Unexplained infertility Evidence based management

Size: px

Start display at page:

Download "Unexplained infertility Evidence based management"

Corey Robertson
5 years ago
Views:

1 Unexplained infertility Evidence based management Dr Mark Hamilton Consultant Gynaecologist NHS Grampian/University of Aberdeen

2 Unexplained infertility Evidence based management Dr Mark Hamilton Consultant Gynaecologist NHS Grampian/University of Aberdeen

3 The assessment of infertility The Paradigm 100 Are eggs available Are sperm available Can the gametes meet % Pregnant Months trying

4 Causes of Infertility (%) Unexplained Tubal Ovulation Male Secondary Primary

5 Unexplained Infertility

6 Diagnoses in unexplained infertility Endocrine factors Abnormal follicle growth Sub-optimal progesterone secretion (luteal phase deficiency) Luteinised unruptured follicle syndrome Hypersecretion of LH Ovulatory hyperprolactinaemia Ovarian factors Zona pellucida antibodies Diminished ovarian reserve (ovarian ageing) Uterine/endometrial factors Congenital uterine abnormalities Submucous fibroids Abnormal uterine perfusion Altered cytokine expression and action Disturbed T cell and natural killer cell function Tubal factors Disturbed tubal function i.e. peristalsis, cilia Sub-optimal metabolic support of gametes and embryos Altered immune activity Peritoneal factors Mild endometriosis Occult infection Altered immune activity Genetic factors Gamete and embryo aneuploidy Poor embryo morphology, cleavage and blastocyst formation Sperm cervical mucus interaction Altered cervical mucus production Anti-sperm antibodies Psychogenic factors Inadequate coital function

7 The place of tubal assessment Is laparoscopy obsolete as a screening test? Effective alternatives? History Basic Ultrasound CAT screening HycoSy

8 Prognosis in unexplained infertility 100 Changing the Paradigm Natural chances vs Intervention % Pregnant Months trying

9 Prognosis in unexplained infertility 100 Variables to consider Age of female Duration of infertility Previous pregnancy % Pregnant Months trying

10 Prognosis in unexplained infertility Age of female Trends in clinics >35yrs doubled <30yrs halved Biological effects Oocyte/embryo quality Implications for treatment Reduced effectiveness % Unexplained infertility vs age >35yrs >35yrs <35yrs <35yrs Primary Secondary Maheshwari et al 2008

11 Prognosis in unexplained infertility Variables to consider Prognosis relevant to duration Normal Age of female Duration of infertility % pregnant Short Previous pregnancy 40 Medium Long Months trying

Prognosis in unexplained infertility 90 80 70 Prognosis relevant to duration Normal Short % pregnant 60

12 Prognosis in unexplained infertility Prognosis relevant to duration Normal Short % pregnant Medium Dynamics of patient decision making Long Months trying

13 Patient concerns re age IVF OUTCOME OVARIAN RESERVE 40 % LBR Age (yrs) HFEA + SART Age (yrs) Broer et al 2014

14 Models in unexplained infertility Age, Duration, Semen quality (Total motile sperm), Previous pregnancy, GP/specialist referral (Hunault 2004)

15 Models in unexplained infertility Age, Duration, Semen quality (Total motile sperm), Previous pregnancy, GP/specialist referral (Hunault 2004) + BMI, FSH level, Cycle length, Tubal pathology (Bensdorp 2017)

16 Prognosis in infertility: concept of nomogram Age of female partner Action line Duration of exposure to pregnancy Gurunath et al HR Update (2011)

17 Management of unexplained infertility Spectrum of invasiveness No treatment Clomifene IUI SO/IUI IVF

18 Controlled ovarian stimulation (COS) Simple treatment (usually clomifene) Little monitoring Correction of subtle ovulatory dysfunction Multiple follicular growth

19 Intra-uterine insemination Widely accepted treatment Increased sperm density in upper reproductive tract Closer proximity to one or more eggs Increased potential for fertilisation With or without superovulation

20 In-vitro fertilisation Widely accepted treatment Bypasses potential reproductive problems Demonstrates fertilisation Essential for tubal and severe male infertility Live birth rate 20-30%

21 Interventions in unexplained infertility IUI Intercourse COS IVF Conventional eset Natural cycle Stimulated Unstimulated IUI I/C

22 Expectant management: Natural conception rates Follow up in observational studies Note 81% conceptions at 3 years follow-up 74% of these arising spontaneously Limited contribution from IVF Brandes et al, Human. Reprod. 2011

23 Randomised Controlled Trial Evidence The Scottish Unexplained Infertility Trial (SUIT) Clomifene n = 192 Expectant n = months follow-up IUI n = 191

24 Expectant management 6 months follow-up The Scottish Unexplained Infertility Trial (SUIT) Expectant n = (17%) 6 months follow-up

