The role of hysteroscopy in the treatment of infertility by in vitro fertilisation

Uvod: Infertilitet pogađa 10-15% parova reproduktivnog doba. Vanetesna oplodnja (VTO) je najefikasniji vid tret-mana infertiliteta, ali uprkos značajnom napretku stopa uspeha VTO u proseku iznosi oko 30% po ciklusu. Glavnim razlogom neuspeha smatra se neadekvatan kvalitet embriona, dok se pretpostavlja da u 10-20% slučajeva razlog neuspeha leži u neadekvatnoj receptivnosti uterusa. Na osnovu inicijalnih istraživanja histeroskopija, koja predstvalja zlatni standard u dijagnostici i tretmanu patologije kavuma uterusa, se često izvodi u svakodnevnoj kliničkoj praksi kako bi se povećala uspešnost VTO. Uprkos širokoj primeni i dalje ne postoji dovoljno kvalitetnih dokaza o realnoj ulozi histeroskopije na ishod VTO kako kod patoloških stanja kavuma tako i rutinski, pre prvog ili rekurentnog pokušaja VTO. Cilj disertacije bio je da se utvrdi uticaj sprovođenja histeroskopije na ishod VTO, ustanovi učestalost prethodno neprepoznate patologije kavuma uterusa, kao i da se ispitaju stavovi pacijenata o primeni rutinske histeroskopije pred VTO. Materijal i metode: Istraživanje je sprovedeno u Kliničkom centru Vojvodine, u formi prospektivne studije u dve sukcesivne etape od 01.01.2015. do 01.04.2017. U prvoj etapi poređen je ishod VTO kod pacijentkinja kojima pred postupak VTO nije sprovedena histeroskopija (Grupa A), pacijentkinja kod kojih je dobijen uredan nalaz histeroskopije pred postupak VTO (Grupa B) i pacijentkinja gde je pred postupak VTO dobijen patološki nalaz kavuma na histeroskopiji koji je u istom aktu tertian (Grupa C). Druga etapa istraživanja predstavljala je randomiziranu kontrolisanu studiju (RCT – randomised controlled trial). Nakon verifikacije urednog ultrazvučnog nalaza pred prvi postupak VTO, pacijentkinje su randomizirane u Grupu A2 kojima pred postupak VTO nije sprovedena histeroskopija i Grupu B2 kojima je pred postupak VTO sprovedena rutinska histeroskopija. Statistička analiza sprovedena je upotrebom odgovarajućeg softvera (JMP Ver. 9). Poređeni su podaci o osnovnim karakteristikama pacijenata, toka i ishoda ciklusa VTO. Primarni parametar ishoda bila je stopa kliničke trudnoće po embriotransferu. Pored analize ishoda primarno konstruisanih grupa, urađena je analiza i naknadno konstruisanih subgrupa, kao i predikcioni model uspeha VTO baziran na logističkoj regresiji. Rezultati: Studija je uključila 253 pacijentkinje (52 pacijentkinja iz Grupe A, 50 iz Grupe B, 50 iz Grupe C, 51 iz Grupe A2 i 50 iz Grupe B2). Nije postojala statistički značajna razlika u karakteristikama pacijentkinja, parametrima ovarijalne rezerve, broju dobijenih jajnih ćelija ni drugim parametrima toka postupka VTO među posmatranim grupama. U prvoj etapi istraživanja dobijena je statistički značajno (p=0,013) veća stopa kliničkih trudnoća kod pacijentkinja kojima je pred postupak VTO sprovedena histeroskopija - 50 % za Grupu B i 42% za grupu C u odnosu na 30,77% kod pacijentkinja bez histeroskopije (Grupa A), bez statistički značajne razlike među histeroskopskim grupama. U drugoj etapi istraživanja stopa kliničkih trudnoća prilikom upotrebe rutinske histeroskopije pred prvu VTO (Grupa B2) iznosila je 46% naspram 31,37% kod pacijentkinja bez histeroskopije pred prvu VTO (Grupa A2), iako uočena razlika nije dostigla statističku značajnost (p =0,089), uz relativan rizik (RR) za ostvarivanje kliničke trudnoće nakon primene histeoskopije uiznosio od 1,47 (95% CI 0,88-2,43) (p=0,13). Analizon subgrupa kod 100 pacijentkinja sa rutinski sprovedenom histeroskopijom pred VTO i 103 pacijentkinje bez histeroskopije pred VTO, dobijena je statistički značajnao veća stopa kliničkih trudnoća (48% naspram 31,07%, istim redom), uz RR od 1,54 (95% CI 1,08-2,20) (p=0,013), kao i stopa tekućih trudnoća od RR 1,49 (CI 1,01-2,19) (p= 0,039). Analiza ukupnog uticaja izvođenja histeroskopije pred VTO dobila je statistički značanjno veću stopu kliničkih trudnoća po ET za grupu histeroskopije uz RR 1,48 (CI 1,06-2,07) (p=0,017). Histeroskopijom je nakon urednog ultrazvučnog nalaza ustanovljeno postojanje patološkog nalaza kod 34,65% pacijenata i to 22,7% major patologije i 11,88% minor patologije kavuma. Nije postojala statistički značajna razlika u uspehu VTO u odnosu na sam nalaz histeroskopije. 