Louise Brown born First IVF baby Born to Lesley Brown, bilateral tubal blockage Natural cycle, single egg fertilization

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2 Louise Brown born First IVF baby Born to Lesley Brown, bilateral tubal blockage Natural cycle, single egg fertilization

3 IVF first reported attempts at IVF IVF births in rabbits in USA first human IVF (Edwards, Bavister) Birth of first IVF baby (Steptoe, Edwards) Birth of first baby after ICSI (intracytoplasmic sperm injection) (Palermo)

4 ICSI Metaphase II oocyte

5 Pronuclear stage hrs 2PN 24 hrs later, ET 8 hrs later

6 Short term consequences oocyte damage embryo transfer similar to IVF no increased morphological abnormality

7 IVF 32,958 treatment cycles conducted 5953 babies were born in Australia more than half the cycles use microinjection/icsi

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9 Higher order multiples clearly associated with adverse neonatal outcomes Twins still 1:5 of pregnancies from ART (compared to 1:80 spontaneously)

10 Increased preterm birth, LBW, perinatal mortality, cerebral palsy Absolute risk much greater than singleton

11 1:6 will be a miscarriage 1:14 will be premature 1:30 will have a birth defect 1:100 will die at or around the time of birth 1:400 will have cerebral palsy 1:14,000 will have imprinting disorder

12 Increased risk after ART from 1/14 to 1/7 RR 2 present for singleton gestation?iatrogenic?underlying pathologies e.g. fibroids (Helmerhorst et al, BMJ 2004;328:261)

13 Increased risk of VLBW (<1500g) RR3 ( ) Increased risk of LBW (<2500g) RR 1.4 ( ) (Helmhorst et al, BMJ, 2004;328:261)

14 RR 1.68 ( )

15 Karyotypic abnormalities Y chromosome deletions Imprinting disorders

16 Sex chromosomal abnormalities After ICSI Risk from 1: in spontaneous conception to 1:100 after ICSI (not IVF) Chorionic villus sampling or amniocentesis offered routinely in Belgium to couples pregnant after ICSI.

17 4% of males with severe male factor infertility have deletions of Y chromosome(daz and RBM) Male offspring generated by ICSI have the same defect (Page et al, Human Reproduction, 1999)(presumably the same manifestation)

18 1:14,000 pregnancies spontaneously conceived have imprinting disorders which predispose to brain abnormalities, tumours e.g. Prader Willi, Beckwith Weidemann, Angelman syndomes.

19 From One allele from a parent is selectively inactivated increased after ART to 1:4000

20 Hansen et al, HumReprod 2005

21 RR 1.3 Background 3% After ART 4% No difference between IVF and ICSI

22 Barker hypothesis - patterns of adult disease associated with low birth weight rather than socio-economic status and other risk factors

23 Dutch famine of 1945 Longitudinal study of adults exposed to maternal starvation whilst in utero at varying gestations 1st trimester - obesity, AS, CAD 2nd trimester - IGTT, COPD 3rd trimester - insulin resistance, IGTT other disease e.g. breast cancer, SZ, cognitive function T Roseboom 2000

24 Does embryo exposure to in vitro culture conditions change programming for fetal and adult life? If so, how? What is the strength of this selective force?

25 Will this be part of our medical history of the future? Birth weight Twinning, triplets ART

26 Spontaneous M/C 1:6 Prem 1:14 Cong abn 1:30 PNM 1:100 Sex chrom abn 1:300 Imprinting disorder 1:14000 After ART M/C?1:4 Prem 1:7 Cong abn 1:25 PNM 1:99 Sex chrom abn 1:100 Imprinting disorder 1:4000

27 More than 90% of children born following ART are healthy and normal ART is increasingly used allowing couples to achieve pregnancies not otherwise achievable. Long term data on the health of ART children are lacking.

28 Appropriate timing of ART Adequate counselling of couples Careful selection of treatments and couples with appropriate workup Optimization of spontaneous conception

29 Reduction of multiple pregnancies = healthy families for Australia BESST - birth emphasising a successful singleton at term

30 Transvaginal oocyte collection Preparation Technique Complications Embryo transfer transcervical Preparation Technique Complications

31 Standard of care Ultrasound guidance

32 Aspiration of follicles Flushing with double lumen needle or no flushing with single lumen buffered solution or media

33 Infection 1/5000, reduced by half with antibiotic Particularly with endometiomata, hydrosalpinges?increased with PID Injury to other structures Blood vessel Bowel

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35 Appropriate timing Full bladder with anteverted uterus

36 Ultrasound control Avoid fundal contact Aim for upper to middle third of uterus

37 ??Infection OHSS if pregnant

38 Prevention of Ovarian Hyperstimulation Syndrome

39 1. To counsel couples on the best protocol for assisted reproduction for their individual case 2. To counsel couples undertaking assisted reproduction of their success rate 3. To appropriately conduct and supervise protocols of assisted reproductive technologies 4. To reduce the occurrence of ovarian hyperstimulation syndrome 5. To treat women with ovarian hyperstimulation syndrome

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41 Mandatory to have written precycle information on OHSS Mandatory to have protocols to reduce the risk of OHSS Mandatory to have clear information on what to do if symptoms develop ie written information on emergency care Mandatory to report all cases requiring admission to Qld Health

42 How can we get our patients to understand the importance of preventing this condition?

43 Preventable condition Difficult to treat once it is established Caused by the stimulation of too many eggs on the PLUS ovaries by FSH LH activity (or HCG) Takes about a week to develop to full extent after LH/HCG given Always a well patient when you are making the decisions to prevent OHSS

44 A medical condition characterized by ovarian enlargement and fluid accumulation with peritoneal, pleural and (rarely) pericardial cavities following treatment with ovarian stimulating drugs, most typically FSH containing preparations. The action of LH or hcg is required to develop the syndrome.

45 PCOS and OHSS

46 What are the symptoms and signs?

47 Clinical consequences are predominantly related to intravascular fluid depletion and include: hypotension haemoconcentration oliguria, renal impairment, hepato-renal syndrome pulmonary thromboembolism respiratory distress Key symptoms are nausea, SOB, abdominal pain and distension. Vomiting is always severe OHSS UPO

48 By what mechanism do these young woman die?

49 1/30,000 = mortality usually die of thromboembolic complications - stroke, PTE, occasionally complications of treatment such as heparin induced thrombocytopenia, also ovarian bleeding

50 How many eggs are enough to give a couple a realistic chance of pregnancy without a significant risk of OHSS?

51 Can get severe OHSS with as few as 13 oocytes in woman, particularly those with risk factors

52 Firstly those you might identify at the time of planning an IVF/ICSI cycle

53 young age low body weight history of OHSS PCO RR 2.46 compared with non-pcos (Delvigne and Rozenberg 2002) PCOS High dose of FSH

54 Formal baseline USS in all patients to pick up PCO Diagnose PCOS Consider metformin particularly if past history of OHSS/cycle cancellation Low dose FSH Warn about variable ovarian response Early scan at 7-8 days to detect hyperstimulatory response

55 iatrogenic ovarian stimulation 2 types early onset: related to hcg trigger / flare late onset: related to ensuing pregnancy spontaneous FSH receptor mutations