Dr. Shavi Fernando MBBS (Hons.) BMedSc (Hons.) Outcomes of Assisted Reproductive Technology (ART) in women with endometriosis Dr. Shavi Fernando MBBS (Hons.) BMedSc (Hons.) Funded by FSA and The BUPA Foundation

Endometriosis 20% of infertile women Commonly on ovaries Fig 1. Normal ovarian follicle 20% of infertile women Commonly on ovaries Pelvic side-wall Recto-vaginal Ovarian endometriomata can be reliably differentiated on US 89% specificity Brosens et al, Fertil Steril, 2004 Garcia-Velasco et al, Fertil Steril, 2004 Stratton et al, Fertil Steril, 2005 Fig 2. Ovarian endometrioma Source: http://www.emedicine.com/radio/ http://www.brooksidepress.org/Products/OBGYN_101/

Current knowledge Reduced uterine receptivity and pregnancy rate after ART Little known about perinatal outcomes Barnhart et al, Fertil Steril, 2002 Olivennes, J Gynecol Obstet Biol Reprod (Paris), 2003 Omland et al, Hum Reprod, 2005 Eutopic endometrium in endometriosis is abnormal Pritts et al, Endocrinol Metab Clin NorthAm, 2003 Taylor et al, Hum Reprod, 1999 Braun et al, Curr Opin Obstet Gynecol, 1998 Ovarian endometriosis is molecularly different to other forms of endometriosis De Placido et al, Hum Reprod, 2001 Nisolle et al, Fertil Steril, 1997

Aim To determine whether women with: Ovarian endometriomata undergoing ART have increased perinatal adverse outcomes compared with: ART non-ovarian endometriosis ART other aetiologies of infertility Subfertile women Fertile women

Definition of Subfertile Registered for ART for infertility: But did not receive ART treatment; OR Had unsuccessful ART AND Subsequently conceived without ART (IVF/ICSI/GIFT) Are adverse outcomes due to ART or infertility? FSA Poster: Jaques et al, 2006

Outcome Measures Singleton live births (≥20 weeks): Low birthweight (LBW) <2500g Preterm <37 wks Small for gestational age (SGA) <10th percentile

Data Sources Monash IVF database Victorian Perinatal Data Collection Unit (PDCU) Mandated data collection of all births ≥ 20 weeks’ gestation (850,000 ) Includes: Perinatal data for live births, still births, neonatal deaths and terminations of pregnancy for birth defects Maternal demographics, reproductive history and obstetric complications Record linkage (LinkageWiz v4.1) matched Monash IVF records to PDCU births

4,113 Monash IVF records of women with singletons (1991-2004) 850,000 PDCU birth records 1,987 medical records accessed 2,126 medical records not accessed 1,201 other aetiology controls 156 subfertile controls 630 cases of endometriosis Subgroup of 95 cases of ovarian endometriomata 1,140 fertile controls (1:12) 1,260 fertile controls (1:2) Matched on maternal age and year of birth

4,113 Monash IVF records of women with singletons (1991-2004) 1,987 medical records accessed 2,126 medical records not accessed 1,201 other aetiology controls 156 subfertile controls 850,000 PDCU birth records 630 cases of endometriosis Subgroup of 95 cases of ovarian endometriomata In total, there were 4,387 singleton babies included in the retrospective cohort Matched on maternal age and year of birth 1,260 fertile controls (1:2) 1,140 fertile controls (1:12)

Diagnosis Dx of Ovarian endometriomata Dx of Non-ovarian endometriosis US report Dx of Non-ovarian endometriosis Laparoscopy and/or histology report

Results – Ovarian Endometriomata SPSSTM v.13 Binomial logistic regression Only significant or close to significant results are shown OR 95% CI p* Ovarian endometriomata vs Non-ovarian Endometriosis LBW 2.55 1.26 – 5.18 .009 SGA 1.20 1.04 – 3.83 .040 Other aetiologies 2.87 1.49 – 5.55 .002 1.95 1.06 – 3.61 .050 * Adjusted for maternal age, parity, smoking, year of birth and sex