25 Expectant management vs Controlled Ovarian Stimulation Scottish Ux Inf Trial OR % CI: Expectant Clomifene P value Odds ratio n = 193 n = 192 (95% CI) 33 (17%) 26 (14%) (0.44, 1.36) Clomifene + hcg trigger OR % CI Multiple pregnancy rates similar Other approaches to COS vs expectant: Clomifene + IUI HMG rfsh FSH hp No differences

26 Expectant management vs Natural cycle IUI (Live Birth Rate) Expectant IUI n = 193 n = (17%) 43 (23%) Scottish Unexplained Infertility Trial data OR % CI Multiple pregnancy rates similar Veltman-Verlhurst et al Cochrane Reviews 2016

27 Expectant management vs Natural cycle IUI (Live Birth Rate) OR % CI Multiple pregnancy rates similar Veltman-Verlhurst et al Cochrane Reviews 2016

Expectant management vs COS + IUI (timed intercourse) OR 0.82 95% CI 0.45 1.

28 Expectant management vs COS + IUI (timed intercourse) OR % CI LBR 20% (COS) LBR 24% (TI) No difference in multiple pregnancy rates Veltman-Verlhurst et al Cochrane Reviews 2016

29 Expectant management vs COS + IUI (timed intercourse) Recent data favours intervention Livebirth with COS + IUI OR % CI Farquhar et al 2018

30 Expectant management vs COS + IUI (timed intercourse) BUT Farquhar et al livebirths: 23 from COS + IUI 8 without assistance before/between IUI cycles!

COS + timed intercourse vs COS + IUI Pregnancy Rate Live Birth Rate OR 1.69 95% CI 1.14 2.

31 COS + timed intercourse vs COS + IUI Pregnancy Rate Live Birth Rate OR % CI Trend in favour of IUI OR % CI Veltman-Verlhurst et al Cochrane Reviews 2016

COS + IUI vs Natural cycle IUI OR 0.48 95% CI 0.29 0.

32 COS + IUI vs Natural cycle IUI OR % CI Less chance of live birth with natural cycle IUI Veltman-Verlhurst et al Cochrane Reviews 2016 Multiple pregnancies: Limited data One trial reported 29% in SO + IUI vs 4% in IUI

33 Natural cycle IUI vs COS + timed intercourse Clomifene IUI n = 192 n = (14%) 43 (23%) Scottish Unexplained Infertility Trial Data In favour of natural cycle IUI Veltman-Verlhurst et al Cochrane Reviews 2016

34 Natural cycle IUI vs COS + timed intercourse BUT No difference in trial between interventions vs expectant management Moderate prognosis patients Need for trial in poor prognosis? Veltman-Verlhurst et al Cochrane Reviews 2016

35 Natural cycle IUI vs IVF Little substantive comparative evidence Usual to consider that with prolonged infertility an intervention is demanded by patients Single trial: 41% pregnancy rate with IVF 26% pregnancy rate with IUI Sample size inadequate to draw conclusions

IVF (up to 6 cycles) Time to pregnancy Time to pregnancy shorter in accelerated arm Gonadotrophins

36 FASTT Trial Randomisation Conventional Fast track 1. CC + IUI (3 cycles) 1. CC + IUI (3 cycles) 2. FSH + IUI (3 cycles) 2. IVF (up to 6 cycles) 3. IVF (up to 6 cycles) Time to pregnancy Time to pregnancy shorter in accelerated arm Gonadotrophins added no value Pregnancy rate 20%/cycle in CC/IUI stage 25%/cycle at FSH/IUI stage 67%/cycle at IVF stage Multiple pregnancy rates in both arms 20%

37 1NeS Trial RCT: Poor prognosis couples: <30% Hunault score COS + IUI (6 cycles) IVF (eset) (3 cycles) IVF (natural cycle) 6 cycles

38 1NeS Trial Live births Controlled Ovarian Stimulation + IUI vs IVF (eset or Modified Natural Cycle) No differences Healthy child (47% vs 52% vs 43%) Multiple pregnancy rates low (5-7%) Bensdorp et al 2015

39 1NeS Trial Time to pregnancy No association between treatment outcome and: BMI Age Ethnicity Smoking status TMSC Tjon-Kon-Fat et al 2015 Bensdorp et al 2015

40 Societal Attitudes: Societal & Individual Plus ça change plus c est la même chose

41 Conclusions Unexplained infertility is relatively common Diagnosis may be increasing Prognosis rather than diagnosis dictates management Impact of female age and duration of infertility Correct identification of couples who need treatment Evidence base on interventions is improving but remains incomplete Need to avoid harm

42 Pragmatism Determine prognosis Good prognosis hands off Poor prognosis - consider intervention Clomifene not helpful IUI on its own not helpful COS + IUI may be helpful but care with multiple pregnancy IVF with eset comparable results and in good hands maintains pregnancy rates and keeps the multiples down

Infertility. Thomas Lloyd and Samera Dean

Infertility. Thomas Lloyd and Samera Dean Infertility Thomas Lloyd and Samera Dean Infertility Definition Causes Referral criteria Assisted reproductive techniques Complications Ethics What is infertility? Woman Reproductive age Has not conceived