital will benefit patients subfertility vs infertility: most couples have some chance of conceiving spontaneously

History: couple How long together How long trying to conceive Pregnancies together and outcomes Pregnancies with previous partners smoking, alcohol coital frequency, timing & problems

History: female cycle weight / change in weight drugs at risk of tubal disease? –STD, IUCD, Ectopic, surgery, –dyspareunia, secondary dysmenorrhoea history of endometriosis?

History: male occupation testicular maldescent trauma infections –STD –mumps orchitis surgery drugs –therapeutic –recreational

Initial investigations Day 2-4 hormone profile –FSH, LH, prolactin, TSH, testosterone Day 21 (or mid luteal) progesterone Semen analysis Rubella cervical smear chlamydia swabs

Interpreting basic investigations 1 Hormone profile –FSH > 10  ovarian reserve –LH > 10 ?PCO –testosterone > 2.5 ?PCO –prolactin > 1000?prolactinoma –progesterone <30anovulation

Interpreting basic investigations 2 Semen analysis volume 2-5 ml count > 15 x 10 6 /ml motility > 42% progressively motile (25% rapidly progressive) morphol >3% normal

Early referral if.... Female age >35 years or baseline FSH >10 amenorrhoea / oligomenorrhoea probable tubal factor probable male factor

Completing investigations Ultrasound scan

Completing investigations Tubal and uterine cavity assessment –HSG –hysterosonography –Laparoscopy and dye and hysteroscopy

Azoospermia centrifuge sample distinguish obstructive from non-obstructive –FSH –testicular size karyotype cystic fibrosis testicular biopsy / exploration

Main causes of subfertility Anovulation Tubal Disease Male factor (40%) Unexplained

Management options: Anovulation normalise weight correct underlying endocrine disease –Hypothyroid or hyperprolactinaemia Ovulation induction –Clomiphene/metformin –Gonadotrophins IVF

Anovulation surgical ovulation induction –Laparoscopic drilling of ovaries for PCO Egg donation for ovarian failure

Management options: Tubal disease TC tubal cannulation Adhesiolysis laparoscopically Open tubal surgery IVF selection important as success of surgery depends on severity of tubal damage

Management options: Male factor SeverityManagement option Mild Moderate Severe Azoospermia Wait, IUI IVF, ICSI ICSI, DI Sperm retrieval + ICSI, DI

Management options: unexplained wait –young (& normal FSH) –trying < 3years Assisted Conception –IUI –IVF

IVF and Natural cycle Natural cycle –Ovaries are not stimulated –Only one egg is produced –Fertilisation occurs in the fallopian tube –Multiple pregnancy is not common IVF cycle –Ovaries are stimulated –More than one egg is produced –Fertilisation occurs outside the body (in a laboratory dish) –Multiple pregnancy is more common

What can you do before treatment?

Stimulation of the ovaries by a daily injection

The late night injection

ICSI: revolution for male subfertility ability to inject single sperm into each oocyte pregnancy rates higher than IVF live birth rates of 35% per cycle started

Sperm retrieval techniques Percutaneous epididymal sperm aspiration (PESA) Testicular sperm extraction (TESE)

ICSI

2 PN zygote

6 cell embryo

Variation in embryo quality

Early human development in vitro 2-cell stage Fertilized egg (zygote) hatching blastocyst morula 8-cell stage 16-cell stage 4-cell stage Early Day 2 Early Day 1 Late Day 1 Early Day 3 Late Day 3 Day 4 Day 5 Day 6

EMBRYO TRANSFER

Side effects/Complications Drug side effects Ovarian hyper-stimulation Multiple pregnancy Infection Pregnancies may miscarry or be ectopic

Guy’s ACU: Jan - June 2014 Positive fetal heart on scan fresh IVF/ICSI cycles started

Guy ’ s ACU: Jan – June 2014 Positive fetal heart on scan for patients having blastocyst transfer %

Why do IVF cycles fail? Failure of embryonic development Poor egg / embryo quality –Female age –FSH Uterine environment –intrauterine lesions –endometrium Embryo transfer technique

Assisted Hatching creates opening in zona pellucida at 8 cell stage may enable normally developing embryos to hatch prior to implantation

Preimplantation Genetic Diagnosis transfer only unaffected embryos back to the patient affected Biopsy Test

Indications for PGD FISH: Sexing for an X-linked disorder Chromosomal re-arrangements PCR: Monogenic single gene disorders

Steps to PGD Embryo biopsy Diagnosis by Transfer 2 unaffected embryos Fertilisation in vitro (IVF or ICSI) PCRFISH Accurate genetic diagnosis Appropriate Genetic Counselling

Diseases detectable by PCR on single cells Cystic Fibrosis Sickle cell disease Haemophilia A and B Thalassaemia Fanconi Anaemia Spinal and bulbar muscular atrophy Retinitis Pigmentosa Alport Syndrome Phenylketonuria Tay Sachs disease Alpha 1 antitrypsin deficiency Myotonic Dystrophy Huntington's disease Adenine deaminase deficiency Fragile X syndrome Ornithine transcarbamylase deficiency X-linked hydrocephalus Crouzon syndrome Stickler syndrome Tuberous sclerosis Central core disease Gaucher's disease Hyperinsulinaemic hypoglycaemia Hunter's syndrome Agammaglobulinaemia Alzheimers disease HLA typing Marfan disease Lesch Nyhan syndrome P53 mutations Epidermolysis bullosa Plakophilin deficiency Kennedy disease Long chain acyl CoA dehydrogenase deficiency Charcot Marie tooth disease type 1a, 2a Spinocerebellar ataxia type 7 Osteogenesis imperfecta type I and IV Duchenne muscular dystrophy Congenital adrenal hyperlasia

PGD technique

Requirements for PGD Multidisciplinary team HFEA approval QC for labs Clinical pathology accreditation (CPA)

Safety of PGD Early days Few small studies: as safe as ICSI Single cell vs two cell biopsy Good survival after cryopreservation

1741 sequential cycles of PGD Stimulated Cycles to OR Cycles to biopsy Cycles to ET 726 (79%) 92 ( 75% ) 437 ( 63% ) 1255 ( 72% ) Clinical Preg Per egg collection 36%31%26% 31% Per Transfer 42%36 %39% 40% Single gene X-linked (Sept Dec 2013) Rearrange Total GSTT Centre for Preimplantation Genetic Diagnosis Centre for Preimplantation Genetic Diagnosis

When should couples stop? variable and individual review after each cycle need careful counselling about realistic chance of success –age –previous response to stimulation –previous egg / embryo quality overall success rates decrease beyond 5 attempts

Why is fertility treatment important? because childlessness matters