Results – Ovarian Endometriomata OR 95% CI p Ovarian endometriomata vs Subfertile LBW 2.29 1.02 – 5.16 .05* SGA 2.11 0.99 – 4.53 .06* Fertile Preterm 1.93 1.03 – 3.62 .04† 1.84 0.99 – 3.44 .06† * Adjusted for maternal age and parity † Adjusted for parity and sex

Limitations Women with endometriosis may have > 1 cause of infertility Endometriosis stage and treatment status unknown Women with ovarian endometriomata may have also had other forms of endometriosis Unlikely that those with other forms of endometriosis had ovarian endometriomata

Conclusion ART patients with ovarian endometriomata have increased likelihood of having: A baby of LBW or SGA compared with: Non-ovarian endometriosis following ART Other aetiologies of infertility following ART A preterm baby compared with: Fertile women Suggests independent effect of ovarian endometriomata on perinatal outcomes

Discussion Ovarian endometriomata Severe form of endometriosis Reduction in uterine receptivity/placentation Khong et al, Br J Obstet Gynaecol, 1986 Eutopic endometrium may be more abnormal → more adverse outcomes Lessey, Fertil Steril, 2000 Kuivasaari et al, Hum Reprod, 2005 Genetic differences? Oocyte quality differences?

Acknowledgements Monash IVF Prof. David Healy Ms. Sue Breheny Murdoch Children’s Research Institute & Perinatal Data Collection Unit A/Prof. Jane Halliday Dr. Alice Jaques Melbourne IVF A/Prof. Gordon Baker http://i6.photobucket.com/albums/y208/momoswords/ivf.jpg

Additional Slides

Future Directions Ovarian endometriomata are associated with more adverse outcomes than other forms of endometriosis after ART Reduction in uterine receptivity/oocyte quality = ? spectrum Lessey, Fertil Steril, 2000 Kuivasaari et al, Hum Reprod, 2005 Should ovarian endometriomata be surgically removed prior to ART? Will this improve outcomes? Prospective studies

Adjustments LBW Not LBW Ovarian endometriomata Other endometriosis 16 All fertile groups were matched for age and YOB Depends on sample size and minimum number of each outcome Continuous - Age, YOB – count for 1 point Categorical - Sex, Parity – count for (Ncat – 1) point(s) Eg. Parity (2) + smoking (1) + year of birth (1) + sex (1) + age (1) = (6) LBW Not LBW Ovarian endometriomata Other endometriosis 16 48 79 487 Totals 64 566

Fertile Population Representative of Victorian population All Endometriosis (RR 1.10, 95% CI 0.90 – 1.34, p=.4) Ovarian Endometriomata RR (1.13, 95% CI 0.92 – 1.39, p=.3) Ovarian endometriomata may genuinely have increased likelihood of LBW and SGA: Sample of ovarian endometriomata too small Need at least n=150 to detect differences in LBW and SGA Ovarian endometriomata may have no increased chances of LBW and SGA: Other endometriosis, other aetiologies and subfertile may have abnormally lower rates of LBW/SGA

Further Recommendations Prospective study - time Ascertain treatment status of endometriosis patients Larger sample of subfertile patients Combine with Melbourne IVF - larger sample of ovarian/other endometriosis: Allow adjustment for the presence of other aetiologies of infertility

Methods Epiinfo™ and SPSS™ v13.0 Multivariate analysis - Binomial regression Adjustments: Parity Gender Year of birth Maternal age Smoking BMI

Omland et al Retrospective cohort Endometriosis (n=212) vs Idiopathic infertility (n=274) following IVF: Lower pregnancy rate in endometriosis compared with idiopathic infertility. Omland et al, Hum Reprod, 2005 OR 95% CI p Birthweight 1.03 0.9-1.28 .36 Gestation 2.6 0.6-11.70 .178

Abbreviations BUPA (British United Provident Association)

Unsuccessful ART treatment: Failed to conceive with ART Couples who conceived with ART but pregnancy loss <20 weeks gestation