98,67% pacijenata podržalo je rutinsku upotrebu histeroskopije pred prvi postupak VTO, dok je 83% pacijenata podržavlo rutinsku upotrebu histeroskopije pred svaki postupak VTO. U finalnom predikcionom modelu se uz AUC od 0,748 jedino postojanje visokokvalitetnog embriona uz odnos šansi (OR) 7,91 (95% CI 1,80-56,06; p=0,0047), transfer blastociste uz OR 3,80 (95% CI 1,90-7,98; p=0,0001) i izvođenje histeroskopije pred VTO uz OR 2,13 (95% CI 1,14-4,08, p=0,0169) pokazalo statistički značajnim prediktorima trudnoće. Diskusija: Studija je dobila pozitivan uticaj histeroskopije na ishod postupka VTO, iskazan pre svega povećanjem stope kliničkih trudnoća nakon sprovođenja histeroskopije (bilo da je na histeroskopiji nađen uredan ili patološki nalaz). Dodatna prednost histeroskopije predstavljala je i i detekcija prethodno nepropoznate patologije kavuma. Umeren efekat na ukupno poboljšanje stope kliničkih trudnoća prilikom rutinskog sprovođenja histeroskopije pred prvu VTO, koji je statističku značajnost dostigao tek analizom subgrupa u skladu je sa nalazima novijih dobro dizajniranih studija koji donekle limitiraju nekritičku upotrebu histeroskopije. Biološko objašnjenje potencijalnog pozitivnog uticaja histeroskopije najverovatnije leži u detekciji i tretmanu prethodno nepropoznate patologije kavuma, olakšavanju procedure embriotransfera, kao i humoralnim i molekularnim promenama koje nastaju u endometrijumu kao posledica odgovarajuće histeroskopske traume a koji su u dosašanjim istraživanjima apostrofirani kao faktori koji mogu povećati receptivnost uterusa. Zaključak: Histeroskopija je efikasna, bezbedna i visoko prihvatljiva procedura koja dovodi do povećanja uspeha VTO u standardnim kliničkim indikacijama (prethodnog neuspelog postupka VTO i sumnje na patološki nalaz kavuma uterusa) bilo da se na samoj histeroskopiji nađe uredan ili patološki nalaz. Rutinska primena histeroskopije pred prvi postupak VTO se na osnovu rezultata studije ne može smatrati apsolutno opravdanom usled statistički nedovoljno značajnog povećanja stope kliničke trudnoće. Uzevši u obzir visoku prihvatljivost od strane pacijenata i najverovatniji pozitivan efekat na stopu trudnoće primena rutinske histeroskopije pred prvu VTO bila bi opravdana ukoliko se implementira koncept ambulantne histeroskopije.Introduction: Infertility affects 10-15% of all couples. In vitro fertilisation (IVF) is the most effective method of infertility treatment, but despite a significant improvement, success rate of IVF is still around 30% per cycle. The main reason for the IVF failure is inadequate embryo quality, but in 10-20% of cases the cause of IVF failure lies in impaired uterine receptivity. Based on earlier studies hysteroscopy, gold standard in the diagnosis and treatment of uterine cavity pathology, is often performed to increase IVF success. Despite its wide use, there is lack of high quality evidence regarding real contribution of hysteroscopy on IVF outcome in situations of uterine cavity pathology or routinely prior to first IVF or after recurrent implantation failure. The aim of this dissertation was to determine the influence of performing hysteroscopy on IVF outcome, as well as the incidence of previously unrecognized uterine pathology, and to examine patient's attitudes about performing routine hysteroscopy prior to IVF. Material and methods: The research was conducted in a prospective manner in two successive stages at Clinical Center of Vojvodina from 01.01.2015. until 01.04.2017. During first stage of the study IVF outcome was compared between patients who did not have a hysteroscopy prior to IVF (group A), patients with normal hysteroscopic finding prior to the IVF (Group B) and patients with abnormal hysteroscopic findings prior to IVF which was treated at the same time (Group C). The second stage of the study was a randomized controlled trial (RCT). After verification of normal ultrasound findings prior to the first IVF, patients were randomized to group A2 in who me hysteroscopy was not performed and group B2 who had routine hysteroscopy prior to first IVF. Statistical analysis was carried out using the appropriate statistical software (JMP Ver. 9). Patient characteristics, course and outcome of IVF cycle were compared between groups. The primary outcome was clinical pregnancy rate (CPR) per embryotransfer. In addition to analyzing the IVF outcomes in primarily defined groups, subgroup analysis was also performed, as well as IVF success pre-diction model based on logistic regression. Results: The study included 253 patients (52 patients in Group A, 50 in Group B, 50 in Group C, 51 in Group A2 and 50 in Group B2). There was no statistically significant difference in patient characteristics, ovarian reserve parameters, number of retrieved oocytes, or other relevant parameters of IVF course between the observed groups. In the first stage of the study there was statistically significant (p = 0.013) higher clinical pregnancy rate in patients who had a hysteroscopy before IVF - 50% for Group B and 42% for group C versus 30,77 % in patients without hysteroscopy before IVF (Group A), without statistically significant difference between hysteroscopic groups. In the second stage of the study, routine hysteroscopy prior to first IVF (Group B2) led to clinical pregnancy rate 46% versus 31.37% in patients without hysteroscopy prior to first IVF (Group A2), although without statistical significance (p = 0.089. Relative risk (RR) for achieving clinical pregnancy after performing hysteroscopy was 1.47 (95% CI 0.88-2.43) (p = 0.13). Subgroup analysis of 100 patients with routinely performed hysteroscopy before IVF and 103 patients without hysteroscopy prior to the IVF showed statistically significant higher rates of clinical pregnancies (48% versus 31.07%, in the same order), with RR of 1.54 (95% CI 1.08-2.20), (p = 0.013), and for ongoing pregnancies RR was 1.49 (95% CI 1.01-2.19) (p = 0.039). Overall effect of performing hysteroscopy prior to IVF resulted in a statistically significant increase in the clinical pregnancy with RR 1.48 (95% CI 1.06-2.07) (p = 0.017). After normal ultrasound finding hysteroscopy revealed 34.65% of pathological finding, 22.7% of major and 11.88% of minor pathology of the cavity). There was no statistically significant difference in IVF outcome based on hysteroscopy findings. 98.67% of patients supported the routine use of hysteroscopy before the first IVF procedure, while 83% of patients supported the routine use of the hysteroscopy before every IVF procedure. In the final prediction model, with the AUC of 0.748, only the presence of high quality embryos with odds ratio (OR) 7,91 (95% CI 1,80-56,06; p=0,0047), blastocyst transfer with OR 3,80 (95% CI 1,90-7,98; p=0,0001) and performing hysteroscopy prior to IVF with OR 2,13 (95% CI 1,14-4,08, p=0,0169) proved to be statistically significant predictors of pregnancy. Discussion: The study shoved a positive influence of hysteroscopy on the IVF outcome by increasing clinical pregnancy rate after performing hysteroscopy (whether hysteroscopy revealed normal or pathological finding). Additional benefit of hysteroscopy was detection of previously unrecognized uterine pathology. A moderate effect on the overall improvement in clinical pregnancy rate with use of routine hysteroscopy, which reached statistical significance only by subgroup analysis, is in line with findings of recent well designed studies that somewhat limit the noncritical use of hysteroscopy. A biological explanation of the potential positive effect of hysteroscopy is most likely due to detection and treatment of the previously unrecognized uterine pathology, facilitating embryotransfer procedure, as well as the humoral and molecular changes that occur in the endometrium as a consequence of the hysteroscopic trauma. Those changes were hypothesized as factors that can increase uterine receptivity by numerous research. Conclusion: Hysteroscopy is an effective, safe and highly acceptable procedure that increases IVF success when performed for accepted clinical indications (previous IVF failures, pathological findings of uterine cavity), whether hysteroscopy reveals normal or pathological finding. The routine use of hysteroscopy prior to first IVF based on this study can not be considered justified since increase in clinical pregnancy rate did not reach statistical significance. Given the high acceptance of this concept by the patients and moderate but probable positive effect on IVF outcome, implementation of routine hysteroscopy prior to first VTO would be justified only in office hysteroscopy setting